NCCS Humphrey Oei Institute of Cancer Research Brochure

Division of Clinical Trialsand EpidemiologicalSciences

Division of Cellular and Molecular Research

Division of MedicalSciences

Clinician-Investigators & Scientists

TODAY’S RESEARCHTOMORROW’S CURE

National Cancer Centre SingaporeHUMPHREY OEI INSTITUTE OF CANCER RESEARCH

Year 2007-2010

contents:

02 > DIRECTOR’S MESSAGE

03 > NCCS BOARD MEMBERS

04 > NCCS RESEARCH COMMITTEE

05 > AWARDS AND ACHIEVEMENTS- NEW APPOINTMENTS

16 > DIVISION OF CELLULAR AND MOLECULAR RESEARCH

34 > DIVISION OF MEDICAL SCIENCES

56 > DIVISION OF CLINICAL TRIALS AND EPIDEMIOLOGICAL SCIENCES

62 > CLINICIAN INVESTIGATORS AND SCIENTISTS

80 > PUBLICATIONS

140 > HUMPHREY OEI DISTINGUISHED LECTURE SERIES

147 > RESEARCH SUPPORT GROUPS

DIRECTOR’SMESSAGE

Medical science has made many rapid developments. Eachday unfolds new insights which give doctors a betterunderstanding of diseases and their behaviourial patterns.The National Cancer Centre Singapore, as a leading cancercentre in Asia, is proud to be among the many centres whichhave been contributing towards this pool of knowledge.

I am pleased that we have many dedicated and committedscientists and researchers in NCCS whose good work areoften not visible to the public eye. Many of their researchfindings have helped our oncologists and other specialiststo improve on our diagnosis and treatment for our cancerpatients. Our findings have been published in internationallyrecognised peer-reviewed medical journals and won acclaimsat overseas conferences. This is what sets NCCS apart fromother cancer treatment centres.

NCCS recognises that the fight against cancer cannot beundertaken alone. We are networking and collaborating withother leading research centres to work on various projectsfrom India to Europe and the US. Top scientists are continuallyinvited to our laboratories just as we send out researchersand doctors to gain exposure overseas.

Apart from retaining and recruiting talents, there is also theneed to acquire the latest technology and equipment. Fundingfor research projects is another hurdle that we must overcome.We welcome your support to be a part of the team and shareour noble goal to free our future generation from the clutchesof cancer. At least we can say we have a purpose in our life.

Professor Soo Khee CheeDirectorNational Cancer Centre Singapore

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NCCSBOARD MEMBERS

NCCS RESEARCH FUND BOARD OF TRUSTEES

CHAIRMANDr Charles TOHConsultant Cardiologist, Charles Toh Clinic

MEMBERSMs Viviana BERNARD

Mr LEE Kim ShinPartner, Allen and Gledhill LLP

Mr LIM Beng Hua

Mr NG Boon YewChairman, Raffles Campus Pte Ltd

Mr SIM Kee Boon (till 9th November 2007)Director, Temasek Holdings Pte Ltd

Prof SOO Khee CheeDirector, National Cancer Centre Singapore

Mr Nicky TANDirector, Ntan Corporate Advisory Pte Ltd

Prof TAN Ser KiatGroup Chief Executive Officer, Singapore Health Services

NCCS SCIENTIFIC ADVISORY BOARD

Professor Kie Kian ANGDepartment of Radiation Oncology, University of Texas MD Anderson Cancer Center,USA

Professor Malcolm K. BRENNERDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston,Texas, USA

Professor Anthony R. MEANSCancer Biology Program, Duke University, Durham, USA

Professor Alan P. VENOOKDivision of Medical Oncology, University of California, San Francisco, USA

Prof Arnold J LEVINE (from 2007 - 2010)Institute for Advanced Study, Princeton


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CHAIRMANProf KON Oi LianHead, Division of Medical Sciences

MEMBERSProf HUI Kam ManHead, Division of Cellular and Molecular Research

Dr Joseph WEEHead, Division of Clinical Trials and Epidemiological Sciences

Prof TEH Bin TeanGroup Director, Translational Research, SingHealth

Prof David M. VIRSHUPProgram Director, Cancer & Stem Cell Biology,Duke-NUS Graduate Medical School

Dr CHUA Eu TiongHead, Department of Radiation Oncology

A/Prof Cynthia GOHHead, Department of Palliative Medicine

Dr James KHOOHead, Department of Oncologic Imaging

A/Prof KOONG Heng NungHead, Department of Surgical Oncology

Dr TOH Han ChongHead, Department of Medical Oncology

Dr TAN Eng HuatDepartment of Medical Oncology (Research)

Dr TAN Hiang KhoonDepartment of Surgical Oncology (Research)

Ms Audrey-Anne OEISenior Manager, Research Administration

MEMBERS (Ex-Officio)Prof SOO Khee CheeDirector

Dr Vijay Kumar SETHIChairman, Medical Board

Dr KOO Wen HsinDeputy Director

Prof London Lucien OOIAdviser

Dr Nicholas TAYChief Operating Officer

NCCSRESEARCH COMMITTEE

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Awards AndAchievementsNewAppointments

AWARDS AND ACHIEVEMENTS

The 1GCEO Excellence Award is the highest honour for staff excellence presented

by SingHealth to outstanding staff who are role models in their respective fields,

and Prof Hui Kam Man is indeed a notable character in his field of research.

Leading the Division of Cellular and Molecular Research, Prof Hui has contributed

significantly to the evolution of NCCS to a world renowned cancer centre which

integrates research and clinical care with the ultimate goal of benefiting patients.

Dr N Gopalakrishna Iyer was awarded the 2Michael E Burt Memorial Awardin 2010, a prestigious award conferred by one of the world’s premier cancer

centres, Memorial Sloan-Kettering Cancer Center in US. Dr Gopal, a surgical

oncologist, was given the award for superior clinical and operative skills, research

and commitment to education. This award is given annually to the best overall

Fellow in the entire division of surgery.

Prof Soo Khee Chee was awarded the 3National Outstanding Clinician MentorAward by the Ministry of Health in 2008 for his outstanding contribution to the

healthcare industry. Also the Director of the National Cancer Centre Singapore,

Prof Soo is well-respected in all aspects of clinician mentorship, training up young

clinicians, setting up a conducive clinical and research environment, and also

leading a team to develop a world-class cancer centre.

Dr Daniel Tan was the first Singaporean to receive the Young Investigator Awardfrom the 4ASCO Cancer Foundation in 2009. His research project will focus

on nose cancer, which is uncommon in the West but more prevalent among

Asians. The project will attempt to find out how a targeted drug works in

nasopharyngeal cancer.

In the subsequent year, Dr Daniel Tan was conferred the Merit Award by4ASCO for his exploration of a new anti-cancer compound in a Phase I trial. Dr

Tan was the primary fellow in charge of a trial that tested for the safety and toxicity

of a novel agent used for the first time in human bodies while at the UK’s Royal

Marsden Hospital on a National Medical Research Council (NMRC) fellowship.

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Dr Iain Tan was awarded the Young Investigator Award by 4ASCO in 2010 for

his research on gastric cancer. Working on the premise that gastric cancer is the

second leading cause of global cancer mortality, Dr Tan identified two genetic

sub-types of gastric cancer with different responses to drugs. He was also the

only doctor to have attained this award while doing his research in an institution

outside of North America.

Dr Tan Min-Han was awarded the 5ASEAN Youth Award for Science andTechnology in 2010 for scientific excellence and his ability to inspire the next

generation. A leader in clinical care and research in patients at elevated genetic

risk of kidney, breast and testicular cancer, his focus is on the practical application

of technology, including genomic profiling and circulating tumor cell isolation, on

immediate patient care."

Prof Teh Bin Tean, the recipient of the Singapore Translational ResearchInvestigator Award (STaR) bestowed by 6NMRC in 2009, is one of the world’s

leading kidney cancer research scientists and a pioneer in molecular profiling of

kidney cancer. In 2007, he was appointed the founding director of the NCCS-

VARI laboratory, which serves as a bridge between translational research and

clinical medicine both at the National Cancer Centre Singapore (NCCS) and at

Van Andel Research Institute (VARI).

Dr Marissa Teo was awarded the 7Unesco-L’Oreal for Women in ScienceInternational Fellowship in 2010. She was the first Singaporean to receive this

award which was first given out 12 years ago. Her research work will focus on

treating patients with nasopharyngeal carcinoma, which is prevalent in southern

China and South-east Asia, by combining chemotherapy with cell therapy.


Dr Toh Han Chong was awarded the Clinician Scientist Award (Investigatorlevel) by 6NMRC in 2009 for his research on Nasopharyngeal Cancer (NPC).

Dr Toh’s research involves a clinical trial to treat newly diagnosed patients with

advanced NPC, and will examine ways to leverage the immune system, or the

killer T-cells that it contains, to fight the NPC cells that contain Epstein-Barr Virus

(EBV) proteins. This clinical trial led by Dr Toh is expected to have potential

breakthroughs in helping NPC patients improve their clinical outcomes and their

quality of life.

Dr Joseph Wee was awarded the Clinician Scientist Award (Senior Investigatorlevel) from the 6NMRC in 2009 for his research on Nasopharyngeal Cancer

(NPC). Dr Wee's research focuses on a phase 3 clinical trial to test the effectiveness

of treating NPC using three chemotherapy drugs. The cancer of the upper throat

or pharynx afflicts about 400 people each year in Singapore, mostly men aged

40 to 60.

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Prof Wong Meng Cheong was awarded the Clinician Scientist Investigator(Senior Clinician Scientist) Award from 6NMRC in 2007 for his project titled as

“Working on DNA damage repair signalling, brain tumour stem cells, biological

agents and immunotherapy for brain tumour relapsed patients”. His research

focuses on improving diagnostic and treatment modalities for patients suffering

from brain disease.

Year 2009

Recipient Award Project

Dr Claramae Chia 9SMF Scholarship Award “Identification of novel biomarkers in predicting

metastases and prognosis of nasopharyngeal

carcinoma using genes that correlate with a

metastatic phenotype”

Dr Ravindran Kanesvaran Merit Award at the 4ASCO “Comparison of the UISS and SSIGN scoresfor

Genitourinary Symposium survival prediction in Asian patients with

2009 clear cell carcinoma”

Dr Richard Quek 6NMRC Medical Research “Translational therapeutics: application of novel

Fellowship Award insights from basic molecular and biochemical

research to the rationale development of

molecularly-targeted anti-cancer therapy”

Ms Tan Hwei Ling 10SGH 18th Annual Scientific “Integrated Genomic Profiles Reveal Therapeutic

Meeting - Young Pathways and Biomarkers for Chromophobe

Investigator's Award Renal Cell Carcinoma and Oncocytoma”

(Basic Science) Finalist.

Dr Iain Tan 11National Research “Predictive and prognostic biomarkers in

Foundation – Ministry of gastric cancers – towards individualized therapy”

Health Healthcare Research

Scholarship

Dr Melissa Teo Ching Ching 6NMRC Medical Research “A study of two cancer care systems:

Fellowship Award Ontario and Singapore”

Dr Wong Nan Soon 6NMRC Medical Research “Phase I clinical trial design and implementation/

Fellowship Award investigational new drug development in

oncology”


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Year 2010


Dr Huang Dachuan 8AACR Scholar-in- “BIRB796, p38o inhibitor inhibits

Training Award cholangiocarcinoma cell migration in a p53-

dependent manner”

Dr Iain Tan 8AACR Scholar-in- “Genomic Profiles of Gastric Cancer Predict Clinical

Training Award Prognosis and May Guide Treatment Selection”


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Year 2008


Dr Chew Joon Lin 9SMF Post-Doctoral “The role of stem-cell regulatory factors in the

Scholarship Award tumorigenesis and metastasis of human pancreatic

cancer”

Mr William Chin Wei Lim 10SGH 17th Annual “Membrane Transport Enhancement of Chlorin e6

Scientific Meeting - – Polyvinylpyrrolidone and its Photodynamic

Best Oral Paper (Scientist) Efficacy on the Chick Chorioallantoic Model”

Dr Lee Ser Yee 9SMF Scholarship Award “Analysis of molecular alterations in human

pancreatic adenocarcinoma using

immunohistochemistry and gene expression

profiling”

Mr Lin Yingbo, 12Singapore Science and “Transport Enhancement and Improved Selectivity

Mr William Chin, Engineering Fair of Chlorin e6 polyvinylpyrrolidone on the

A/Prof Malini Olivo - Silver Award chorioallantoic tumor model”

Dr Grace Pang Su Yin 9SMF Scholarship Award “The effect of single nucleotide polymorphisms in

the opioid receptor”

Dr Daniel Tan 6NMRC Medical Research “Accelerating molecularly targeted drug

Fellowship Award through rational design of hypothesis-testing early

clinical trials”

4Merit Award: ASCO-NCI “Why excision repair cross complementing-1

-EORTC Annual meeting (ERCC1) cannot yet be used to personalize

on Molecular Markers in chemotherapy regimens in advanced non-small

Cancer, Florida cell lung carcinoma (aNSCLC): a systematic review”

Dr Tan Min-Han 13National Youth Council - -

Singapore Youth Award,

Science and Technology

Mr Wang Zihua 14Chinese Government -

National Award for

Outstanding Self-Financed

Students Abroad


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Year 2007


Dr Ang Mei-Kim 9SMF Scholarship Award “Immunohistochemical analysis and gene

expression profiling in peripheral T-cell lymphomas”

Ms Cheng Shi Yuan 10SGH 16th Annual Scientific “Identifying RhoGEF Ect2 as a novel drug target

Meeting - Young for synergistic therapy with irradiation and

Investigator's Award chemotherapy in malignant gliomas”

(Basic Science)

Mr William Chin Wei Lim 9SMF Scholarship Award “Targeted delivery of photosensitizer using

biomedical polymers for biophotonic therapeutics

and diagnostics of cancer”

Dr Dulloo Muhammad Iqbal 9SMF Scholarship Award “Elucidating the mechanisms regulating the stability

of p73, the homologue of the tumor suppressor

p53”

Dr Kang Khong Bee 9SMF Post-Doctoral “Radioresistance of brain tumor stem cells”

Scholarship Award

Mr Leong Siew Hong 9SMF Scholarship Award “miRNA expression profiling and functional analysis

in gastric cancer”

Dr Ooi Aik Seng 9SMF Post-Doctoral “The extracellular signaling pathway that mediates

Scholarship Award the vasculature reorganization in the arrival

of metastatic cancer cells”

Dr Pang Su Yin Grace 6NMRC Medical Research “To screen for variant SNPs in genes encoding

Fellowship Award opioid drug receptors in Asian cancer patients and

to identify functional SNPs and to determine their

influence on the PK/PD of opiods in cancer patients”

Dr Felicia Tan Li Sher 9SMF Scholarship Award “Analysis of Immunohistochemistry and Gene

Expression in Human Cholangiocarcinomas”

Dr Tan Min-Han 9SMF Scholarship Award “Molecular genetics of clear cell renal cell

carcinoma”

Dr Tan Poi Kiang 9SMF Post-Doctoral “Selective gene transfer into human brain tumors

Scholarship Award by using MG11-mediated adenoviral vectors

with native tropism”

Ms Tan Sze Huey 6NMRC Medical Research “Sensitivity analysis for an Asthma Trial

Scientist Award with Missing Data”

Dr Marissa Teo 9SMF Post-Doctoral “Tumor suppressor network in hepatocellular

Scholarship Award carcinoma”


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Abbreviation and Award Summary1Singhealth GCEO Excellence AwardIn recognition of outstanding contribution to research in SingHealth.

2Memorial Sloan-Kettering Cancer Center Michael E Burt Memorial AwardA prestigious award given by Memorial Sloan-Kettering Cancer Center annually to the best overall fellow in the entiredivision of surgery.

3National Outstanding Clinician AwardThis award recognizes individuals who have contributed substantially in the training of young clinicians and clinicianscientists via mentorship or by virtue of academic positions.

4ASCO - American Society of Clinical OncologyASCO Merit Award: ASCO-NCI-EORTC Annual meeting on Molecular Markers in Cancer 2008, Florida – The awardis designed to promote clinical research by young scientists and provide fellows with an opportunity to present theirresearch and interact with other clinical cancer investigators at ASCO scientific meetings.

Young Investigator Award - to provide funding to promising investigators to encourage and promote quality researchin clinical oncology.

5ASEAN Youth AwardThe ASEAN Youth Award recognises the outstanding contributions of ASEAN youth towards regional developmentand cooperation. The award is given to winners of National Youth Awards from the respective ASEAN countries fortheir active work in the field of youth development.

6NMRC – National Medical Research CouncilThe NMRC Medical Research Fellowship/Scientist Award aims to provide doctors with the training necessary tobecome clinician scientists. This can include overseas research training or pursuing a PhD in research at a localinstitution.

The Clinician Scientist Investigator (CSI) / Clinician Scientist Award(CSA) Award aims to provide adequate salary& funding support for selected outstanding clinician scientists, who possess a consistent record of excellence inresearch, to enable them to carry out internationally competitive and influential translational and clinical research.

The STaR Investigator Award is a prestigious award to recognise and support outstanding investigators in translationaland clinical research.

7Unesco-L’Oreal for Women in Science International FellowshipAims to promote and highlight the critical importance of ensuring greater participation of women in science. Eachyear, the programme recognises the achievements of exceptional female scientists across the globe and awardsthem with fellowships to help further their research.

8AACR – American Association for Cancer Research The AACR Scholar-In-Training Award is open to medical students, graduate students and residents who wish tocompete in the annual AACR abstract competition. Winners will be required to present their abstract at the AACRAnnual Convention.

9SMF – Singapore Millennium FoundationThe Scholarship / Post-Doctoral Scholarship Award is designed to promote and nurture R&D talent in areas of studythat are of strategic importance to Singapore's economy and national development.

10SGH – Singapore General HospitalThe Annual Scientific Meeting provides the opportunity for the young clinicians, researchers, academicians, nursesand allied health staff in Outram Campus and Dukes-NUS GMS to interact and present their work.

11National Research Foundation – Ministry of Health Healthcare Research ScholarshipThe scholarship provides support to Advanced Specialty Trainee (AST) doctors who wish to enrol in a PhD programmelocally or overseas. It is targeted at clinicians intending to pursue a career in research.

12 The Singapore Science and Engineering Fair (SSEF) is intended for students who have conducted researchover the past year to showcase their findings. Awards are given out to recognise the outstanding work producedby the students.

13 National Youth Council - Singapore Youth Award, Science and TechnologyThis award is given out to honour youths in Singapore who have significantly achieved excellence and contributedto the society.

14Chinese Government National Award for Outstanding Self-Financed Students AbroadThe China Scholarship Council gives these awards annually to recognize the academic merit and researchaccomplishments of exceptional, self-financed students from China who are pursuing doctoral degrees in foreigncountries.


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NEW APPOINTMENTS

Dr Alexandra PIETERSENSenior Scientist

[email protected]

Alexandra Pietersen received her PhD from Erasmus University for investigating

the use of gene therapy to induce tumour-specific apoptosis. Following postdoctoral

work on cell fate decisions in the haematopoietic system at Utrecht University

Medical Centre, she became a senior postdoc with Maarten van Lohuizen at the

Netherlands Cancer Institute. There she investigated the epigenetic regulation of

mammary stem cells and its link to breast cancer. In July 2008, she started her

Laboratory of Mammary Gland Biology in the division of Cellular and Molecular

Research at the National Cancer Centre Singapore, in affiliation with the Cancer

and Stem Cell Biology programme at Duke-NUS Graduate Medical School. She

holds an adjunct Assistant Professor position with the department of Physiology

of the National University Singapore.

Dr Gediminas GREICIUSVisiting Senior Scientist

[email protected]

Originally from Lithuania, Gediminas Greicius performed graduate studies in the

field of B lymphocyte biology at Karolinska Institutet, CMB and Stockholm

University, Sweden, at the laboratory of Prof Eva Severinson. Thereafter, he joined

Prof Sven Pettersson’s laboratory at Karolinska Institutet, MTC where he was

involved in studies of cancerogenesis in APCmin+/ mice, a model of colorectal

carcinoma.

Currently, Gediminas Greicius is a Visiting Senior Scientist at the Laboratory of

Inflammation Biology in National Cancer Centre Singapore. Host-microbe interaction

in cancer models is the main area of his interest.

Dr Patrick REILLYSenior Scientist

[email protected]

Originally from Canada, Dr. Patrick Reilly performed his graduate research on

viral-host cell interactions in Dr. Winship Herr's lab at the Cold Spring Harbor

Laboratory.

He later joined Dr. Tak Mak's laboratory at the Campbell Family Institute for Breast

Cancer Research, where he developed numerous animal models for studies of

cancer biology. He was also pivotal in scientific mentoring of several graduate

students within the lab.

He continues his interest in mouse genetic models of cancer as a Senior Scientist

within the Laboratory of Inflammation Biology.

NEW APPOINTMENTS

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Prof TEH Bin TeanMD, PhD

Principal [email protected]

Professor Bin Tean Teh obtained his medical degree (1992) from the University

of Queensland, Australia and his Ph.D. (1997) from the Karolinska Institute,

Sweden. Following postdoctoral work in multiple endocrine neoplasia at Karolinska

Institute, Dr. Teh joined the Van Andel Research Institute (VARI) as a Senior

Scientific Investigator in the Laboratory of Cancer Genetics since January 2000.

He is currently a Professor at the Duke-NUS Graduate Medical School, Singapore

and serves as the Group Director for Translational Research at SingHealth. He

also holds Adjunct Professorships in Universities/Institutes in Sweden, USA, and

China. He also co-directs the Kidney Cancer Research Program at the Van Andel

Research Institute in the USA. Additionally, Dr. Teh has published extensively in

over 260 publications in high impact scientific journals and also sits on various

Editorial Boards such as Lancet Oncology, Cancer Research, International Journal

of Oncology, the Journal of Endocrine Genetics, the Journal of Clinical Endocrinology

and Metabolism, Clinical Genitourinary Cancer, and the American Journal of

Translational Research.

Prof Sven PETTERSSONPrincipal Investigator

MD, [email protected]

Prof Pettersson received his PhD in 1985, MD from Umeå University in Sweden

in 1986. After his postdoc training in Cambridge, UK, he was recruited to Karolinska

Institutet (KI) in 1991.Since 2001 he holds a strategic professorship in the field

of host-microbe interactions at KI. His research aims to understand how normal

commensal flora modulates host physiology. During his scientific career, Prof

Pettersson has made many pioneering contributions in the field of genetics,

immunology and recently also in neurobiology His publication list is extensive

and he has co-authored some 130 publications. He is a cofounder of a small

drug company, Index Ltd, in Sweden which has its first drug against colitis in a

phase III trial. For this discovery, he was awarded an Astra-Zeneca prize for novel

discoveries in 1996. He is also the Director for Germ-Free research at KI.

Prof TAK Wah MakPrincipal Investigator

[email protected]

Prof Mak holds the distinction of being the first scientist to clone the genes of

the human T-cell receptor in 1984. During his scientific career, he has made many

pioneering contributions in the genetics of immunology.

In 2004, he took on the position of Director at the Campbell Family Institute for

Breast Cancer Research with a focus on breast cancer research. Also a University

Professor at the University of Toronto, he co-authored over 500 scientific papers

which have been published in top international scientific journals.

For his contributions to medicine, Prof Mak has garnered numerous accolades

such as the Emil von Behring Prize, Paul Ehrlich Prize, King Faisal Prize for

Medicine and Sloan Prize of the General Motors Cancer Foundation, among

others.


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Integrate basic, clinical and translationalresearch aimed at the prevention, diagnosisand treatment of human cancers

Division of

Cellular andMolecularResearch

BEK CHAI HEAH LABORATORY OFCANCER GENOMICS

Revolutionising Cancer Treatment through Personalised and TargetedTherapies

Cancer arises from the accumulation of genetic changes. In our laboratory, wehave focused on studying human hepatocellular carcinoma (HCC). To accelerateour effort to identify the molecular and genetic basis of HCC, we systematicallystudy the expression of genes which expression is specifically altered. Theavailability of these “gene expression molecular maps” would indirectly informus the genomic changes associated with these cancers and thus enable theidentification of novel cancer-specific biomarkers and the design of noveltherapeutic strategies.

Kam Man HUIPrincipal Investigator & Head, Division ofCellular & Molecular ResearchPhD (Northwestern), FRCPath (UK)[email protected]

Research StaffZhao Hui LI (PhD)Tina H T ONG (PhD)Rui ZHOU (PhD)Amudha DEVIASIGAMANIJie GAODerrick T H LOWBaskaran s/o NARAYANANFeng SUNHong Ping XIA

Gene expression profiling between normal and cancerous tissues provides an unprecedented opportunity to identify

holistically the biological pathways and processes that mediate carcinogenesis. The ability to determine which biological

pathways are associated with differentially expressed genes form an unbiased way to gain an understanding of the

molecular processes affected by the gene expression changes. The overall goal of our laboratory is therefore to interpret

comprehensive gene expression changes in the context of underlying biological pathways and processes to identify

the molecular pathways and processes affected upon carcinogenesis to enable the development of therapeutic strategies.

Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality.

Hepatocellular carcinoma (HCC) accounts for between 85% and 90% of primary liver cancers. HCC is one of the globe’s

most common types of cancer and one of the most fatal. It is an epithelial cancer originating from hepatocytes and has

been postulated to result from a series of genetic alterations attributable to a diverse range of causes. HCC has several

distinctive epidemiologic features. Its worldwide prevalence varies widely and mirrors closely the geographical distribution

of chronic viral hepatitis, its most important etiological agent. Surgery is currently the standard-of-care in the management

of HCC and remains the only modality of treatment that most consistently prolongs patient survival. Patients with early

stage category tumours may be effectively treated with surgical resection, transplantation, or percutaneous ablation.

The 5-year survival rate can exceed 50%. However, currently available biomarkers for the detection of HCC are both

non-specific and insensitive and there is considerable overlap between patients with chronic viral hepatitis and frank

HCC. As a consequence, less than 20% of patients with HCC are amenable to surgery at the time of diagnosis and the

overall prognosis of patients with inoperable HCC is dismal. Hence, there is an urgent and compelling need to identify

biomarkers that could provide the early detection of HCC when the disease is most treatable, and to identify new

molecular therapeutic targets that can be potentially developed into more efficacious treatment modalities.

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New technologies such as gene expression profiling are indispensable for

further elucidation of the molecular events underlying hepatocarcinogenesis

and enable the concurrent identification of potentially novel liver-specific

therapeutic targets and/or specific transcriptional regulators to be incorporated

into strategies to control the growth of HCC. One of our research focuses is

to identify novel HCC-specific diagnostic and prognostic biomarkers through

comprehensive gene expression profiling of normal and cancerous liver

tissues. New molecular biomarkers with high sensitivity and specificity could

eventually be made available for the early diagnosis of HCC. The challenge,

however, remains in being able to validate these novel molecular therapeutic

targets through clinical validations as efficacious therapies for HCC, both

when HCC is inoperable and as adjuvant therapy in operated cases to

significantly improve survival. We believe the early detection of HCC, when

it is most treatable, is essential. The molecular function of some of these

newly identified HCC-specific biomarkers are being studied in our laboratory.

Figure 1: Chromosomal localization of the 101 human HCC-specific genes identified bycomprehensive gene profiling experiments.


Figure 2: Ability to segregate blood samples from HCC and normal patients by HCC-gene signature derived in our laboratory.

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Selected Publications

Subramaniam K, Ooi LL, Hui KMTranscriptional down-regulation of IGFBP-3 in human hepatocellular carcinoma cellsis mediated by the binding of TIA-1 to itsAT-rich element in the 3'-untranslatedregion.Cancer Lett. (2010) 297(2):259-68.

Hui KMHuman Hepatocellular Carcinoma:Expression Profiles-based MolecularInterpretations and Clinical Applications.Cancer Lett. (2009) 286(1):96-102.

Puan KJ, Low JS, Tan TW, Wee JT, TanEH, Fong KW, Chua ET, Jin C, Giner JL,Morita CT, Goh CH, Hui KMPhenotypic and functional alterations ofV 2V 2 cell subsets in patients with active

Tan MG, Kumarasinghe MP, Wang SM,Ooi LL, Aw SE, Hui KMModulation of iron-regulatory genes inhuman hepatocellular carcinoma and itsphysiological consequences.Exp. Biol. Med. (Maywood)(2009) 234(6):693-702.

Linn YC, Lau SK, Liu BH, Ng LH, YongHX and Hui KMCharacterization of the recognition andfunctional heterogeneity exhibited bycytokine-induced killer cell subsets againstacute myeloid leukaemia target cell.Immunology (2009) 126:423-435.

Liu BH, Goh CH, Ooi LL, Hui KMIdentification of unique and common lowabundance tumour-specific transcripts bysuppression subtractive hybridization andoligonucleotide probe array analysis.Oncogene (2008) 27(29):4128-36.

Wang SM, Ooi LL, Hui KMIdentification and validation of a novelgene signature associated with therecurrence of human hepatocellularcarcinoma.Clin. Cancer Res. (2007) 13(21):6275-6283.

Tan K, Cheang P, Ho AW Ivy, Lam YPPaula and Hui KMNano-sized bio-ceramic particles couldfunction as efficient gene delivery vehicleswith target specificity for the spleen.Gene Therapy (2007) 14:828-835.

Lau WM, Ho TH, Hui KMp16INK4A-silencing augments DNA damage-induced apoptosis in cervical cancer cells.Oncogene (2007) 26:6050-6060.

nasopharyngeal carcinoma.Cancer Immunol. Immunother. (2009)58(7):1095-1107.

LABORATORY OFMOLECULAR ENDOCRINOLOGY

Novel Therapeutic Approaches for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasmaccounting for approximately 667,000 worldwide cases annually. To improve ourcurrent therapies and to identify novel treatment for HCC, our laboratory hasdeveloped the models of HCC from patient’s tumour specimens. In this model,intact fragments of human HCC taken from patients are implanted into the liverof immuno-deficient mices. We have successfully used these tumour models astools to identify effective therapies for patients.

National Xenograft Therapeutic Programs (NXTP): Translational platforms for pre-clinical and clinical studies in hepatocellular carcinoma

Discovery-driven translational research in HCC is moving steadily from the study of xenograft models derived from

established cell lines towards patient-derived xenograft models. To identify effective therapies, we have successfully

developed patient-derived HCC mouse model xenografts. They have proven to be an indispensable asset in drug

discovery, especially in targeted and combined therapies. Our group has profiled the protein expression of the primary

tumours and comparison with corresponding xenografts show striking resemblance in the protein profile between the

two. With the support from Singapore Cancer Syndicate, our group established the National Xenograft Therapeutic

Program (NXTP) for HCC in 2006. NXTP is fast becoming a recognised industry and academic leader in the area of HCC

drug development. Scientists from various pharmaceutical and biotechnology firms including AstraZeneca, Eli Lilly, Bristol

Myers Squibb, GlaxoSmithKline, Novartis, and Roche have collaborated with our laboratory to provide their newly

developed drugs to test on our xenograft models. As a direct result of our collaboration, AstraZeneca has signed an

alliance with National Cancer Centre Singapore and other Singapore institutions both on a pre-clinical and clinical level.

Recently, a joint research project between our laboratory and Roche has been established. This pre-clinical translational

programme aims to study the in vivo mechanisms underlying Avastin action and Avastin-resistance in HCC and gastric

cancer tumour models. Besides collaborations with pharmaceutical industries, we are working closely with a team of

dedicated clinical scientists in NCCS who are enthusiastic about bench-to-bedside research and are committed to

translating our laboratory findings onto clinical setting. Our clinical group (Dr Choo Su Pin, PI) designed a Phase I Study

of Rapamycin in combination with Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma. From pre-

clinical work on tumour vasculature to the mTOR signaling pathway in our laboratory, this clinical trial has provided novel

molecular, cellular, and functional insights on tumour angiogenesis of HCC. We just completed the Phase I study and

demonstrated the combination of bevacizumab with rapamycin showed promise for realistic benefit in patients enrolled

in this trial. A Phase II Study of RAD001 in combination with Bevacizumab in Patients with Unresectable Hepatocellular

Carcinoma will start in early 2010. We recently reported that inhibition of the MEK/ERK pathway enhanced the antitumour

effect of sorafenib in both orthotopic and ectopic models of HCC. These findings led to a Phase I/II study of sorafenib

in combination with AZD6244 in advanced hepatocellular carcinoma, which started in January 2010.

The Hung HUYNHPrincipal [email protected]

Joint Appointments:Adjunct Professor,McGill University, Canada

Adjunct Associate Professor,National University of Singapore

Research StaffValerie CHONGChun Tzen JONGIrene W.L. LAMSwee Shean LEE

Tuan D.A. LUURichard ONGWeng Hua KHOOYang SHU

> 20


Huynh HAZD6244 (ARRY-142886) enhances theantitumor activity of rapamycin in mousemodels of human HCC.Cancer (2010) 116(5):1315-25.

Huynh H, Ngo VC, Koong HN, Poon D,Choo SP, Toh HC, Thng CH, Chow P,Ong HS, Chung A, Goh BC, Smith PD,Soo KCAZD6422 (ARRY-142886) enhances theantitumor activity of sorafenib in ectopicand orthotopic models of humanhepatocellular carcinoma (HCC).J Hepatol. (2010) 52:79-87.

Huynh HTyrosine kinase inhibitors to treat livercancer.Expert Opin. Emerging Drugs (2010)15:1-14.

Huynh H, Ngo VC, Choo SP, Poon D,Koong HN, Thng CH, Zheng L, Ong LC,Jin Y, Ong HS, Chung A, Chow P, ChangA, Soo KCSunitinib (SUTENT, SU11248) suppressestumor growth and induces apoptosis inxenograft models of human hepatocellularCarcinoma.Current Cancer Drug Targets (2010)9:738-747.

Huynh H, Fargnoli JBrivanib Alaninate.Drugs of the Future. (2009) 34:881-895.

Huynh H, Ngo VC, Koong HN, Poon D,Choo SP, Thng CH, Chow P, Ong HS,Chung A, Soo KCSorafenib and rapamycin induce growthsuppression in mouse models ofhepatocellular carcinoma.J Cell. Mole. Med. (2009) 13(8B):2673-83.

Yang S, Ngo VC, Lew GB, Chong LW,Lee SS, Ong RWJ, Lam WLI, Thng CH,Koong HN, Ong HS, Chung A, Chow P,Lee J, Soo KC, Huynh HAZD6244 (ARRY-142886) enhances thetherapeutic efficacy of sorafenib in mousemodels of gastric cancer.Mol. Cancer Ther. (2009) 8(9):2537-2545.

H Huynh, Ngo VC, Fargnoli J, Ayers M,Soo KC, Koong HN, Thng CH, Ong HS,Chung A, Chow PK, Pollock P, ByronS, Tran EBrivanib (BMS-582664), a dual inhibitor ofvascular endothelial growth factor andfibroblast growth factor receptor tyrosinekinases, induces growth inhibition inmouse models of human hepatocellularcarcinoma.Clin. Cancer Res. (2008) 14:6146-6153.

Huynh H, Palanisamy N, Salto-Tellez M,Goh BC, Lee CK, Somani A, Lee HS,Kalpana R, Yu K, Tan PH, Wu J, SoongR, Lee MH, Hor H, Soo KC, Toh HC,Chow PK, Tan PEffective inhibition of tumor growth inpatient-derived xenografts ofhepatocellular carcinoma by rapamycinand bevacizumab.J Hepatol. (2008) 49:52-60.

Figure 1: Schematic showing how orthotopic models of human hepatocellular carcinoma(HCC) are created from primary HCC tumours. The human HCC tumours are grown inthe livers of the mice and are parallel transplanted. Mice bearing human HCC tumoursare used to identify the most effective therapies for the individual patients (individualisedtherapy) and to evaluate the efficacy of novel or existing drugs prior to clinical trials.

RESEARCH OUTCOMES: CLINICAL TRIALS

(1) Co-Principal Investigator (PI: Dr. Choo Su Pin). A Phase I Study of

Rapamycin in combination with Bevacizumab in Patients with

Unresectable Hepatocellular Carcinoma (Completed)

(2) Co-principal Investigator: A Phase II Study of RAD001 in combination

with Bevacizumab in Patients with Unresectable Hepatocellular

Carcinoma (Started in 2010).

(3) Co-Principal Investigator: Phase I/II study of sorafenib in combination

with AZD6244 in advanced hepatocellular carcinoma (Started in

January 2010)


> 21

LABORATORY OFCANCER GENE THERAPY

The main focus in our laboratory is to develop an ideal carrier or gene vector forthe delivery of therapeutic agents into human cancer cells. Conventional cancertherapy has its limitations; surgery may not be the most appropriate treatmentespecially for tumours that are inaccessible, on the other hand, radiotherapy andchemotherapy are known to kill normal proliferating cells in addition to the cancercells. As a result, patients often suffer from unpleasant side effects. Thus, oneof our research objectives is to develop novel delivery vectors or carriers tocomplement the conventional therapy.

We are interested in the development of viral vectors, in particular, the Herpes Simplex Virus type 1

(HSV-1) amplicon viral vectors for gene therapy purposes. The advantages of these vectors include the ability to infect

a broad range of mammalian cells, large DNA insert capacity up to 150kb, with minimal cytotoxicity due to the lack of

helper viruses during the viral packaging process. Cancer is characterised by uncontrolled cellular proliferation. We

capitalised on this unique property of cancer cells to develop a strategy whereby the transcription of the therapeutic

gene is only activated in rapidly proliferating cells. The specificity of the vector is improved with the aid of cell-type

specific promoter and/or glial-specific peptide incorporated into the viral-envelope coat. Furthermore, the therapeutic

gene is fused with the luciferase reporter gene to better study the regulation and functionality of these viral vectors in

mice bearing fluorescent proteins expressing tumour cells so as to demarcate the tumour boundary with clarity. This

improvement has enabled us to understand how therapeutic modalities are activated in vivo, and significantly contributed

to the overall design of the therapy regimens.

Human mesenchymal stem cells (MSC) have generated a great deal of excitement as a potential source of cells for cell-

based therapeutic strategies. In general, MSC appear to be a non-immunogenic population of cells and exhibit a unique

property of tumour tropisms. One of our interests is to use the MSC as a carrier to deliver therapeutic agents especially

to disseminated tumour cells. We are the first group to show that MSC can be readily infected by the HSV-1 amplicon

viral vectors with no alterations in the intrinsic properties of the cells. This finding has led to the award of a travel

fellowship to the EMBO International Cancer Conference 2005 and a Postdoctoral Fellowship from the Singapore

Millennium Foundation.

Paula Y.P. LAMPrincipal [email protected]

Joint Appointments:Associate Professor, NUSAssociate Professor, Duke-NUS Graduate Medical School

Research StaffIvy AW HO (PhD)Tin Lum LAM (PhD)Berwini B ENDAYAJennifer P NEWMANKian Chuan SIAYULYANA

> 22


Sia KC, Chong WK, Ho IA, Yulyana Y,Endaya B, H Huynh and Lam PYHybrid HSV/EBV amplicon viral vectorsconfer higher transgene expression inprimary human tumors and human bone-marrow-derived mesenchymal stem cells.J. Gene Medicine (2010) 12(10):848-58.

Ho IA, Ng WH, Lam PYFasL and FADD delivery by a glioma-specific and cell cycle-dependent HSV-1amplicon virus enhanced apoptosis inprimary human brain tumors.Molecular Cancer (2010) 9:270.

Ho IA, Hui KM, Lam PYIsolation of peptide ligands that interactspecifically with human glioma cells.Peptides (2010) 31(4):644-650.

Ho IA, Miao L, Sia KC, Wang GY, HuiKM, Lam PYTargeting human glioma cells using HSV-1 amplicon peptide display vector.Gene Therapy (2010) 17(2):250-260.

Ho IA, Chan KY, Ng WH, Guo CM, HuiKM, Cheang P, Lam PYMatrix metalloproteinase 1 is necessaryfor the migration of human bone marrow-derived mesenchymal stem cells.Stem Cells (2009) 27(6):1366-1375.

Ho IA, Chan KY, Miao L, Shim WS, GuoCM, Cheang P, Hui KM, Lam PYHSV-1 amplicon vector mediated genetransfer to human bone marrow-derivedmesenchymal stem cells. Cancer GeneTherapy (2008) 15(9):553-562.

Lam PY, Sia KC, Khong JH, De GeestB, Lim KS, Ho IA, Wang GY, Miao LV,Huynh H, Hui KMAn efficient and safe herpes simplex virustype 1 amplicon vector for transcriptionallytargeted therapy of human hepatocellularcarcinomas.Mol Ther. (2007) 15(6):1129-36.

Sia KC, Wang GY, Ho IA, Khor HY, MiaoL, Hui KM, Lam PYOptimal purification method for herpes-based viral vectors that confers minimalcytotoxicity for systemic route of vectoradministration.Journal of Virological Methods (2007)139(2):166-174.

Wang GY, Ho IA, Sia KC, Miao L, HuiKM, Lam PYEngineering of an improved cell cycleregulatable HSV-1 amplicon vector withenhanced transgene expression inproliferating cells yet attenuated activitiesin resting cells.Human Gene Therapy (2007) 18(3):222-231.

Ho IA, Hui KM, Lam PYTargeting proliferating tumor cells via thetranscriptional control of therapeutic genes.Cancer Gene Therapy (2006) 13(1):44-52.

Lam PY, Lim KS, Wang SM and Hui KMApoptosis induced by TIMP-3 in gliomacells.Molecular Therapy (2005) 11(7):144-152.

Systemic delivery of MSC circumvents problems associated with site-

specific delivery, such as calcification and tissue damage. However, during

systemic application, MSC must transmigrate across the endothelium to

exit the blood circulation, and subsequently invade their target tissues. In

the process of unraveling the signaling cues to MSC migration, we show

that the matrix metalloproteinase-1 (MMP1) is a key regulator of the tumour-

homing property exhibited by the MSC. Targeted knockdown of MMP1

abolished the migration ability of the MSC, while overexpression of MMP1

in poorly migrating cells restored the defects. Apart from dissecting the

molecular pathway to MSC migration, we are also keen to better understand

the potential cross-talks between MSC and the tumour cells in an attempt

to weigh out the pros and cons of using MSC to treat human cancers.

Figure 1: Human bone marrow-derived mesenchymal stem cell (blue or fluorescentred), when injected into the contralateral hemisphere, migrate toward brain tumourcells (green).


> 23

LABORATORY OFINFLAMMATION BIOLOGY

Our research uses animal models of colorectal cancer (CRC) as a foundation for investigating inflammatory initiation

and signaling. Inflammation in the colon is very tightly regulated in light of the myriad of microbes that are constantly

exposed to the gut epithelia. Most of these microbes are bacteria that are co-evolved with mammals to improve the

health of the host. A small minority, however, can be pathogenic and can cause or aggravate inflammatory bowel

disorders (IBD). Through various lines of evidence, we now know that gut bacteria are also able to accelerate CRC

progression, most likely through these same inflammatory processes.

Identifying Specific Pathogenic Bacteria in CRC

The identification of the bacteria Helicobacter pylori as the causative agent in stomach cancer has enlightened the

scientific community on the possibility that certain strains of bacteria could also be responsible for enhancing CRC.

One of our overall aims is to identify such bacteria and understand how they might function in disease progression.

We are now testing clinical isolates of bacteremia cases from CRC see their effects on inflammation in vitro as well as

intestinal cancer progression in vivo.

Tak Wah MAKPrincipal [email protected]

Joint Appointment:Professor, University of TorontoDirector, Campbell Family Inst. ofBreast Cancer Research

Sven PETTERSSONPrincipal InvestigatorMD, [email protected]

Joint Appointment:Professor, Karolinska InstituteGroup Leader, Genome Instituteof Singapore

Research StaffGediminas GRECIUS (PhD)Patrick REILLY (PhD)Shih Wee SEOW (PhD)

The role of the immune system in cancer is far more complex than originallyimagined. It is increasingly accepted that chronic inflammation can advance localtumour growth. Our research sets out to examine the role of inflammation incancer by combining cutting-edge imaging technique and novel mouse models.

> 24


Reilly PT, Afzal S, Wakeham A, You-TenA, Haight J, Zaugg K, Dembowy J,Young A, and Mak TWGeneration and characterization of theAnp32e-deficient mouse.PLoS One (2010) 5(10):e13597.

McIlwain DR, Pan Q, Reilly PT, Elia AJ,McCracken S, Wakeham AC, Itie-Youten A, Blencowe BJ, Mak TWSmg1 is required for embryogenesis andregulates diverse genes via alternativesplicing coupled to nonsense-mediatedmRNA decay.Proc. Natl. Acad. Sci. USA (2010)107(27):12186-91.

McGovern DP et al.Genome-wide association identifies ,ultipleulcerative colitis susceptibility loci.Nature Genetics (2010) 42:332-7.

Maria Genander, Michael M. Halford,Zuoren Yu, Anna Martling, Nan-Jie Xu,Gedas Greicius, Richard G. Pestell, SvenPettersson, Mark Henkemeyer ,JonasFrisénDissociation of EphB2 signaling pathwaysmediating progenitor cell proliferation andtumor suppression.Cell (2009) 139:679-92.

Britta Björkholm, Chek Mei Bok, AnnelieLundin, Joseph Rafter, Martin LloydHibberd, Sven PetterssonThe intestinal microbiota modulatexenobiotic metabolism physiology in theliver.PLoS ONE (2009) 9:4-10.

Lechmann M, Shuman N, Wakeman A,Mak TWThe CD83 reporter mouse elucidates theactivity of the CD83 promotor in B, T anddendritic cell Populations in vivo.PNAS (2008) 105(33): 11887-92.

Brü'fcstle A, Heink S, Huber M,Rosenplänter C, Stadelmann C, Yu P,Arpaia E, Mak TW, Kamradt T, LohoffMThe development of inflammatory T(H)-17cells requires interferon-regulatory factor4.Nat. Immunol. (2007) 8(9):958-66.

Kelly D, Campbell JI, King TP, Grant G,Jansson EA, Coutts AG, Pettersson S,Conway SCommensal anaerobic gut bacteriaattenuate inflammation by regulatingnuclear-cytoplasmic shuttling of PPAR-gamma and RelA.Nat. Immunol. (2004) 5(1):104-12.

Genetic influences on inflammation response

The outcome for individuals in response to an environmental cue will commonly

be different based on their genetic diversity. This is almost certainly true of

inflammatory processes in tumourigenesis. Thus, by identifying and testing

disease-related genes we can get greater understanding on the best therapeutic

strategies. To this end, we have focused on the genetics of patients with

IBD and other chronic inflammatory disorders. Using cutting-edge genomic

techniques we have identified numerous candidate genes for testing in animal

models. One gene of particular focus is the anti-inflammatory Aryl hydrocarbon

receptor (AhR). We are currently investigating the detailed mechanism by

which AhR responds to small molecule messages to suppress inflammation

in IBD and cancer.

Improved platforms for studying inflammation in CRC

Although CRC is a common type of cancer both in Singapore and throughout

the world, it can be difficult to study in animal models. For one thing, the

influence of gut microbiota on the disease means that there is inconsistency

among different laboratories. For analysing the bacterial contribution to

diseases as well as normal development, we have initiated a germ-free animal

colony within SGH, the first of its kind in South-East Asia. Using this germ-

free environment, we can analyse with high fidelity the contributions of either

specified or general microbes in an array of physiological activities.

Another major drawback to our understanding of CRC is our limited capacity

to track the disease over time to determine the dynamics of different

interventions. To this end, we are generating several potential models for

fluorescent and luminescent detection of early tumourigenesis. Such models

will be valuable additions to the scientific community where in vivo detection

of disease is becoming a critical tool in testing the actions of environmental

factors.

Figure 1: Imaging of small intestinal tumours in the mouse ileum. Red foci mark regionsof cancer-associated cathepsin activity. Green staining displays immune-associatedmatrix metaloproteinase activity with green arrow displaying a Peyer’s Patch, an immunefollicle of the intestinal tract.


> 25

LABORATORY OFMAMMARY GLAND BIOLOGY

Some tumour cells share characteristics with tissue stem cells, and it may bethese properties that render tumour cells particularly difficult to kill. We studywhat mechanisms govern mammary stem cells and how their deregulationcontributes to breast cancer.

Alexandra PIETERSENSenior [email protected]

Joint Appointments:Assistant Professor, Duke-NUS GraduateMedical School

Assistant Professor, Dept of Physiology, NationalUniversity of Singapore

Research StaffGerard TARULLI (PHD)Duvini DE SILVAKakaly GHOSHJen Nee GOHVictor HO

Mammary stem cells and breast cancer

Of all the cells in a tissue, stem cells seem to be especially sensitive to signals from their surroundings, therefore it is

important to analyse these cells in vivo, e.g. in a mouse. The mouse mammary gland provides a unique model system

to study epithelial stem cell biology because stem cell activity can be quantified in vivo, unlike tissues such as the

intestine or the skin. In addition, we have the means to isolate breast stem cells based on their cell surface profile with

a cell sorter, and subsequently alter genes in these cells to mimic what is observed in breast cancer. After transplanting

these cells back into the mouse, we can study the effect on the behaviour of the stem cells and the cells they generate.

The problem with studying cancer is that by the time a tumour is detected, so much has changed that it is difficult to

determine what alterations were driving the tumorigenic process and which ones are a mere byproduct of uncontrolled

growth. By approaching this question from the other side, i.e. by changing genes one by one in normal cells, we hope

to gain a better understanding what changes are relevant and whether these changes could be targeted in specialised

cancer therapy.

My previous studies at the Netherlands Cancer Institute (NKI) demonstrated that a gene that is overactive in breast

cancer and was thought to play a role in stem cells, called Bmi1, which in fact only had a minor role in breast stem cells.

Importantly, our studies showed that women with too much Bmi1 in their breast tumour have a better chance of surviving,

and it is Bmi1’s counterpart Ezh2 that correlates with stem cell characteristics and poor survival rates. At the moment,

studies at NKI are carried out to test an inhibitor of Ezh2 (discovered by Yu Qiang at the Genome Institute Singapore)

in mouse models of breast cancer.

At the National Cancer Centre Singapore, we are currently focusing on two different classes of genes and their role in

mammary stem cells and breast cancer: T-box repressors and the Wip1/p38 pathway.

> 26


Puppe J, Drost R, Liu X, Joosse SA,Evers B, Cornelissen-Steijger P,Nederlof P, Yu Q, Jonkers J, vanLohuizen M, Pietersen AMBRCA1-deficient mammary tumors cellsare dependent on EZH2 expression andsensitive to Polycomb Repressive Complex2-inhibitor 3-deazaneplanocin A.Breast Cancer Res. (2009) 11(4):R63.

Pietersen AM, Horlings HM, HauptmannM, Langerø'f8d A, Ajouaou A,Cornelissen-Steijger P, Wessels LF,Jonkers J, Van de Vijver MJ, VanLohuizen MEzh2 and Bmi1 inversely correlate withprognosis and p53 mutation in breastcancer.Breast Cancer Research (2008) 10(6):R109.

Pietersen AM, Evers B, Prasad AA,Tanger E, Cornelissen-Steijger P,Jonkers J, Van Lohuizen MBmi1 regulates stem cells and proliferationand differentiation of committed cells inmammary epithelium.Current Biology (2008) 18(14):1094-9.

Pietersen AM, Van Lohuizen MStem cell regulation by Polycombrepressors: postponing commitment.Current Opinion in Cell Biology (2008)20(2):201-207.

Pietersen AM, Rutjes SA, van TongerenJ, Vogels R, Wesseling JG, NotebornMHThe tumor-selective viral protein apoptineffectively kills human biliary tract cancercells.J. Mol. Med. (2004) 82(1):56-63.

Van der Eb MM, Pietersen AM,Speetjens FM, Kuppen PJK, Van deVelde CJH, Noteborn MHM, Hoeben RCGene Therapy with Apoptin inducesregression of xenografted humanhepatomas.Cancer Gene Therapy (2002) 9(1):53-61.

Pietersen AM, Van der Eb MM,Rademaker HJ, Van den WollenbergDJM, Rabelink MJWE, Kuppen PJK, VanDierendonck JH, Van Ormondt H,Masman D, Van de Velde CJH, Van derEb AJ, Hoeben RC, Noteborn MHMSpecific tumor-cell killing with adenovirusvectors containing the Apoptin gene.Gene Therapy 1999 6(5):882-892.

Figure 1: Mammary gland development is visualised by carmine staining.At the left, a small mammary tree is visible in the fatty breast tissue of a mouse beforepuberty (black oval is a lymph node). During puberty, the milk ducts fill the fat andgrow beyond the lymph node.

Tbx3 is important for embryonic stem cells, involved in the earliest stages

of breast development and highly active in some breast cancers. By putting

overactive Tbx3 into mammary stem cells and transplanting them back into

the mouse, we hope to understand how Tbx3 affects the different cell types

in the mammary gland and how it could contribute to breast cancer.

Our collaborator at the Institute of Molecular and Cell Biology in Singapore,

Dmitry Bulavin, recently demonstrated that Wip1 determines the sensitivity

of stem cells in the intestine to radiation. Since Wip1 is overactive in 15%

of human breast cancer, we are now studying whether Wip1 plays a similar

role in mammary stem cells, and if targeting Wip1 could make radiotherapy

against breast cancer more effective.

Figure 2: Analysis of cell identity in breast tissue using fluorescently labeled markers.Left picture is a section through a normal mammary milk duct, right picture shows anearly stage of a mouse breast tumour.


> 27

LABORATORY OFMOLECULAR CARCINOGENESIS

Tumour formation is a multi-step process involving the deregulation of specificgenes and the pathways they control in regulating cell growth and cell death.These genetic changes confer a selective growth or survival advantage to themutant cells that no longer respond to normal regulatory signals, as well as totherapeutic agents, and grow in an uncontrolled manner, resulting in malignantdisease. The goal of our research is thus to understand the cause and nature ofthese changes so that efficient molecular-based therapeutic strategies can bedeveloped to eradicate cancerous cells.

Kanaga SABAPATHYPrincipal [email protected]

Research StaffWilawan BUNJOBPOL (PhD)Iqbal DULLOO (PhD)Kenneth M.K. LEE (PhD)Anbalagan MOORTHY (PhD)Deepa SUBRAMANIUM (PhD)Rami SUKRIEH (PhD)

Eric ALLENAmy H.W. CHUAShin Yuen NAMBeng Hooi PHANGWei Wei TEOHMin XIE

Figure 1: Genetically engineered mouse models to studyhepatocellular carcinoma (HCC) formation and role of p53.

The molecular basis of carcinogenesis and therapeutic resistance

The focus of the laboratory is to understand the molecular mechanisms contributing to carcinogenesis – the process

of cancer formation, and the alterations that lead to therapeutic resistance, with the aim of finding ways to combat

cancer and enhance treatment response.

As cells are constantly exposed to a variety of signals including growth promoting factors and detrimental stresses, cell

fate determinations have to be constantly and correctly made such that an appropriate response ensues. Defects in

signaling mechanisms will inadvertently lead to altered cell fate responses resulting in both altered physiological processes

and the development of pathological conditions such as cancer. The determination of cell fate is a tightly orchestrated

process regulated by the interplay of various cellular signaling

cascades. Prominent among them is the proto-oncogene c-

Jun, a member of the AP-1 family of transcription factors, and

the tumour-suppressors p53 and p73. All 3 gene-products

are transcription factors involved in regulating gene expression,

and hence, have the ability to turn on the appropriate target

genes for cell fate determination.

Alterations in p53 are one of the most frequent occurrences

in cellular transformation, and hence, p53 is not functional in

more than 50% of ALL human cancers, indicating its critical

role in maintaining a cancer-free environment in the organism.

In normal cells, p53 regulates cell growth by controlling cell

proliferation and cell death. Mutations in p53 lead to the loss

of these growth suppressive functions, and have also been

thought to provide novel growth promoting gain-of-functions,

thus leading to uncontrolled growth. We are therefore

investigating the specific roles of mutant p53, not only in

leading to cancer formation, but also in preventing proper

therapeutic response, with specific focus on hepatocelluar

carcinoma (figure 1).

> 28


Lee MK, Tong WN, Wang ZQ, SabapathyKSerine 312 phosphorylation is dispensablefor wild-type p53 functions in vivo.Cell Death & Diffn. (2010) Epub aheadof print.

DullooD, Gopalan G, Melino G,Sabapathy KThe anti-apoptotic DeltaNp73 is degradedin a c-Jun-dependent manner upongenotoxic stress through the antizyme-mediated pathway.PNAS. (2010) 107(11):4902-7.

Toh WH, Nam SY, Sabapathy KAn essential role for p73 in regulatingmitotic cell death.Cell Death & Diffn . (2010) 17(5):787-800.

Lee MK, Sabapathy KThe R246S hot-spot p53 mutant exertsdominant-negative effects in embryonicstem cells in vitro and in vivo.J. Cell Science (2008) 121:1899-906.

Lum SS, Chua HW, Li H, Li WF, Rao N,Wei J, Shao Z, Sabapathy KMDM2 SNP309 G allele increases risk butthe T allele is associated with earlier onset-age of sporadic breast cancers in theChinese population.Carcinogenesis (2008) 29(4):754-61.

Toh WH, Logette E, Corcos L,Sabapathy KTAp73 and DNp73 activate the expressionof the pro-survival caspase-2S.Nucleic Acids Res. (2008) 36(13):4498-509.

Vikhanskaya F, Toh WH, Dulloo I, WuQ, Boominathan L, Ng HH, Vousden KH,Sabapathy Kp73 supports cellular growth through c-Jun-dependent AP-1 transactivation.Nature Cell Biol. (2007) 9(6):698-705.

Hettinger K, Vikhanskaya F, Poh MK,Lee MK, de Belle I, Zhang JT, ReddySA, Sabapathy Kc-Jun promotes cellular survival bysuppression of PTEN.Cell Death Differ. (2007) 14(2):218-29.

Vikhanskaya F, Siddique MM, BrogginiM, Sabapathy KEvaluation of the combined effect of p53codon 72 polymorphism and hot-spotmutations in response to anticancer drugs.Clin. Cancer Res. (2005) 11:4348-56.

Toh WH, Kyo S, Sabapathy KRelief of p53-mediated telomerasesuppression by p73.J. Biol Chem. (2005) 280(17):17329-38.

Sabapathy K, Hochedlinger K, Nam SY,Bauer A, Karin M, Wagner EFDistinct roles for JNK1 and JNK2 inregulating JNK activity and c-Jun-dependent cell proliferation.Mol. Cell. (2004) 15(5):713-25.

Unlike p53, its relative and homologue, the p73 tumour suppressor gene, is

not mutated but over-expressed in many cancers. The cause and consequence

of overexpression of p73 is at present unclear. Evidence indicate that p73

overexpression can lead to chemoresistance. In addition, we have recently

shown that p73 overexpression is capable of promoting cellular survival as

well, in defined cellular contexts (figure 2). Thus, we are focusing on

understanding the role and regulation of p73, particularly with reference to

its ability to induce both cell death and promote survival.

Activation of the proto-oncogene gene product, c-Jun, has been shown to

induce both cell death and proliferation. How c-Jun executes such opposite

cellular effects is still enigmatic. Importantly, its activity is elevated in cancers,

raising the possibility that it can affect cancer development and therapeutic

response. Thus, we are trying to understand how c-Jun cooperates with

various co-activators in bringing about these diverse effects, such that we

can find ways to skew the decision favorable to the inhibition of cancer

development and to enhance response.

Eventually, it is hoped that the knowledge gained through such studies will

allow the identification of suitable targets for therapy and the design of better

approaches to treat cancer.

Figure 2: p73 overexpression in cancers - evidence for promotion of cellular growthand survival.


> 29

LABORATORY OFGENOMIC ONCOLOGY

Cancers between individual patients often display strikingly different types ofclinical behaviour including disease aggressiveness and responses to treatment.Many of these differences are currently not predictable using conventionaltechniques for cancer classification, such as light microscopy andimmunohistochemistry. Our laboratory employs genome-profiling technologiesto identify molecular features of tumours that will enable such predictiveclassification, and to ultimately provide personalised cancer care.

Patrick TANAdjunct Principal InvestigatorMD, [email protected]

Joint Appointments:Associate Professor, Duke-NUS Graduate MedicalSchool

Group Leader, GenomeInstitute of Singapore

Program Leader (GenomicOncology), Cancer SciencesInstitute of Singapore

Research StaffNian Tao DENGYujing LIUQin LUOHue Kian OHChia Huey OOIKalpana RAMNARAYANANAngie L.K. TANIain Bee Huat TANJiong TAOHannah Z.A. WANGJeanie WUYonghui WUShenli ZHANGZhijiang ZHANGYansong ZHUHermioni ZOURIDIS

Our group focuses on the application of genome-scale technologies to address biological questions in cancer. We are

also intrigued by the rapid mutability and genetic plasticity of the cancer genome and believe that developing whole

genome cartographies of tumours will enable us to better understand the molecular basis of cancer and to identify

cellular pathways and molecular nodes for intervention. A major disease focus for our group is gastric cancer, which is

the second leading cause of global cancer mortality. Despite this clinical importance, relatively little is known about the

specific oncogenic pathways that regulate different aspects of the gastric cancer phenotype. We hope to identify and

understand these pathways and ultimately use this knowledge to define rational therapeutic strategies for gastric cancer

patients.

For example, using a novel computational approach, we showed that gastric cancers can be subdivided into different

subtypes with differing patterns of oncogenic pathway activity and clinical outcomes. To achieve a better understanding

of gastric cancer at the levels of systems topology, functional modules, and constituent genes, we formed an international

Gastric Cancer Consortium comprising members from Australia, Hong Kong, Japan and Singapore, to pool expression

data from more than 300 human samples profiled at various histological stages of gastric tumorigenesis, ranging from

normal gastric tissue, chronic gastritis, intestinal metaplasia, to overt carcinoma. Using this combined database, we

were able to show a conserved interaction between PLA2G2A, a gene whose expression was previously correlated with

patient prognosis, and the EphB2 receptor, raising the possibility that signalling through this receptor may contribute

to gastric carcinogenesis. We further extended this work to show that PLA2G2A is a novel target of the Wnt signalling

pathway that functions to inhibit gastric cancer metastatasis.

> 30


Ooi CH, Ivanova T, Wu J, Lee M, Tan BIain, Tao J, Ward L, Koo JH,Gopalakrishnan V, Zhu Y, Cheng LL,Lee J, Rha SY, Chung HC, Ganesan K,So J, Soo KC, Lim D, Chan WH, WongWK, Bowtell B, Yeoh KG, Grabsch H,Boussioutas A, and Tan POncogenic Pathway Combinations PredictClinical Prognosis in Gastric Cancer.PLoS Genet. (2009) 5(10):e1000676.

Yu K, Ganesan K, Tan LK, Laban M, WuJ, Zhao XD, Li H, Zhu Y, Wei CL, HooiSC, Miller L, Tan PA Precisely Regulated Gene ExpressionCassette Potently Modulates Metastasisand Survival in Multiple Solid Cancers.PLoS Genet. (2008) 4(7): e1000129.

Hou Q, Wu YH, Grabsch H, Zhu Y, LeongSH, Ganesan K, Cross D, Tan LK, TaoJ, Gopalakrishnan V, Tang BL, Kon OL,Tan PIntegrative Genomics Identifies RAB23 asan Invasive Mediator Gene in DiffuseGastric Cancer.Cancer Res. (2008) 68: 4623-4630.

Ganesan K, Ivanova T, Wu YH,Rajasegaran V, Wu J, Lee MH, Yu K,Rha SY, Chung HC, Ylstra B, Meijer G,Kon OL, Grabsch H, Tan PInhibition of Gastric Cancer Invasion andMetastas is by PLA2G2A, a Novel β -catenin/TCF Target Gene.Cancer Res. (2008) 68(11):4277-4286.

Aggarwal A, Guo DL, Hoshida Y, YuenST, Chu KM, So S, Boussioutas A, ChenX, Bowtell D, Aburatani H, Leung SY,Tan PTopological and Functional Discovery ina Gene Co-expression Meta-Network ofGastric Cancer.Cancer Res. (2006) 66, 232-241 (citedon journal cover).

In addition to our focus on gastric cancer, we have also actively participated

in numerous projects involving lung, liver, and breast cancers.

Figure 1: Systems-Map of Gastric Cancer – Each circle represents a collection ofgenes that are tightly co-regulated across more than 300 gastric tissues. For moredetails see Aggarwal et al., (2006).


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MOLECULAR RADIOBIOLOGY LABORATORY(GENOME MAINTENANCE/DNA REPAIR)

Research in our laboratory primarily focuses on undertaking a series of hypothesis-driven, mechanistic studies into various components of genome maintenancenetwork (GMN). Cancer, at its very core, is a genetic disease with its molecularunderpinnings traced to a group of genes coding for proteins that mediate cellcycle progression, DNA repair, programmed suicide (apoptosis) and the ‘upstream’cell membrane signaling and transduction regulatory cascades. Collectively,these systems form a complex, interconnected homeostatic circuitry – denotedgenome maintenance network (GMN) – that enables a human cell to sense andrespond to different types of genotoxic stress (e.g. solar UV rays or toxic chemicals).

Susan L. LOONGAssociate InvestigatorFRCP (Edinburgh)FRCR (Clinical Oncology)MD (Edinburgh)[email protected]

Research StaffRajamanickam BASKAR (M.Sc., M.Phil., Ph.D.)Seow Fong YAP (PhD)Cynthia S.K. BOO (BSc)

Deregulation of GMN, arising from mutations in the genes encoding key network-mediating proteins,

constitutes a common thread in the origin of genomic instability. This is now widely held as the initiating

and rate-limiting event in many forms of malignant growth.

Human radiosensitive syndromes have also been linked to many genes that mediate the repair of various

DNA lesions. Examples of these syndromes include Fanconi Anemia, Ataxia Telangiectasia, Nijmegen

Breakage Syndrome, LIG4 syndrome and RS-SCID. The genes mutated in the latter syndromes are all

involved in the response to and repair of DNA double strand breaks (DSBs).

The primary focuses of research in our laboratory are on undertaking a series of hypothesis-driven,

mechanistic studies into various components of GMN, which include follow-up investigations into our

recent findings that:

1. ATM, the serine-threonine protein kinase mutated in the rare cancer-prone and radiotherapy-sensitive

syndrome ataxia telangiectasia (A-T), operates as a molecular switch for integrating calcium signaling

and stress-response pathways (e.g. S-phase checkpoint in which DNA replication is transiently

arrested in response to -radiation);

2. Treatment of cultured skin cells derived from A-T patients with the eicosanoid prostaglandin E2

(PGE2) corrects the inability of these ATM- deficient cells to undergo S-phase checkpoint after

-irradiation. This surprising finding implies that PGE2 can act as an extracellular signaling molecule

in -ray-damaged A-T cells, inducing DNA synthesis shutdown via an alternative, ATM-independent

signal transduction pathway;

3. The SWI/SNF chromatin remodeling complexes are known to mediate the repair of DNA double-

strand breaks (DSB) in -irradiated human cells; similarly, activation of ATM protein kinase is crucial

to efficient DSB repair and our preliminary data suggests that the SWI/SNF complexes interact

closely with activated ATM in response to DSB, triggering multiple signaling cascades culminating

in both DSB repair and checkpoint control to arrest cell cycle progression until repair processes have

run their course;

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4. Cell lines from adult cancer patients with untoward responses to standard

courses of ionising radiation (IR) have impaired fast component of IR

induced DNA DSBs (D-NHEJ) and this is associated in vitro with increased

but error prone DNA end-joining. Since D-NHEJ is associated with the

pathway of DNA-DSBs carried out by the DNA-PK heterotrimer complex,

research is currently focused on the protein-protein interplay of the known

interacting proteins.

DNA Damage

Transcription DNA RepairApoptosisCell CycleControl

STOP R.I.P

DNA damage response pathways

Figure 1: DNA Damage response pathways.


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Wee JT, Ha TC, Loong SL, Qian CNIs nasopharyngeal cancer really a"Cantonese cancer"?.Chinese J. of Cancer (2010) 29(5): 517-26.

Baskar REmerging role of radiation inducedbystander effects: Cell communicationsand carcinogenesis.Genome Integrity (2010) 1(1):13.

Gurung RL, Lim SN, Khaw AK, Soon JF,Shenoy K, Mohamed Ali S, Jayapal M,Sethu S, Baskar R, Hande MPThymoquinone induces telomereshortening, DNA damage and apoptosisin human glioblastoma cells.PLoS One (2010) 5(8):e12124.

Loong SL, Hwang JS, Li HH, Wee JT,Yap SP, Chua ML, Fong KW, Tan TWWeak expression of cyclooxygenase-2 isassociated with poorer outcome inendemic nasopharyngeal carcinoma:analysis of data from randomized trialbetween radiation alone versus concurrentchemo-radiation (SQNP-01).Radiat. Oncol. (2009) 4:23.

Baskar R, Hande MPA comparative study of protein kinase C

Loong SL, Hwang JS, Lim ST, Yap SP,Tao M, Chong TW, Tan LH, Huynh HAn Epstein-Barr virus positive natural killerlymphoma xenograft derived for drugtesting.Leukemia Lymphoma (2008) 49(6):1161-7.

Tan WM, Paterson MC, Koo GC, Li HH,Price A, Loong SLIncreased but error-prone nonhomologousend joining in immortalized lymphoblastoidcell extracts from adult cancer patientswith late radionecrosis.Int. J. Radiat. Oncol. Biol. Phys. (2008)72(1):178-85.

Baskar R, Moore PKNuclear accumulation and up regulationof p53 and its associated proteins afterH(2)S treatment in human lung fibroblasts.J. Cell. Mol. Med. (2008) 12: 2297-300.

Baskar R, Balajee AS, Geard CRIsoform-specific activation of proteinkinase c in irradiated human fibroblastsand their bystander cells.Int. J. Biochem. Cell Biol. (2008)40(1):125-34.

Baskar R, Sparatore A, Del Soldato P,Moore PKEffect of S-diclofenac, a novel hydrogensulfide releasing derivative inhibits ratvascular smooth muscle cell proliferation.Eur. J. Pharmacol. (2008) 594(1-3):1-8.

activation in -irradiated proliferating andconfluent human lung fibroblast cells.J. Radiat. Res. (2009) 50(5):415-23.

The Division of Medical Sciences,through clinician-scientist networks,innovates new methods for patient-centred cancer diagnosis, treatmentand prevention.

Division of

MedicalSciences

Clinical Pharmacology Studies

(A) Pharmacogenetics of Irinotecan

Irinotecan is a topoisomerase I inhibitor used in

the treatment of colorectal cancer. It has a complex

pharmacology involving the participation of several

phase I and II drug metabolising enzymes as well

as phase III drug transporters. Two main toxicities

associated with the use of irinotecan include severe

diarrhoea and neutropenia. The occurrence of these

toxicities depends on the presence or absence of

two polymorphic variants in the UGT1A1 gene,

namely, UGT1A1*28 and UGT1A1*6. Our laboratory

has characterised the influence of these UGT1A1

polymorphisms as well as other polymorphisms

across the irinotecan biochemical pathway. Our

findings have recently led to a local drug label change for irinotecan whereby dosage reduction is recommended in

patients homozygous for the UGT1A1*28 or UGT1A1*6 allele. A prospective phase I study involving genotype-directed

dosing of irinotecan is ongoing.

LABORATORY OFCLINICAL PHARMACOLOGY

The Clinical Pharmacology Laboratory is involved in (a) early phase I and II clinicaltrials, and (b) studying the causes and consequences of inherited variations ingenes encoding drug-metabolising enzymes, drug transporters and drug targets.These are either investigator initiated studies or pharmaceutical industry initiatedstudies.

There are often significant differences in the way drugs act in patients belongingto different ethnic populations and these observations may be due to the presenceor absence of specific functional polymorphisms in genes involved in regulatingthe disposition of drugs. The primary objectives of our research activities are toidentify the genetic causes of interindividual or interethnic variability in drugdisposition and translating the basic pharmacogenetic findings into predictiveinformation pertaining to patient response to drugs.

The research approach in our lab includes pharmacokinetic, genetic, molecularbiology and analytical techniques on humans, human tissues, animal models,cloned genes and expressed gene products to analyse drug disposition, genestructure, gene regulation, and allelic variations.

Balram CHOWBAYPrincipal [email protected]

Research StaffPrathap BALASUBRAMANIANXiang Ai CHENSubramaniyan KOILANAnupama MAHAJANRathi RAMASAMYSaminathan RAMASAMYOnkar SINGH

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Core ResearchActivities:

(B) Doxorubicin-Cyclophosphamide (AC) Metabolism and Transport

The combination of doxorubicin and cyclophosphamide is commonly used

in the treatment of breast cancer. Both drugs have a very complex

pharmacology and several drug enzymes and drug transporters are involved

in influencing their pharmacokinetics. Side effects to these drugs may be

due to altered drug disposition in cancer patients. Present research includes

characterising the pharmacogenetic profile across the doxorubicin metabolic

pathways with a focus on newly identified doxorubicin transporter proteins

as well as an understanding of their impact on disposition of doxorubicin in

breast cancer patients receiving adjuvant chemotherapy.

(C) Tamoxifen pharmacogenetics

Tamoxifen (TAM) is a selective estrogen receptor modulator drug that is widely

used in the prevention and treatment of breast cancer. Genetic alterations

in certain CYP-450 enzymes alter the conversion of tamoxifen into its most

active form, endoxifen. Our laboratory is currently investigating the

pharmacogenetics of tamoxifen in Asian breast cancer patients.

(D) Pharmacogenetics of Taxanes

Taxanes (paclitaxel or docetaxel) belong to a class of anti-mitotic

chemotherapeutic agent. They are frequently used in the treatment of a wide

variety of solid tumours such as breast, prostate, ovarian and lung, as well

as less common malignancies of gastric, and head and neck. Our laboratory

is interested in investigating the genetic variations in the genes encoding the

drug metabolism enzymes and transporters across the taxane biochemical

pathway, and their influence on the pharmacokinetics and pharmacodynamics

of taxanes in Asian cancer patients.

(E) Imatinib pharmacogenetics

Imatinib is a tyrosine kinase inhibitor and acts by competitively inhibiting the

ATP binding sites of tyrosine kinases in leukaemic cells. Recent data suggests

that intracellular levels of imatinib are affected by the degree of SLC22A1

expression levels in leukaemic cells in CML patients. The expression levels

of SLC22A1 may be influenced by functional SNPs in the SLC22A1 gene.

Our laboratory is investigating the SNP profile of SLC22A1 gene as well

as other genes across the imatinib biochemical pathway and their impact on

the pharmacokinetics and pharmacodynamics of imatinib in Asian

CML patients.

Sandanaraj E, Lal S, Cheung YB, XiangX, Kong MC, Lee LH, Ooi LL, ChowbayBVKORC1 diplotype-derived dosing modelto explain variability in warfarin doserequirements in Asian patients.Drug Metab. Pharmacokinet. (2009)24(4):365-75.

Zhou SF, Liu JP, Chowbay BPolymorphism of human cytochrome P450enzymes and its clinical impact.Drug Metab. Rev. (2009) 41(2):89-295.

Lal S, Sandanaraj E, Wong ZW, Ang PC,Wong NS, Lee EJ, Chowbay BCBR1 and CBR3 pharmacogenetics andtheir influence on doxorubicin dispositionin Asian breast cancer patients.Cancer Sci. (2008) 99(10):2045-54.

Wang XD, Deng XY, Chen J, Li JL, ChenX, Zhao LZ, Lu Y, Chowbay B, Su QB,Huang M, Zhou SFSingle nucleotide polymorphisms of thepregnane x receptor gene in Han Chineseand a comparison with other ethnicpopulations.Pharmacology (2008) 81(4):350-4.

Sandanaraj E, Selvarajan V, Lal S, OoiLL, Wong ZW, Ang PC, Lee EJ, ChowbayBPXR Pharmacogenetics: Association ofhaplotypes with hepatic CYP3A4 andABCB1 mRNA expression and doxorubicinclearance in Asian breast cancer patients.Clin. Cancer Res. (2008) 14(21):7116-7126.

Lal S, Wong ZW, Sandanaraj E, XiangX, Ang PC, Lee EJ, Chowbay BInfluence of ABCB1 and ABCG2polymorphisms on doxorubicin dispositionin Asian breast cancer patients.Cancer Sci. (2008) 99(4):816-823.

Sandanaraj E, Jada SR, Shu X, Lim R,Lee SC, Zhou Q, Zhou SF, Goh BC,Chowbay BInfluence of UGT1A9 intronic I399C>Tpolymorphism on SN-38 glucuronidationin Asian cancer patients.Pharmacogenomics J. (2008) 8:174-185.

Pharmacokinetics: HPLC quantification ofdrugs metabolites, analysing ADMEparameters and PK-modelling.

Pharmacogenetics: DNA sequencing, SNPdetection and genotyping, Real-time RT-PCR, Taqman genotyping, High Resolutionmelting, miRNA profiling, and reporter-gene assay etc

Pharmacoproteomics: Serum profiling,Biomarker discovery, Immunoblotting,Sandwich-ELISA etc

Bioinformatics: Dosing models, Haplotypeand Tag-SNP analysis, Genotype andphenotype correlation, Transcription factorbinding analysis, pathway network analysisetc



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LABORATORY OFONCOPROTEOMICS

Gastric cancer is a significant public health burden, being the second leadingcause of cancer-related deaths worldwide. Our laboratory aims to reduce gastriccancer mortality and to improve patient outcomes via (1) the discovery of sensitiveand specific protein markers for early disease detection and (2) elucidate themechanism of gastric oncogenesis so that molecularly-directed therapies canbe developed to intercept cancer development and progression.

Mac M.F. HOPrincipal InvestigatorDPhil (Oxon)[email protected]

Research StaffCeline Seow Ching CHUAHuimin CHUASiok Yuen KAM

I. Biomarker Discovery in Gastric Cancer Using Proteomic Approaches

While the incidence of gastric cancer is slowly declining in many developed countries, it is the leading cause of cancer

deaths in many developing countries and in some East Asian countries such as China, Korea, and Japan. Globally, there

are nearly one million new cases of gastric cancer diagnosed every year and more than 700,000 individuals die from

this cancer annually. Its lethality is mainly due to the lack of reliable and clinically acceptable techniques for diagnosing

early-stage gastric cancer (Figure 1). In addition, there are currently no biomarkers of acceptable sensitivity and specificity

for gastric cancer.

The prognosis for late-stage gastric cancers is poor owing to limited treatment options. But when it is detected early,

the 5-year survival for gastric cancer patients exceeds 90%. Thus, we believe that one of the key strategies to reduce

gastric cancer mortality and to improve patient outcomes lies in the discovery of highly specific and sensitive biomarkers

for early disease detection. Informative biomarkers will aid diagnosis and ensure early clinical intervention, thereby

preventing mortality and reducing morbidity.

Figure 1. Examples of advanced gastric carcinoma.

Proteomics is a rapidly emerging field in medical science that has provided key tools for biomarker discovery in cancer

and other human diseases. Proteomics refers to the comprehensive study of all proteins (including their identification,

relative abundance, distribution, function, post-translational modifications, and interactions with other macromolecules)

in a cell or tissue. It aims to correlate the functional diversity of proteins with the physiological status of the cell or tissue.

Systematic proteomic studies are important because proteins perform the main cellular functions that control cell growth,

differentiation, proliferation, and death.

To identify biomarkers for gastric cancer, we are using multiple proteomic approaches (gel-based and gel-free strategies)

to compare the protein profiles of malignant and normal (I) gastric tissues and (II) gastric fluid, to identify differentially

expressed proteins.

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Figure 2. Representative silver-stained two-dimensional electrophoresis gels of proteinsisolated from normal (A) and tumour (B) gastric tissues. Examples of differentiallyexpressed proteins in gastric cancer are highlighted by arrows.

From our gel-based analysis of gastric tissues, we have identified several

differentially expressed proteins in gastric cancer (Figure 2). Some of these

proteins are well-characterised (e.g. heat shock proteins) while others are

novel. For novel proteins, we are conducting further analysis to determine

their biochemical properties and their role, if any, in gastric oncogenesis

(Figure 3).

Figure 3. Immunohistochemical analysis of a candidate biomarker in normal, preneoplastic,and neoplastic gastric tissues to evaluate its utility as a marker for early detection ofgastric cancer.

II. Investigating the Gastric Oncogenesis Pathway

The differentially expressed proteins identified in our biomarker discovery

program may provide insights into the gastric oncogenesis pathway. Using

these proteins as leads, we are reconstructing the gastric oncogenic pathway

by characterising their biochemical properties and identification of their

interacting partners.

For proteins that are novel, we are developing genetically engineered mouse

models to elucidate their function and their role in the pathogenesis of gastric

cancer. These animal models should be useful for dissecting the gastric

oncogenesis pathway and for testing new therapies and drugs.


Zhu X, Rivera A, Golub MS, Peng J, ShaQ, Wu X, Song X, Kumarathasan P, HoM, Redman CM, Lee SChanges in red cell ion transport, reducedintratumoral neovascularization, and somemild motor function abnormalitiesaccompany targeted disruption of theMouse Kell gene (Kel).Am. J. Hematol. (2009) 84(8):492-8.

Kon OL, Yip TT, Ho M, Chan WH, WongWK, Tan SY, Ng WH, Kam SY, Eng AKh,Ho P, Viner R, Ong HS, KumarasingheMPThe distinctive gastric fluid proteome ingastric cancer reveals a multi-biomarkerdiagnostic profile.BMC Med. Genomics (2008) 1:54.

Wenzel K, Zabojszcza J, Carl M, TaubertS, Lass A, Harris CL, Ho M, Schulz H,Hummel O, Hubner N, Osterziel KJ,Spuler SIncreased susceptibility to complementattack due to down-regulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy.J. Immunol. (2005) 175(9):6219-25.

Ho M, Post CM, Donahue LR, Lidov HG,Bronson RT, Goolsby H, Watkins SC,Cox GA, Brown RH JrDisruption of muscle membrane andphenotype divergence in two novel mousemodels of dysferlin deficiency.Hum. Mol. Genet. (2004) 13(18):1999-2010.

Bejaoui K, Uchida Y, Yasuda S, Ho M,Nishijima M, Brown Jr RH, Holleran WM,Hanada KHereditary sensory neuropathy type 1mutations confer dominant negative effectson serine palmitoyltransferase, critical forsphingolipid synthesis.J. Clin. Invest. (2002) 110(9):1301-8.

Ho M, Gallardo E, McKenna-Yasek D,De Luna N, Illa I, Brown RH JrA novel, blood-based diagnostic assay forlimb girdle muscular dystrophy 2B andMiyoshi myopathy.Ann. Neurol. (2002) 51(1):129-33.

Ho M, Amato A, Brown RH JrDysferlinopathies in Structural andMolecular Basis of Skeletal MuscleDiseases.(G. Karpati, ed), pp29-32, ISN NeuropathPress, Basel (2002).

We reasoned that the transformation from normal gastric epithelium to pre-

neoplastic states and eventually to gastric carcinoma will entail a sequence

of molecular and genetic changes that will affect protein expression. Identification

of abnormal protein expression in pre-neoplastic and malignant biological

samples should lead to the discovery of candidate biomarkers for diagnosis,

prognosis, and as therapeutic targets. This study is conducted in collaboration

with the Kon laboratory (Applied Human Genetics), clinicians from the Singapore

General Hospital (General Surgery, Gastroenterology, and Pathology), Union

Hospital (Wuhan, China), and technical specialists from Agilent Technologies

and Applied Biosystems.


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WEE KIM WEE LABORATORY OFSURGICAL ONCOLOGY

Our laboratory aims to individualise cancer therapeutics by integrating basicbiology with translational research in head and neck cancers, and using theappropriate platforms to:

1. Identify and understand the genes or factors involved in the cell-death pathways2. Determine DNA damage response pathways involved in cancer stem cell

biology3. Identify genetic determinants and potential biomarkers that can direct cancer

therapy in future

N Gopalakrishna IYERPrincipal InvestigatorMBBS (Hons), FRCS(Gen), FAMS, PhD (Cambridge)[email protected]

Hiang Khoon TANCo-Investigator,Senior Consultant, Department of Surgical OncologyMBBS (Singapore), FRCS (Edin), [email protected]

Research StaffClaramae CHIAFui Teen CHONGHui Sun LEONGSu-Ghim SIA

In the last few decades, advances in cancer research have highlighted the complexities involved in dealing with cancer.

Cancer progression is an evolving multi-pronged process involving the deregulation of pathways that control cell growth

and cell death. Furthermore, we now know that tumours comprise a heterogeneous group of cells which contain a

subpopulation of highly aggressive cells, which are probably responsible for tumour growth, metastases and resistance

to treatment. A small remnant population is sufficient to repopulate and reconstitute the tumour - the cancer stem cell

hypothesis. An understanding of the pathways involved in cell death and how these confer selective resistance to

conventional methods of killing cancer cells, which utilise chemotherapy and radiotherapy, would be critical to the future

of cancer therapeutics. As these abnormalities may exist in various permutations, it is believed that the future of cancer

therapy is in individualising treatment to the genetic profile of each tumour, in each patient. In our laboratory, we have

taken a three-pronged approach to deal with this issue. The first two involve basic biological techniques aimed at

identifying novel, hitherto uncharacterised pathways that modify cellular response to chemo- and radiotherapy, especially

those deregulated in cancer stem cells. The third is a translational approach, using molecular profiling to identify markers

that predict the behaviour of head and neck cancers under different circumstances.

Factors Involved in the Cell-death Pathways

The eventual aim of chemo- and radiotherapy is to induce death specifically in

cancer cells. Cell death or apoptosis is a well-orchestrated process regulated

by several players, mainly involving the p53 protein. However, it is well known

that the p53 pathway is disrupted in a large majority of cancers. Hence, we aim

to identify and study novel candidates involved in cell death, independent of

p53 function.

In this regard, we have identified KLF5 as an important modulator of cell death,

which appears to function even in the absence of p53, through a protein called

Pim1. Using cellular models we have identified mechanisms through which these proteins function, and use these

pathways to promote cell death in a p53-independent manner. We are currently in the process of testing several inhibitors

of KLF5 and Pim1 and assessing their role as novel chemotherapeutic agents.

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Tan HK, Saulnier P, Auperin A, LacroixL, Casiraghi O, Janot F, Fouret P,Temam SQuantitative methylation analyses ofresection margins predict local recurrencesand disease-specific deaths in patientswith head and neck squamous cellcarcinomas.Br. J. Cancer (2008) 99(2):357-63.

Zhao Y, Hamza MS, Leong HS, Lim CB,Pan YF, Cheung E, Soo KC, Iyer NGKruppel-like factor 5 modulates p53-independent apoptosis through Pim1survival kinase in cancer cells.Oncogene (2008) 27(1):1-8.

Iyer NG, Xian J, Chin SF, Bannister AJ,Daigo Y, Aparicio S, Kouzarides T,Caldas Cp300 is required for orderly G1/S transitionin human cancer cells.Oncogene (2007) 26(1):21-29.

Ahmed AA, Mills AD, Ibrahim AE,Temple J, Blenkiron C, Vias M, MassieCE, Iyer NG, McGeoch A, Crawford R,Nicke B, Downward J, Swanton C, BellSD, Earl HM, Laskey RA, Caldas C,Brenton JDThe Extracellular Matrix Protein TGFBIInduces Microtubule Stabilization andSensitizes Ovarian Cancers to Paclitaxel.Cancer Cell (2007) 12(6):514-527.

Bundyc JG*, Iyer NG*, Gentile M, HuDE, Kettunen M, Maia AT, Caldas C,Brindle KMMetabolic consequences of p300 genedeletion in human colon cancer cells.Cancer Res. (2006) 66(15):7606-7614.

Iyer NG, Chin SF, Ozdag H, Daigo Y, HuDE, Cariati M, Brindle K, Aparicio S,Caldas Cp300 regulates p53-dependent apoptosisafter DNA damage in colorectal cancercells by modulation of PUMA/p21 levels.Proc. Natl. Acad. Sci. (2004)101(19):7386-7391.

*Co-first author.

Head and Neck Cancer Stem Cells

It is believed that all tumours have small subpopulation of cells, which havean aggressive phenotype, and are able to withstand the damage induced bychemotherapy and radiotherapy. This population is called cancer stem cells,and it is the survival of these cells after conventional therapy that results inrecurrent disease and distant metastasis. We have optimised a number oftechniques to isolate these cells. Early experiments also show that these areresistant to radiotherapy and chemotherapy, and continue to proliferate despitethe effects of these treatment modalities. We are currently in the process ofelucidating the mechanisms through which these cells evade death, andwhether any of these pathways are amenable to targeting by available ornovel compounds.

Molecular Profiling of Head and Neck Cancers

Head and neck cancers (HNCs) pose a significant world-wide public-healththreat, branded with one of the lowest survival rates with fewer than 50% ofpatients surviving more than five years. Current treatment strategies inmanaging these cancers involve a multimodality approach, with a combinationof surgery, chemo- and radiotherapy. Unfortunately, despite advances indetection and treatment of these cancers, survival rates remain alarminglylow. Furthermore, there is a disturbing trend that the incidence of oral / tonguecancers is increasing in younger age groups in several countries. One of themajor paradoxes apparent in oral cancers is the inexplicable imbalancebetween disease burden and the theoretical ease in decreasing mortality withearly detection. One attractive explanation for this imbalance is that thesecancers are heterogeneous in nature, thus requiring more precise diagnosticand prognostic tools to permit individualised treatment.

Our approach to dissecting the heterogeneity of HNCs is based on severalkey prerequisites that few other institutions can match:

1) Tissue repositories, collecting a spectrum of clinical material2) Clinical databases3) Easy access to technology, which in our case involves established

Affymetrix based microarray profiling techniques and next generationsequencing technology (Solexa)

Using these platforms, we intend to identify genetic determinants and potentialbiomarkers that can direct future therapy. These have been divided in severalwell-established clinical scenarios:1) Recurrence of early oral cancers despite optimum treatment2) Comparing classical oral cancers versus oral cancers in young patients3) Metastatic markers in nasopharyngeal cancers

Data obtained from these studies would be crucial in future prospective studiesto establish these signatures as therapeutic guides or in the discovery of novelpathways involved in HNC carcinogenesis.


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LABORATORY OFAPPLIED HUMAN GENETICS

The Laboratory of Applied Human Genetics focuses on (a) gastric cancer research;and (b) developing cellular therapy for metabolic disorders. The model metabolicdisorders we work on are diabetes mellitus and haemophilia A becausecurrent treatments are sub-optimal, costly or both.

Gastric cancer causes more cancer deaths worldwide (> 700,000 each year) thanall other cancers, except lung cancer, despite good evidence that gastric cancershould be both preventable and curable. Our work aims to translate the curablepotential of gastric cancer into real cures for nearly one million new patientsdiagnosed each year with this lethal cancer. Our research focuses on identifyingmolecular alterations (chromosomes, genome, genes and proteins) that arereliable signatures of gastric cancer. This should enable development of sensitiveand accurate detection methods for highly curable early stage gastric cancerand could provide clues for new treatments for patients whose cancers cannotbe totally eradicated by surgery.

Oi Lian KONPrincipal Investigator & Head, Divisionof Medical SciencesMBBS, FRCPC Diplomate ABIM, [email protected]

Research StaffNelson K.F. CHENTiannan GUOSivalingam JAICHANDRANFrank Myo Lwin KYAWLouise S.S. LEESiew Hong LEONGWai Har NG

Gastric Cancer

As a result of its declining incidence, gastric cancer now accounts for only 10% of all new cancer cases globally. However,this favourable trend has not been matched by increasing cure rates. Gastric cancer thus retains its pole position asthe second most common cause of cancer mortality worldwide. Two-thirds of gastric cancer cases are in the developingcountries and there is a particularly high incidence among East Asians.

Gastric cancer is both preventable and curable. Paradoxically, it continues to be one of the more lethal cancers, havingan overall 5-year survival rate of about 23% that is considerably lower than other common cancers e.g. breast andcolorectal cancer, partly because curative treatments for gastric cancer have been relatively intractable to significantimprovements.

Our efforts are directed at addressing the disparity between the potential and actual curability of gastric cancer.We aim to (a) develop detailed and comprehensive pathway maps of molecular and cellular changes that lead to gastriccancer; (b) identify biomarkers for sensitive and accurate detection of curable early stage gastric cancer; (c)identify and molecularly characterise signature translocations in gastric cancer; and (d) document the activated kinomein gastric cancer as a means of developing targeted therapies to complement surgical resection – currently the onlycurative treatment; (e) search for and characterise candidate tumour-initiating cells. Our lines of serially passageablexenotumours in immunocompromised mice established from surgically resected gastric adenocarcinomas are a resourcein our search for tumour-initiating cells and for testing kinase modulators.

We have discovered a multiprotein profile in endoscopic gastric fluid samples that diagnoses gastric cancer with 93%

specificity and 88% sensitivity (Figure 1). Building on this pilot study, our collaborators are now expanding and refining

the biomarker study to a larger number of subjects in Singapore and China using protein mass spectrometry.

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Guo T, Lee SS, Ng WH, Zhu Y, Gan CS,Zhu J, Wang H, Huang S, Sze SK, KonOLGlobal molecular dysfunctions in gastriccancer revealed by an integrated analysisof the phosphoproteome andtranscriptome.Cellular and Molecular Life Sciences(2010) In Press.

Guo T, Zhu Y, Gan CS, Lee SS, Zhu J,Wang H, Li X, Christensen J, Huang S,Kon OL, Sze SKQuantitative proteomics discloses METexpression in mitochondria as a directtarget of MET kinase inhibitor in cancercells.Molecular & Cellular Proteomics (2010)In Press.

Chen NKF, Tan SY, Udolph G, Kon OLInsulin expressed from endogenouslyactive glucose-responsive EGR1 promoterin bone marrow mesenchymal stromalcells as diabetes therapy.Gene Therapy (2010) 17(5):592-605.

Jaichandran S, Shruti K, Ng WH, LeeSS, Phan TT, Kon OLBiosafety assessment of site-directedtransgene integration in human umbilicalcord-lining cells.Molecular Therapy (2010) 18(7):1346-1356.

Li G, Luo R, Zhang J, Yeo KS, Lian Q,Xie F, Tan EKW, Caille D, Kon OL, Salto-Tellez M, Meda P, Lim SKGenerating mESC-derived insulin-producing cell lines through anintermediate lineage-restricted progenitorline.Stem Cell Research (2008) 2(1):41-55.

Kon OL, Yip TT, Ho M, Chan WH, WongWK, Tan SY, Ng WH, Kam SY, Eng AKH,Ho P, Viner R, Ong HS, KumarasingheMPThe distinctive gastric fluid proteome ingastric cancer reveals a multi-biomarkerdiagnostic profile.BMC Medical Genomics (2008) 1:54.

Guo T, Gan CS, Zhang H, Zhu Y, KonOL, Sze SKHybridization of pulsed-Q dissociation andcollision-activated dissociation in linearion trap mass spectrometer for iTRAQquantitation.J. Proteome Res. (2008) 7(11):4831-4840.

Chen KF, Wong JS, Kee IH, Lai SH, ThngCH, Ng WH, Ng RT, Tan SY, Lee SY,Tan ME, Sivalingam J, Chow PK, KonOLNonvirally modified autologous primaryhepatocytes correct diabetes and preventtarget organ injury in a large preclinicalmodel.PLoS ONE (2008) 3(3):e1734.

Hou Q, Wu YH, Grabsch H, Leong SH,Tang BL, Kon OL, Tan PIntegrative genomic analysis identifiesRAB23 as an invasion mediator geneassociated with diffuse type gasticcarcinoma.Cancer Res. (2008) 68(12): 4623-4630.

Our lab has identified several chromosomal translocations of high frequencyin gastric cancer cell lines. We have found disruptions of chromosome 18qin about 50% of gastric cancer tissues, among which 20% show fusion ofchromosome 18q with chromosomes 6, 8 or 9 (Figure 2). Of interest, we haveobserved a high frequency of chromosome 18q disruptions also in lung cancertissues but not in non-gastric cancers. The lab is now focused on molecularlycharacterising this and other signature chromosome breakpoints and fusionsusing a range of techniques such as chromosome sorting, deep sequencing,bioinformatics and fluorescence in situ hybridization on tissue microarrays.We also collaborate in projects directed at documenting the gastric proteomeand phosphoproteome in particular, as another entree into the molecularpathways of gastric oncogenesis.

Cellular Therapy of Metabolic Disorders

Work from our lab has shown that autologous primary hepatocytes can bemodified to serve as an effective source of insulin secretion in a large pre-clinical model of diabetes. Liver cells were prepared from diabetic Yorkshire-Landrace pigs. After introducing an insulin gene, the modified liver cells wereimmediately re-implanted into the liver of the same pig. This study resultedin significant metabolic improvement of severe diabetes. It also showed thatdiabetes inflicts damage on multiple target tissues within weeks of onset andthat early metabolic correction has significant benefit in this regard (Figure 3).

We have now shown that primary bone marrowstromal cells can be modified to acquireglucose-responsive insulin secretion. Pendingfunds, this approach will be tested in anautologous setting in diabetic Yorkshire-Landrace pigs as proof-of-concept, prior topossible clinical trials.

In other work related to cell therapy, we haveevaluated the biosafety of site-directedtransgene integration using the phiC31integrase system. We are currently assessingthe feasibility of employing zinc finger nucleases for site-specific transgenesisin umbilical cord-lining cells with the goal of developing autologous bioimplantsthat could restore coagulation factor VIII production in hemophilic patients(Figure 4).

Figure 1: Gastric fluid:cancer biomarker profile.

Figure 2: Gastric cancer chromosomaltranslocation.

Figure 4: Secretion ofhuman coagulation factorVIII by primary humanumbilical cord lining cellsstably integrated with thetransgene.

Figure 3: Basement membranethickening of choroidal capillariesin diabetic pigs is corrected bytreatment with autologous insulin-secreting hepatocytes.


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LABORATORY OFMOLECULAR ONCOLOGY

Breast cancer is the most common cancer among women in Singapore, with arising incidence. Our research focuses on the study of breast cancer susceptibilitygenes in our local Asian population, using a comprehensive molecular andbioinformatic strategy. In addition, our group is utilising genetic and genomicapproaches to identify novel cancer related genes for potential application incancer prevention and treatment.

Breast Cancer Susceptibility

Breast cancer is the most common cancer among women in Singapore, with an age-standardised rate of 57.1 per

100,000 per year, which translates to approximately 1,300 new cases being diagnosed each year. The majority of breast

and ovarian cancers are “sporadic” cancers, however, between 5% and 10% of all breast cancer cases are hereditary.

Mutations in two breast cancer susceptibility genes, called BRCA1 and BRCA2, occur in patients with hereditary breast

and ovarian cancer. Women who carry a mutated BRCA1 or BRCA2 gene have a significantly higher risk of developing

breast cancer by age 70, of between 40 to 80%. Recent studies have also implied treatment differences for cancers

developing in such patients. Other genes such as TP53 and PTEN, with an autosomal dominant pattern of inheritance,

may also play a role in patients with hereditary breast cancer, and their contribution can be identified through risk

assessment and genetic testing.

The research goal of our laboratory is to expand on strategies that can improve the detection rate of mutations in breast

cancer susceptibility genes in our local Asian population. We are focussing on discovering genes associated with

susceptibility and developing efficient methods for mutation detection, with the long-term aim of cancer prevention and

early cancer detection.

Ann S.G. LEEPrincipal InvestigatorBSc (Hons), MSc, DPhil (Oxon)[email protected]

Peter ANGVisiting Consultant & AssociateInvestigatorMBBS, MMed (Int Med),MRCP (UK) , FAMS (Med Oncol)[email protected]

Eric YAPAdjunct Principal InvestigatorMBBS (Hons), DPhil (Oxon)[email protected]

Research StaffMaurice CHAN, (PhD)Jia Mei CHUA, BSc(Hons)Joshua WONG, BSc(Hons)Shenmo JI, (DipBiotech)

Figure 1: Schematic diagram showing the 8.46kb Alu-mediated BRCA1 exon 13 duplication. AluSp in intron 12 (grey); AluSq in intron13 (black). (For more details, please refer to Clin. Genet. (2006) 70:80-82)

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(a) Exon 13 duplication with elevated peak.

(b) Result for a normal control.

Research Highlights of our Laboratory

• Our team reported the identification of a BRCA1 founder mutation amongbreast cancer patients of Malay ethnicity (Human Mutation (2003) 22:178.Mutation in Brief #633, 1-8).

• We have developed a comprehensive screening strategy for improvedBRCA1 and BRCA2 mutation screening for breast and/or ovarian cancerpatients. The strategy incorporates the detection of large genomicrearrangements, evaluation of splice site alterations and the computationalevaluation of missense mutations (Clin Genet (2006) 70:80-82; CancerEpidemiol Biomarkers Prev (2007) 16:2276-84; Amino Acids (2008)35:615-26).

• We have recommended that screening for the CHEK2*1100delC mutationin Asian women with a family history of breast cancer is unwarranted,in contrast to recommendations for such screening in Northern or EasternEuropean women with a similar history (J Clin Oncol (2008) 26:2419).

• We have identified the first family in Singapore with Li-Fraumeni syndrome(Clin Genet (2009) 75:294-7).

• We have identified a gene that has tumour suppressive functionalcharacteristics in breast and colorectal cancer (Oncogene (2009) 28:4189-200).

Current Research Interests

Cutting edge technologies for mutation screening and genotyping, such ashigh resolution melting analysis, next generation sequencing and bioinformaticanalysis are currently being employed for the discovery and validation ofnew biomarkers for cancer and to understand the molecular mechanismsof drug resistance in Mycobacterium tuberculosis.

In collaboration with oncologists at our Centre, we are also actively engagedin translational cancer research projects aimed at identifying novel biomarkersfor patient stratification for improving treatment strategies of breast cancerpatients.


Ong DCT, Ho YM, Rudduck C, Chin K,Kuo W-L, Lie DKH, Chua CLM, Tan PH,Eu KW, Seow-Choen F, Wong CY, HongGS, Gray JW, Lee AS*LARG at chromosome 11q23 hasfunctional characteristics of a tumorsuppressor in human breast and colorectalcancer.Oncogene (2009) 28(47):4189-200.

Ang P, Lim IHK, Yong RYY, Lee AS*A molecular approach for identifyingindividuals with Li-Fraumeni Syndromewho have a limited family history.Clin. Genet. (2009) 75(3):294-7.

Lee AS*, Ang PCHEK2*1100delC screening of Asianwomen with a family history of breastcancer is unwarranted.J. Clin. Oncol. (2008) 26(14):2419.

Ang P, Lim IH, Lee TC, Luo JT, Ong DC,Tan PH, Lee AS*BRCA1 and BRCA2 mutations in an Asianclinic-based population detected using acomprehensive detection strategy.Cancer Epidemiol. Biomarkers and Prev.(2007) 16(11):2276-84.

Lai PS, Cheah PY, Kadam P, Chua CL,Lie DK, Li HH, Eu KW, Seow-Choen F,Lee AS*Overexpression of RB1 transcript issignificantly correlated with 13q14 allelicimbalance in colorectal carcinomas.Int. J. Cancer (2006) 119(5):1061-1066.

Toh HC, Teo M, Ong KW, Lee V, ChanE, Lee AS, Vathsala AUse of sirolimus for Epstein-Barr virus-positive smooth-muscle tumour.Lancet Oncol. (2006) 7(11):955-957.

*Corresponding author.


Figure 2: Detection of an exon 13 rearrangement in the BRCA1 gene using multiplexligation-dependent probe amplification (MLPA). Arrows indicate the peak for exon 13in (a) and (b).

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LABORATORY OFLIVER CANCER FUNCTIONAL GENOMICS

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwideand especially so in the Asia Pacific region. Our laboratory’s key research goalis to elucidate the molecular pathway(s) leading to HCC. Using a cDNA microarrayapproach, we have identified several genes that are significantly differentiallyexpressed between the tumour and adjacent normal tissues and are in the processof characterising some of them.

Caroline G.L. LEEPrincipal [email protected]

Joint Appointments:Associate Professor,Department of Biochemistry, NationalUniversity of Singapore

Associate Professor,Duke-NUS Graduate Medical School

Research StaffCheryl CHANWay Champ MAHLizhen LIUJianwei RENPui Hoon SEWSteven Setiawan THENGSu Ting TOHJingBo WANGYu WANGYin Yee WONGJin YU

Clinical AttachmentGrace PANG (MBBS)

I. Functional Genomics of Hepatocellular Carcinoma

Interestingly, we found that cells over-expressing one of these genes escape mitotic arrest and have more variable

chromosome numbers per cell. We hope that this gene or other novel genes identified through cDNA microarray approach

will serve as:

(a) prognostic markers, or

(b) markers to identify individuals who are at

high risk of developing HCC, or identify

(c) markers to identify individuals at high risk

of having recurrence of the tumour in HCC

patients. We also hope that target-specific

therapies can be developed with the

identification of the pathway(s) responsible

for HBV-associated HCC.

Infection by the Hepatitis B virus HBV is

predominant in HCC patients in this part of the world. Hence, we are utilising ultra-high throughput technologies to

fully characterise the HBV DNA, integrants and transcript in Singaporean HBV-associated HCC patients so as to identify

HBV chimeras/variants that may be associated with poor prognosis and help us elucidate their role in tumorigenesis.

Another research focus of our lab is to examine the role that HBx, a protein in HBV, plays in the carcinogenesis process.

As HBx is a known transcriptional coactivator, we are utilising high throughput strategies to identify and characterise

deregulated direct gene targets of HBx from indirect protein-DNA binding as well as transcriptional factors directly

interacting with HBx. We are also examining if HBx can deregulate miRNAs which is often deregulated in HCC patients.

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SUNG W-K, LU Y, LEE WH Charlie,ZHANG D, RONAGHI M, LEE GLCarolineDeregulated Direct Targets of the HepatitisB Viral (HBV) protein, HBx, identifiedthrough chromatin immunoprecipitationand expression microarray profiling.J. Biol. Chem. (2009) 284(33):21941 –21954.

Wang Y, Lee AT, Ma JZ, Wang JB, RenJ, Yang Y, Tantoso E, Li KB, Ooi LL, TanP, Lee CGProfiling microRNA Expression inHepatocellular Carcinoma revealsmicroRNA-224 Upregulation andApoptosis Inhibitor-5 as a microRNA-224-Specific Target.J. Biol. Chem. (2008) 283(19):13205-13215.

Wang Z, Wang J, Tantoso E, Wang B,Tai AY, Ooi LL, Chong SS, Lee CGSignatures of Recent Positive Selectionat the ATP-Binding Cassette (ABC) DrugTransporter Superfamily Gene Loci.Hum. Mol. Genet. (2007) 16(11):1367-1380.

Ren J, Kan A, Leong SH, Ooi LL, JeangKT, Chong SS, Kon OL, Lee CGFat10 plays a role in the regulation ofchromosomal stability.J. Biol. Chem. (2006) 281(16):11413-11421.

Wang Z, Wang B, Tang K, Lee EJ, ChongSS, Lee CGA functional polymorphism within theMRP1 gene locus identified through itsgenomic signature of positive selection.Hum. Mol. Genet. (2005) 14(14):2075-2087.

Lee AT, Ren J, Wong ET, Ban KH, LeeLA, Lee CGThe hepatitis B virus X protein sensitizesHepG2 cells to UV light- induced DNAdamage.J. Biol. Chem. (2005) 280(39): 33525-33535.

II. Human / Pharmaco Genetics

Polymorphisms are known to contribute to variations in disease susceptibility

or drug response. Although millions of polymorphisms have been found in

the human genome, not all of these polymorphisms affect phenotype or are

causally associated with disease risk or drug response. Our laboratory focuses

on identifying potentially functionally significant polymorphisms that may be

useful for disease/drug response association studies. We utilised more than

40 different resources to select a set of potentially functional SNPs (pfSNPs)

database based on their predicted/inferred functional significance as well as

documented disease-association/functional importance. We are validating

our resource for its usefulness in disease/drug response association studies.

Our laboratory is also interested in understanding the architecture and

population distribution of polymorphisms in the human genome. We are

focusing on SNPs that are significantly different amongst different ethnic

groups to evaluate if some of these SNPs may account for the great variation

in drug response / disease susceptibility amongst different ethnic groups.


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TAN CHIN TUAN LABORATORY OF OPTICAL IMAGINGAND PHOTODYNAMIC THERAPY OF CANCER

We are the pioneers in clinical applications of fluorescence diagnosis andphotodynamic therapy (PDT) in Singapore. The focus of this laboratory is toinvestigate minimally invasive methods in cancer detection and therapy usingbiophotonics applications and nano-biotechnology for oral and bladder cancers.The novel optical methods being investigated are fluorescence endomicroscopy,surface enhanced Raman spectroscopy (SERS), optical imaging of nanogoldconjugated biomarkers as contrast agents in optical coherence tomography(OCT) and reflectance spectroscopy. PDT is a promising alternative cancertreatment modality that is known to be able to activate the body’s anti-tumourimmunity. The laboratory is investigating the treatment of head and neck andbladder cancers using new generation photosensitisers.

Early Cancer Detection Using Optical Imaging Techniques

We have a multidisciplinary, highly interactive research environment comprising clinicians, physicists, biologists, chemists,

pharmacists and computer engineers. We are currently employing optical imaging techniques to investigate bladder and

oral cancers. Our major objective is to devise real-time optical imaging systems. We are also implementing fluorescence

and autofluorescence image processing software and endomicroscopic approaches to develop an optical biopsy

technique to stage cancer (Figure 1). This may prove to be a superior method to the current widely used white light

endoscopy. We are exploring the use of nanotechnology in combination with biophotonics for molecular imaging for

early cancer detection. Nanoparticles combined with biomakers would be used as contrast agents in novel optical

coherence tomography and reflectance based imaging. We also focus on SERS-based nanophotonics of biofluids of

proteins and aptamers for early cancer detection. Our ex-vivo methods in fluorescence based cytology of urine and

saliva combines the use of multiphoton confocal microscopy and fluorescence lifetime imaging to grade cancer

histopathologically. We are currently developing sensitive biocompatible SERS nanotags for in-vivo sensing and imaging

of head and neck cancers. We have also successfully developed quantum dot capped magnetite nanorings as high

performance nanoprobe for multiphoton fluorescence and magnetic resonance imaging (Figure 2). Terahertz Time-domain

spectroscopy (THz -TDS) technology is being tested for early-stage cancer diagnosis. A catheter-based OCT probe for

a 3D volumetric diagnosis of cancer by incorporating microelectromechanical systems (MEMS) technology to OCT.

Khee Chee SOOPrincipal Investigator& Director,National Cancer Centre SingaporeMBBS, MD, FRACS, FACS, [email protected]

Malini Carolene OLIVOCo-Principal InvestigatorBSc, BEd (Hon), [email protected]

Research StaffNagamani DENDUKURI (PhD)Kiang Wei KHO (PhD)Patricia S.P. THONG (PhD)Bhuvaneswari RAMASWAMYLucky SASIDHARANChuan Sia TEE

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Bhuvaneswari R, Thong PS, Gan YY,Soo KC, Olivo MEvaluation of hypericin-mediatedphotodynamic therapy in combination withangiogenesis inhibitor bevacizumab usingin vivo fluorescence confocalendomicroscopy.J. Biomed Opt. (2010) 15(1): 011114.

Chin WW, Praveen T, Heng PW, OlivoMEffect of polyvinylpyrrolidone on theinteraction of chlorin e6 with plasmaproteins and its subcellular localization.Eur. J. Pharm. Biopharm. (2010)76(2):245-252.

Thong PS, Olivo M, Chin WW,Bhuvaneswari R, Mancer K, Soo KCClinical application of fluorescenceendoscopic imaging using hypericin forthe diagnosis of human oral cavity lesions.Br. J. Cancer (2009) 101(9):1580-1584.

Bhuvaneswari R, Gan YY, Soo KC, OlivoMTargeting EGFR with photodynamictherapy in combination with Erbituxenhances in vivo bladder tumour response.Mol. Cancer (2009) 8:94.

Chin WW, Thong PS, Bhuvaneswari R,Soo KC, Heng PW, Olivo MIn-vivo optical detection of cancer usingchlorin e6--polyvinylpyrrolidone inducedfluorescence imaging and spectroscopy.BMC Med. Imaging (2009) 9:1.

Kho KW, Qing ZM, Shen ZX, Ahmad IB,Lim SS, Mhaisalkar S, White TJ, WattF, Soo KC, Olivo MPolymer-based microfluidics withsurfaceenhanced Raman-spectroscopy-active periodic metal nanostructures forbiofluid analysis.J. Biomed. Opt. (2008) 13(5):054026.

Thong PS, Ong KW, Goh NS, Kho KW,Manivasager V, Bhuvaneswari R, Olivo,M, Soo KCPhotodynamic Therapy-Activated ImmuneResponse Against Distant UntreatedLesions In Recurrent Angiosarcoma.Lancet Oncol. (2007) 8(10):950-952.

Kho KW, Shen ZX, Lei Z, Watt F, SooKC, Olivo MInvestigation into a surface plasmon relatedheating effect in surface enhanced Ramanspectroscopy.Anal. Chem. (2007) 79(23):8870-8882.

Kah JC, Kho KW, Lee CG, Sheppard R,Shen ZX, Soo KC, Olivo MEarly Diagnosis of Oral Cancer based onthe Surface Plasmon Resonance of GoldNanoparticle. Int. J. Nanomed. (2007)2(4):785-798.

Photodynamic Therapy Using New GenerationPhotosensitisers and their Formulations

In the area of cancer therapy we are investigating the novel use of photosensitiser

and light to treat cancer as an alternative modality in inoperable cancers. Our

aim is to develop novel nano-photosensitisers for clinical application in head

and neck and bladder cancers. By studying the photobiology of these novel

compounds in terms of its mechanism of action in both cellular (apoptosis

and necrosis) and vascular modes, we strive to better understand the tumour

response to PDT. Combination treatment modalities with immunotherapy and

anti-angiogenesis therapy to enhance the efficacy of PDT are also being

investigated. In the area of photobiology, we aim to develop virosomes (a

reconstituted virus envelope) as targeted delivery vehicles of a chlorin based

photosensitiser (Ce6) using a monoclonal antibody as a molecular specific

contrast agent targeted against EGFR for in vivo assessment of oral cancer

(Figure 3). During our pilot clinical trial using PDT for treatment of recurrent

angiosarcoma, we have observed PDT-induced anti-tumour immunity against

both treated and untreated distant tumours (Figure 4). We hypothesized that

PDT can activate a cell-mediated immune response against untreated tumours.

This was supported by immunohistochemistry of biopsies from a lesion

showing a shift from CD4+ to CD8+ dominance in the T lymphocyte infiltrate.

In conclusion, PDT is a promising alternative modality for cancer therapy and

is suitable for use in lesions that are accessible to an endoscope. PDT also

offers good cosmetic results with excellent normal tissue regeneration and

minimal systemic toxicity.

Figure 1 . Rea l- t ime measurement ofmicrostructures and reconstruction of optical slicesstack to achieve 3D visualization using confocalendomicroscopy of mouse tongue.

Figure 2. Representative two-photonfluorescence image (756 nm excitation)of the stained bladder cancer cellswith (a) yellow- and (b) red-coloredinternalized quantum dots (QDs)capped magnet i te nanor ings.

Figure 3. Virosome as a targeted delivery vehicle of aphotosensitiser using a monoclonal antibody and goldnanoparticle as a molecular-specific contrast agenttargeted against EGFR for in vivo assessment ofepithelial neoplasia.

Figure 4. Angiosarcoma on upper limbs (a) main cluster before PDT on right upper limb,(b) scarring at site treated with PDT and spontaneous regression of untreated tumourson right upper limb 18 months after treatment, (c) tumours on left upper limb beforePDT, (d) spontaneous regression of untreated tumours on left upper limb 4 months afterPDT.


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LABORATORY OFCELL THERAPY AND CANCER VACCINE

Our laboratory’s main focus is on bench-to-bedside translational research intoimmune-based cancer therapies. The immune system identifies and destroysforeign antigens by discriminating ‘self’ from ‘non-self’ antigens. Although cancercells originate from patients’ own cells, they may be recognised as foreign andattacked by the immune system due to expression of tumour-associated antigensthat are not normally expressed by normal cells. We believe that immunotherapyhas the potential to develop into a relevant therapeutic option and may offerpotential benefits to cancer patients. Thus, we have developed clinical cell-basedimmunotherapeutic strategies including nonmyeloablative blood stem celltransplantation, dendritic cell cancer vaccines and T cell therapies for solidtumours.

Han Chong TOHPrincipal InvestigatorBSc, MBBChir, MRCP, FRCP, [email protected]

Research StaffMarissa TEO (PhD)Peter Who-Whong WANG (PhD)Chit Lai CHEELip Seng KOHJoanna Hui Ting NGYatanar SOEElizabeth Yoke Yoke YEO

Our first cell therapy clinical trial was a non-myeloablative blood stem cell transplantation +/- delayed donor lymphocyte

infusion therapy for twenty-one refractory Stage IV nasopharyngeal carcinoma (NPC) patients. NPC is an Epstein-Barr

virus (EBV)-associated cancer endemic in southern China and South-East Asia. 37% of patients evaluated achieved

significant tumour shrinkage (partial response, PR) and 16% achieved stable disease (SD), for an overall disease control

rate of 53%, with evidence for delayed graft-versus-tumour responses.

In collaboration with Dandrit Biotech A/S, we completed a Phase II clinical trial of an allogeneic lysate-pulsed autologous

dendritic cell (DC) cancer vaccine (MelCancerVac®) in twenty advanced colorectal cancer patients. The study was

initiated in January 2006 and completed in October 2008. Our results showed a clinical benefit rate of 40% (1 PR and

7 SD), with some patients achieving prolonged disease control.

In partnership with the Center for Cell and Gene Therapy (CAGT), Baylor College of Medicine, Houston, Texas, USA,

we conducted a DC vaccine clinical trial to treat advanced refractory NPC patients. We vaccinated NPC patients with

DCs transduced with a replication-deficient Ad5f35 adenoviral vector encoding LMP-1 and LMP-2, two EBV genes

expressed by NPC. Sixteen patients received a combination treatment of this DC vaccine plus celecoxib, a non-steroidal

anti-inflammatory drug that exhibits anti-inflammatory, analgesic, antipyretic and anti-angiogenesis activities. Two patients

(12.5%) achieved disease stabilisation for more than 18 weeks and one patient achieved PR, leading to an overall clinical

benefit rate of 19%, and the treatment was very well tolerated overall.

We have recently initiated another cell-based translational program for treating NPC patients, using adoptive EBV-

specific T cell therapy. Autologous EBV-specific cytotoxic T cells in these patients are reactivated and expanded ex vivo

from peripheral blood mononuclear cells. This is achieved through repeated stimulation with EBV-transformed autologous

lymphoblastoid cell lines (LCL). Previous adoptive CTL studies in a small number of NPC patients had yielded clinical

benefits and had been well tolerated. This clinical trial is currently ongoing.

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Figure 2: Colonies of proliferating EBV-specific T cells in culture.


Toh HC, Chia WK, Sun L, Thng CH, SoeY, Phoon YP, Yap SP, Lim WT, Tai WM,Hee SW, Tan SH, Leong SS, Tan EHGraft-vs-tumor effect in patients withadvanced nasopharyngeal cancer treatedwith nonmyeloablative allogeneic PBSCtransplantation.Bone Marrow Transplant (2010) Epubahead of print.

Chew V, Tow C, Teo M, Wong HL, ChanJ, Gehring A, Loh M, Bolze A, Quek R,Lee VK, Lee KH, Abastado JP, Toh HC,Nardin AInflammatory tumour microenvironment isassociated with superior survival inhepatocellular carcinoma patients.J. Hepatol. (2010) 52(3):370-9.

Toh HC, Wang WW, Chia WK, KvistborgP, Sun L, Teo K, Phoon YP, Soe Y, TanSH, Hee SW, Foo KF, Ong S, Koo WH,Zocca MB, Claesson MHClinical benefit of allogeneic melanomacell lysate-pulsed autologous dendriticcell vaccine in MAGE-positive colorectalcancer patients.Clin. Cancer Res. (2009) 15(24):7726-36.

Kvistborg P, Bechmann CM, PedersenAW, Toh HC, Claesson MH, Zocca MBComparison of monocyte-derived dendriticcells from colorectal cancer patients, non-small-cell-lung-cancer patients and healthydonors.Vaccine (2009) 28(2):542-7.

Ong KW, Teo M, Lee V, Ong D, Lee A,Tan CS, Vathsala A, Toh HC.Expression of EBV latent antigens,mammalian target of rapamycin, and tumorsuppression genes in EBV-positive smoothmuscle tumors: clinical and therapeuticimplications.Clin. Cancer Res. (2009) 15(17):5350-8.

Toh HC, Sun L, Soe Y, Wu Y, Phoon YP,Chia WK, Wu J, Wong KY, Tan P.G-CSF induces a potentially tolerant geneand immunophenotype profile in T cellsin vivo.Clin. Immunol. (2009) 132(1):83-92.

Toh HC, Teo M, Ong KW, Lee V, ChanE, Lee AS, Vathsala AUse of sirolimus for Epstein-Barr virus-positive smooth-muscle tumour.Lancet Oncol. (2006) 7(11):955-7.

You Z, Huang X, Hester J, Toh HC, ChenSYTargeting dendritic cells to enhance DNAvaccine potency.Cancer Res. (2001) 61(9):3704-11.

Our laboratory is also collaborating with the Department of Renal Medicine

at the Singapore General Hospital, to study the molecular characteristics of

a rare EBV-related cancer, EBV+ smooth muscle tumour.

We are also involved in hepatocellular carcinoma (HCC) translational research.

We have carried out various studies to investigate prognostic markers of

HCC, both in the intrinsic tumour (seed) and the surrounding microenvironment

(soil). We have established a prognostic role for FOXP3+ regulatory T cells

in patients with resected HCC as a determinant of overall survival. Other

studies involving analysing various immunologic parameters and molecular

biomarkers in HCC are ongoing. We are currently further investigating a gene,

FOXO3a, a Forkhead box O transcription factor, which we have also established

as a prognostic survival marker in this cancer and is part of the

AKT/FOXO3a/Pml signaling pathway. We have also established the gene

IL12RB1 as a potential prognostic marker in resected HCC and analysed Treg

and Th17-related markers in a series of HCC patients. One of our ongoing

HCC projects is to study the immune-based signatures in the HCC

microenvironment.

Figure 1: Dendritic cells generated in culture. Cells shown in this figure areready for harvest and used as cancer vaccine.


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BRAIN TUMOUR RESEARCHLABORATORY

In translational research, we seek to develop insights into brain tumour biologyand novel treatment strategies. Our laboratory has developed in vitro and in vivorodent pathologic and MRI brain tumour models, local patient brain tumour celllines from specimens resected by our neurosurgery colleagues and gene therapyincorporating anti-angiogenic, pro-apoptotic, antisense and stem cell approaches.Our strategy is “from the operating theatre, clinic to research bench” cohesion,marrying basic science with clinical brain tumour problems. Our two areas ofresearch focus are:

1. Molecular pharmacological studies of glioma chemotherapy2. Cancer stem cells in the brain

Meng Cheong WONGPrincipal InvestigatorMBBS, MMed, MRCP, Dip. Amer. Bd.Neur., FRCP, FAMS, [email protected]

Research StaffKhong Bee KANG (PhD)Congju ZHU (PhD)Ian Bolun ZHAO (MSc)Eugene Y M TAN (BSc, Hon)Kareen Y L WONG

Molecular Pharmacological Studies of Glioma Chemotherapy

Gliomas are among the most chemo-resistant types of human cancers. Chemotherapeutic drugs, such as alkylating

agents, kill tumour cells through interrupting DNA replication. Tumour cell DNA repair and cell survival capacities are

major factors determining chemosensitivity.

Our team works on two important pathways of DNA damage induced cell signaling:

I. Chemotherapy-induced tumour cell response. Temozolomide (TMZ) is a key-methylating agent for treatment of gliomas

and DNA repair (including mismatch repair, DNA double strand break repair etc.) that plays a vital role in mediating TMZ

cytotoxicity. Gliomas often have a deregulated cell growth and survival signalling, which significantly confer chemoresistance

to TMZ.

By using quiescent and proliferating glioma cell models, we are investigating the interaction of DNA repair and cell

growth / survival signalling in glioma chemoresistance. We strive to improve tumour cell killing by harnessing novel

mechanisms of DNA damage-induced type II program cell death (autophagy).

II. Epithelial cell transforming sequence 2 (ECT2) and cell growth control. ECT2 is an oncoprotein, which transforms

fibroblast cells following N-terminal truncation. ECT2 is overexpressed in gliomas, and it has been proposed as a

potential prognostic marker for glioma tumours. We have found that ECT2 has novel functions in G1-phase cell growth

and cell cycle progression.

Currently, we are defining the role of ECT2 in G1/S cell cycle transition and oncogenic cell growth, which contain critical

cellular signaling events underpinning glioma malignancy and chemosensitivity. Our study of ECT2 will contribute to

the understanding of glioma pathology and the improvement of glioma chemosensitivity.

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Wong MC, Zhu CJ, Cheng SYModulators of cell cycle progression.US Provisional Patent (No. 61/263,620)(2009)

Kang KB, Zhu C, Yong SK, Gao Q, WongMCEnhanced sensitivity of celecoxib in humanglioblastoma cells: Induction of DNAdamage leading to p53-dependent G1 cellcycle arrest and autophagy.Mol. Cancer (2009) 8:66-81.

Kang KB, Wang TT, Woon CT, CheahES, Moore XL, Zhu CJ, Wong MCEnhancement of glioblastomaradioresponse by a selective COX-2inhibitor celecoxib: Inhibition of tumourangiogenesis with extensive tumournecrosis.Int. J. Radiat. Oncol. Biol. Phys. (2007)67(3): 888-896.

Ty AU, See SJ, Rao JP, Khoo JB, WongMCOligodendroglial tumour chemotherapyusing “decreased-dose-intensity” PCV: aSingapore experience.Neurology (2006) 66(2):247-249.

Moore XL, Lu J, Sun L, Zhu CJ, Tan P,Wong MCEndothelial progenitor cells “homing”specificity to brain tumours.Gene Ther. (2004) 11(10):811-818.

Zhu CJ, Li YB, Wong MCExpression of antisense bcl-2 cDNAabolishes tumorigenicity and enhanceschemosensitivity of human malignantglioma cells.J. Neurosci. Res. (2003) 74(1):60-66.

Zhu CJ, Cheng SY, Teng SW, MooreXL, Wong MCTemozolomide induces a network signalingof DNA repair in human malignant gliomacells.Eur. J. Biochem. (2003) 270(suppl):140.

Wu M, Das A, Tan Y, Zhu CJ, Cui T,Wong MCInduction of apoptosis in glioma cell linesby TRAIL/Apo-2l.J. Neurosci. Res. (2000) 61(4): 464-470.

Cancer Stem Cells in the Brain

Accumulating evidence has implicated cancer as a disease of stem cells.

In this context, a small fraction of cancer cells adopt the properties of stem

cells such as unlimited self-renewal, contributing to tumourigenesis.

Our lab has established several techniques necessary for isolation of clonal

Brain Tumour Stem Cells (BTSCs). We have successfully isolated and

characterised cancer stem cells from our patients’ primary glioma brain

tumours and shown their enhanced DNA repair capacity, as well as enhanced

resistance to radiation and chemotherapy.

Our study of these important BTSCs will seek to identify novel targets for

improved cancer treatment so as to overcome chemo-radioresistance, the

primary current cause of brain tumour relapse and recurrence.

Conclusion

The Brain Tumour Research Laboratory works closely with clinicians, including

neuro-oncologists, neurosurgeons, radiation oncologists and other colleagues

to improve molecular and cellular characterisation of brain tumours in our

local population, and to improve chemotherapy and biological based therapies

(e.g. receptor tyrosine kinase inhibition, immunotherapeutic) in our clinic.

We believe that scientific advancement is an integral part of improving survival

and quality of life for our brain tumour patients.

Figure 1: MRI brain scans – malignant glioma.

Left: Pre-chemotherapyRight: Post-chemotherapy

Figure 2: Growth of primary culture from brain tumour tissues as neurospheres(left) and differentiated glioma cells (right).

Figure 3:Immunofuorescencestaining of neurospheresa n d d i f f e re n t i a t e dprogenies.


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NATIONAL CANCER CENTRE SINGAPORE –VAN ANDEL RESEARCH INSTITUTE TRANSLATIONALRESEARCH LABORATORY

Bin Tean TEHPrincipal InvestigatorMD, [email protected]

Research StaffAnna H.H GANDachuan HUANGGhee Chong KOOLian Dee LERSwe Swe MYINTChoon Kiat ONGPauline ONGChao-Nan(Miles) QIANEe Yan SIEWHwei Ling TANBernice WONGWillie S.S YU

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The NCCS-VARI translational research laboratory has several functions.Scientifically, it focuses on genomic profiling of Asian cancers using cutting-edgetechnologies such as third-generation sequencing – the data is then correlatedwith clinicopathological information including how patients respond to certaindrugs. The goals are to 1) understand the molecular mechanism underlying thesecancers; 2) to identify novel biomarkers than can help determine the nature andbehavior of the disease as well as predicting patients’ response to certain drugs;and 3) to identify novel therapeutic targets that can be further developed intocancer drugs. In collaboration with practicing oncologists, the group is conductingresearch to understand the mechanisms of certain drug resistance that havebeen used in treating certain cancer types.

The group has hosted and trained clinician scientists, both locally and abroad,who are interested in pursuing translational research. To date, the laboratory hasbeen instrumental in establishing several cancer type-based translational researchgroups at the National Cancer Center Singapore including lymphoma, sarcoma,head and neck cancer, kidney cancer, and peritoneal cancer. The group alwaysemphasizes on collaboration (both local and international) which is key to scientificbreakthroughs.

The laboratory focuses on translational research of different cancer types. Examples of these works are illustrated below

which illustrate the importance in working closely with practicing oncologists to correlate molecular, cellular, functional

studies with clinic-pathological and follow-up information. The close collaboration between scientists and clinicians

working in synergy will ensure an efficient process in facilitating breakthroughs and translating these discoveries into

clinical applications. In addition, the group forms close and extensive collaboration with local and international groups,

as well as with pharmaceuticals and biotechs.


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Varela I, Tarpey P, Raine K, Huang D,Ong CK, Stephens P, Davies H, JonesD, Lin M-L, Teague J, Bignell G, ButlerA, Cho J, Dalgliesh GL, GalappaththigeD, Greenman C, Hardy C, Jia M, LatimerC, Lau KW, Marshall J, McLaren S,Menzies A, Mudie L, Stebbings L,Richard S, Kahnoski RJ, Anema J,Tuveson D, Perez-Mancera P, MustonenV, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K,Campbell PJ, Teh BT, Stratton MR,Futreal PAExome sequencing identifies frequentmutation of the SWI/SNF complex gene,PBRM1, in renal carcinoma.Nature (2010) In press (co-corresponding author).

Tan S-Y, Ooi A-S, Ang M-K, Koh M,Wong J-C, Dykema K, Ngeow J, LoongS, Gatter K, Tan L, Lim L-C, Furge K,Tao M, Lim S-T, Loong F, Cheah PL, TehBTNuclear expression of MATK is a novelmarker of type II enteropathy associatedT-cell lymphoma.Leukemia (2010) In press.

Furge KA, Mackeigan JP, Teh BT Kinase targets in renal-cell carcinomas:reassessing the old and discovering thenew.Lancet Oncol. (2010) 11(6):571-578.

Dalgliesh GL, Furge K, Greenman C,Chen L, Bigness G, Butler A, Davies H,Edkins S, Hardy C, Latimer C, TeagueJ, Andrews J, Barthorpe S, Beare D,Buck G, Campbell PJ, Forbes S, Jia M,Jones D, Knott H, Kok CY, Lau KW,Leroy C, Lin ML, McBride DJ, MaddisonM, Maguire S, McLay K, Menzies A,Mironenko T, Mulderrig L, Mudie L,O’Meara S, Pleasance E, RajasinghamA, Shepherd R, Smith R, Stebbings L,Stephens P, Tang G, Tarpey PS, TurrellK, Dykema KJ, Khoo SK, Petillo D,Wondergem B, Anema J, Kahnoski RJ,Teh BT, Stratton MR, Futreal PASystematic sequencing of renal carcinomareveals inactivation of histone modifyinggenes.Nature (2010) 463(7279):360–363 (co-corresponding author).

Huang D, Ding Y, Li Y, Luo WM, ZhangZF, Snider J, Vandenbeldt K, Qian CN,Teh BTSunitinib acts primarily on tumorendothelium rather than tumor cells toinhibit the growth of renal cell carcinoma.Cancer Research (2010)70(3):1053–1062.

Huang D, Ding Y, Zhou M, Rini BI, PetilloD, Qian CN, Kahnoski R, Futreal PA,Furge KA, Teh BTInterleukin-8 mediates resistance toantiangiogenic agent sunitinib in renal cellcarcinoma.Cancer Research (2010)70(3):1063–1071.

Kidney Cancer

Through molecular profiling, several potential therapeutic targets in differenttypes of kidney cancer have been identified (Furge et al., Lancet Oncol,2010). Very recently, collaboration with the Cancer Genome Program of theSanger Institute, UK, and the Van Andel Research Institute, USA, has led tothe identification of the SWI/SNF chromatin remodeling complex gene PBRM1as a second major gene in the most common type of kidney cancer (i.e.,clear cell renal cell carcinoma), with truncating mutations in 41% (92/227)of cases (Varela I et al., Nature, in press). These findings, together with ourprevious report on the identification of a group of histone modifiers (UTX,JARID1C and SETD2) being mutated in the same cancer (Dalgliesh GL etal., Nature, 2010) further confirm the important role of chromatin remodelingenzymes in ccRCC. These data further elucidate the somatic geneticarchitecture of ccRCC and emphasize the marked contribution of aberrantchromatin biology. Further molecular and cellular studies are underway toelucidate the mechanistic roles these ccRCC genes play in the tumorigenesisof ccRCC.

Our group at the Van Andel Research Institute has recently published studieshow a popular drug, sunitinib, acts on renal cell carcinoma (Huang D et al.,Cancer Res, 2010) and why a significant number of patients develop resistanceafter a period of usage (Huang D et al., Cancer Res, 2010). The group iscurrently testing the effects of several novel drugs to establish their effectsin overcoming this resistance. In addition, the group continues to explorethe molecular mechanism of drug resistance in kidney cancer.

Bile Duct Cancer

Bile duct cancer or cholangiocarcinoma is an aggressive cancer withouteffective therapy. It is also endemic in certain parts of South East Asia,particularly in the north east region of Thailand where the disease is considereda long-term outcome of chronic liver fluke-related infestation through localdietary habits. In collaboration with the University of Khon Kaen, the grouphas been studying this cancer by focusing on its genome and drug screeningfor affordable and effective drugs. Through molecular profiling, the grouphas identified the molecular signatures of this cancer. One of them, MAPKinase13, has been found to be frequently overexpressed and serves as both adiagnostic and potential therapeutic target (Tan FL et al., Int J Cancer, 2010). As most of these patients come from low-income families in society, wealso plan to undertake high-throughput screening for affordable and effectivedrugs by focusing on off-label, FDA approved drugs that have run out oftheir patency.

T-cell lymphoma

In working closely with Drs Lim Soon Thye and Tan Soo Yong, a lymphomatranslational research group has been established. The group consists ofpracticing oncologists, pathologists and scientists throughout the countryand has extensive international collaborations. It is now a member of theNational Cancer Institute (USA) TCGA (The Cancer Genome Atlas) lymphomaprogram. By molecular profiling and immunohistochemistry, the group hasrecently identified a novel biomarker for Type II enteropathy associated T-cell lymphoma, a rare but very aggressive lymphoma (Tan S-Y et al., Leukemia,in press). Further validation studies to discover additional novel biomarkersfor different subtypes of T-cell lymphoma are currently underway. In addition,the group is generating lymphoma cell lines and model systems to screenfor effective therapeutic agents.

Clinical Trials – bringing newmedicines and new hope to ourpatients. CTE provides a centralizedservice to perform these trials.

Division of

ClinicalTrials andEpidemiologicalSciences

CLINICAL TRIALS OFFICE

Cancer is a major health problem worldwide. About 10 million people annuallyare diagnosed with this disease and six million are expected to die from it. InSingapore the crude cancer incidence rate is expected to rise for the next twodecades as the baby boomers now reach the age when most cancers develop.Unfortunately, despite the best efforts, we are still unable to cure most patientswith recurrent cancer. Hence, search for new therapies, is critical for the cure ofcancer, for the prolongation and the improvement of quality of life. These therapiesare developed through clinical trials, which involve regulated and closely-monitoredprocesses of testing new drugs and drug combinations in humans, so as toevaluate and confirm their efficacy and safety. The Clinical Trials Office of theHumphrey Oei Institute of Cancer Research provides the infra-structural supportfor the conduct of all phases of clinical trials at the National Cancer CentreSingapore.

Joseph WEEHead, Division ofClinical Trials &EpidemiologicalSciencesFAMS, MBRS, [email protected]

Ai Lin LOWSenior ManagerBSc (Pharm)(Hons)[email protected]

Research StaffJia Ling CHEONGAi Mee CHUAMichellore T DANNUGKathleen Garcia DAVIDCarreon Sharleen ESGUERRAWin Win HANGenevieve HONHtar Htar HWERuth KHOOWen Ya K KHOOEmily LIMLi Shan LOWMaria Carlota F MACAPAGALSu Mon MYATZar Yar MYINTYin Yin Pyone NANGMadeline P C NG

Darice Jill NGRu Yi ONGArmina G PILAPILThet Pang PHOONoryati ABD RAHMANWei Yan SEHValencia Agnes SHAHMa Than Than SHWEYi Hui TANSheila Rose Morales -TAPANGJulia TOHMa Zin Mar WAILan Ying WANGMung Peng WONGBelinda P Y WOONSook Kwan YEOLiz ZHONG

We have a team of dedicated staff to support investigators in areas such as trial co-ordination, budget and project

planning, protocol development, negotiation of agreements, ethical and regulatory submissions, case report form design

and data discrepancy management.

Research Experience

We have more than 16 years of experience in conducting clinical trials and to date, have completed over a hundred

clinical trials. Currently we have about 100 ongoing trials. Of particular interests are trials of the new small molecular

targeted agents, vaccines, stem-cell mini-transplants and adoptive T cell therapies on the different cancers types such

as breast, lung, nasopharynx, stomach, colorectum and liver cancers. Our investigators are constantly in search of new

methods and treatments, and actively coming up with new ideas and protocols for clinical testing.

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Selected PublicationsOur Infrastructure

The National Cancer Centre Singapore has obtained Federalwide Assurance

from the United States Department of Health and Human Services for human

subject protection. This certification allows NCCS to qualify for US Government

supported research from CTEP of the US National Cancer Institute.

Our research co-ordinators (CRC) are stringently selected to ensure that they

have the aptitude, qualification and interests suitable for the work. Most of our

coordinators have at least a degree in medicine, nursing, life or health sciences

and have to undergo rigorous training under strict supervision.

We are well equipped to carry out routine trial procedures. We have the facilities

and knowledge to ensure that biological specimens for central laboratories

are handled carefully under protocol prescribed conditions. NCCS also has

a GMP laboratory for preparing some of our biological agents.

We have dedicated Clinical Trial Pharmacists. The Ambulatory Care Unit nurses

play an active role as part of the study team to ensure that the administration

and handling of study drugs are performed according to the protocol. We are

also involved in research areas such as DCE-CT and DCE-MRI. PET and

SPECT are available in the campus, and the Nuclear Medicine Department

has its own in-house radio-chemist. We also work closely with the Singhealth

Investigational Medicine Unit, which has a 30-bed inpatient unit for early phase

trials.

We use the Oracle Clinical Data Management System to manage data. Our

team includes a trained system analyst, data management co-ordinators and

statisticians.

Future DirectionWe aim to continue to provide a centralised service for investigators and

industries to conduct clinical trials.

LIM WT, Tan EH, Toh CK, Hee SW,Leong SS, Ang PCS, Wong NS,Chowbay BPhase I pharmacokinetic study of a weeklyliposomal paclitaxel formulation (Genexol-PM) in patients with solid tumors.Ann. Oncol. (2010) 21(2):382-8.

Leong SS, Fong KW, Lim WT, Toh CK,Yap SP, Hee SW, Tan EHA phase II study of induction gencitabineand vinorelbine followed by concurrentvinorelbine and radiotherapy in locallyadvancednon-small cell lung cancer.Lung Cancer (2010) 67(3):325-9.

Tan EH, Rolski J, Grodzki T, SchneiderCP, Gatzemeier U, Zatloukal P, Aitini E,Carteni G, Riska H, Tsai YH, Abratt RGlobal Lung Oncology Branch trial 3(GLOB3): final results of a randomisedmultinational phase III study alternatingoral and IV vinorelbine plus cisplatin versusdocetaxel plus cisplatin as first-linetreatment for advanced non-small cell lungcancer.Ann. Oncol. (2009) 20(7):1249-1256.

Loong SL, Hwang JS, li HH, Wee JT etal.Negligible or weak expression ofcyclooxygenase-2 is associated withpoorer outcome in endemicnasopharyngeal carcinoma: analysis ofdata from randomised trial betweenradiation alone versus concurrent chemo-radiation (SQNP-01).Radiat. Oncol. (2009) 4(1):23.

Wang A, Lal S, Sandanaraj E, Lim WT,Leong SS, Tan EH, Chowbay BPhase I dose finding study of Genexel-PM in Asian cancer patients.J. Clin. Oncol. (2008) 26:621s (Abstr13512).

Yap SP, Lim WT, Foo KF, Hee SW,Leong SSm Fong KW, Eng P, Hsu, AA,Wee JTS, Agasthian T, Koong HN, TanEHInduction concurrent chemoradiotherapyusing Paclitaxel and Carboplatincombination followed by surgery inlocoregionally advanced NSCLC – Asianexperience.Ann. Acad. Med. Singapore (2008)37(5):377-82.

Leong SS, Wee J, Rajan S, Toh CK, LimWT, Hee SW, Tay MH, Poon D, Tan EHTriplet combination of gemcitabine,paclitaxel and carboplatin followed bymaintenance 5-fluorouracil and folinic acidin patients with metastatic nasopharygealcarcinoma.Cancer (2008) 113(6):1332-1337.

Wong ZW, Ang PC, Chowbay B, WongNS, See HT, Khoo KSPhase I / II trial of gemcitabine withpegylated liposomal doxorubicin as first-line therapy in Asian women withmetastatic breast cancer.Breast (2008) 17(5):517-22.


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BIOSTATISTICS UNIT

The Biostatistics and Epidemiology Unit primarily provides statistical andepidemiological support for clinical trials and other studies conducted at theNational Cancer Centre Singapore. This is in the form of consultations,collaborations as well as teaching. We also initiate and engage in relevant areasof applied biostatistics and epidemiology research.

The conduct of good biomedical research requires the appropriate disease expertise and rigorous research methodology

combined with strong quantitative analyses. The added value of statistical techniques to biomedical research is well

recognised. In biomedical studies the correct design, analysis and interpretation of the study all require the development

and application of good statistical methods. While many such techniques have already been developed, only a relatively

small number of these are routinely used in practice. A key reason for this is that many of these methods have not made

the transition from the ‘statistical lab’ to the clinic. However, these methods may potentially help improve all aspects

of the biomedical research process, ultimately resulting in more accurate conclusions being drawn e.g. regarding the

usefulness of new treatments. This has important ethical implications as patients consent to have their data used for

biomedical research with the expectation that the information that they provide will be used in the most optimal way

to provide benefits for future patients and potentially themselves as well. Research thus needs to be carried out to test

and bring better biostatistical and clinical research methodologies into clinical practice.

Moreover, there are many problems in biomedical research for which better (albeit less well known) statistical methods

could be employed, to allow for a better analysis and interpretation of the data. This can be achieved through the conduct

of applied biostatistics research and teaching.

Some of the projects currently engaged include cancer epidemiology modeling, clinical trial methodology, applications

of Bayesian statistics in medicine and applications of statistics in genetics. The Biostatistics Unit also provides expert

biostatistics support for all clinical trials and related studies conducted at the National Cancer Centre Singapore.

Tam Cam HASenior [email protected]

Say Beng TANPrincipal BiostatisticianMA, MSc, PhD, [email protected]

Joint Appointments:Senior Vice President & ChiefScientific Officer Singapore ClinicalResearch Institute

Associate Professor and Director,Centre of Quantitative Biology andMedicine, Duke-NUS GraduateMedical School.

Research StaffWallace CHENXuan HOUWhee Sze ONGSze Huey TAN

Director,Biostatics and QuantitativeEpidemiology, Singhealth

Adjunct Associate Professor,Department of Epidemiology andPublic Health, YLL School ofMedicine, NUS

Adjunct Associate Professor,Department of Biostatistics andBioinformatics, Duke University

Fei GAOAdjunct Principal InvestigatorMSc, [email protected]

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Li H, Ha TC, Tai BCXRCC1 Gene Polymorphisms and BreastCancer Risk in Different Populations: AMeta-Analysis.The Breast (2009) 18(3):183-91.

Machin D, Campbell M, Tan SB, Tan SHSample Size Tables for Clinical Studies.3rd Edition. Wiley-Blackwell (2009).

Gao F, Ng GY, Cheung YB, Thumboo J,Pang G, Koo WH, Sethi VK, Wee J, GohCThe Singaporean English and Chineseversions of the EQ-5D achievemeasurement equivalence in cancerpatients.J. Clin. Epidemiol. (2009) 62(2):206-213.

Gao F, Tan SB, Machin D, Wong NSConfirmation of double-peaked timedistribution of mortality among Asian breastcancer patients in a population-basedstudy.Breast Cancer Research (2007)9(2):R21.

Ha TC, Li HMeta-analysis of Clodronate and BreastCancer Survival.British Journal of Cancer (2007)96(12):1796-1801.

Li H, Tai BCRNASEL gene polymorphisms and the riskof prostate cancer: a meta-analysis.Clinical Cancer Research (2006)12(19):5713-5719.

The primary objective of the Epidemiology Unit is to conduct clinical

translational research to investigate the risk factors for cancer and the

patterns of disease in the wider population at large. This provides a platform

for the development of studies to investigate possible interventions to increase

survival and reduce the incidence of cancer or the stage at which the disease

is diagnosed. As new technology becomes available, such as the ability to

detect molecular biomarkers, better treatment outcomes for patients will

also become available. The design and conduct of scientifically sound

epidemiological studies is important in ensuring quality results for the future

benefit of all patients. The conduct and provision of epidemiological research

is able to provide direct clinical applications for patient care.

Almost all aspects of medical research require the use of statistical and

epidemiological techniques at some point of the research process. Inefficient

or erroneous methodology could have severe consequences on the

interpretations of the research findings. This could eventually result in patients

having less than optimal or worse still, inappropriate treatment.

The unit applies principles of evidence-based medicine when designing

studies to ensure that the most feasible study has been conducted. A variety

of studies are currently being investigated including studies in genetic

epidemiology, screening and cancer risk factors. With collaborations both

locally and internationally, the unit aims to investigate population risk factors

for cancer.

EPIDEMIOLOGY UNIT

Tam Cam HASenior [email protected]

Joint Appointments:Assistant Professor and CourseDirector, Investigative Methods andTools, DUKE-NUS Graduate MedicalSchool

Research StaffGrace Sook Kwin YONG


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ClinicianInvestigatorsand Scientists

DEPARTMENT OFMEDICAL ONCOLOGY

Oncology Research Groups:• Breast• Gynae-oncology• Gastrointestinal• Lymphoma• Thoracic and Head & Neck• Urologic• Early Clinical Research Unit (ECRU)

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Nan Soon WONGSenior Consultant,

Department of MedicalOncology

Director, Public Education &Patient Support

MBBS, MMed (InternalMedicine), MRCP (UK)

[email protected]

Breast Oncology Research

Clinician Scientists:

Soo Kien LORaymond NGYoon Sim YAP

Specific Projects:

1) Role of carboplatin as neoadjuvant chemotherapy for triple negative breast

cancer

2) Feasibility and efficacy of a non-anthracycline regimen as neoadjuvant therapy

for locally advanced breast cancer incorporating docetaxel pharmacokinetic

and pharmacogenomic studies

3) Efficacy of metronomic chemotherapy in combination with aromatase inhibitors

in metastatic breast cancer correlating response with circulating endothelial

progenitor cell levels

4) Impact of CYP2D6 polymorphisms on tamoxifen metabolism in Asian women

5) Establishment of repository of clinically annotated core biopsies from metastatic

sites at time of tumour progression or recurrence, or prior to neoadjuvant

therapy for future gene expression profiling to explore predictive markers of

treatment sensitivity and resistance

Han Chong TOHSenior Consultant & Head,Department of MedicalOncology

Principal Investigator,Laboratory of Cell Therapyand Cancer VaccineBSc(Lond), MBBChir(Camb),MRCP(UK), FRCP(Edin),[email protected]



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John W.K. CHIAConsultant, Department of

Medical OncologyMBBS, MMed (InternalMedicine), MRCP (UK)

[email protected]

Gynae-oncology Research

Clinician Scientists / Collaborators:

Immunotherapy : Dr Han Chong TOH, Dr Marissa TEO, Dr Peter WANG, Dr Giogia

PASTORIN, Dr Rod DUNBAR, Dr Albert DEISSEROTH, Dr Stephen GOTTSCHALK

Inflammation and Cancer : Dr Han Chong TOH, Dr Raghib ALI, Dr Simon ONG,

Dr Chee Kian THAM, Dr R. SIM, Dr G. LOPES (and other regional collaborators)

Gynaecology : Dr LT SOH, Dr Lynette NGO, Dr YN CHIA, Dr YK LIM, A/Prof TH

HO, A/Prof SK TAY, Dr Cindy PANG, Dr Elisa KOH, Dr Ivy CHEW, Dr SH CHEW,

Asst Prof LK GOH, A/ Prof The Hung HUYNH , Prof Bin Tean TEH

Areas of Clinical Research:

Immunotherapy for Solid Tumors, Inflammation and Cancer, Gynaecological

Malignancies

Specific projects:

1) Dendritic Cell vaccine (Ad5F35-dLMP1-LMP2) for Metastatic Nasopharyngeal

Cancers

2) Adoptive T cell therapy with EBV specific Cytotoxic T Lymphocytes for

Nasopharyngeal Cancers

3) MUC1-CD40L vaccine for MUC1 expressing tumors

4) EBV peptide vaccination strategies for Nasopharyngeal Carcinoma

5) ASCOLT study – Adjuvant Aspirin for Dukes B and C Colorectal cancers

6) Mutational and Immune analysis of Gynaecological Tumors

7) Prognostic classifiers for Leiomyosarcoma of the Uterus

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Su Pin CHOOConsultant, Department of

Medical OncologyBMBS (Nottingham),

MRCP(UK)[email protected]

Breast Oncology Research

Gastrointestinal Oncology Research

Clinician Scientists:Han Chong TOH(Head of DMO)Wen Hsin KOO (Deputy Director, NCCS)Simon ONG (Director of Education, NCCS)Hwee Yong LIMJoanne NGEOWChee Kian THAM

The Gastrointestinal (GI) Cancer team of the Department of Medical Oncology(DMO) consists of a group of highly specialized medical oncologists who treatmalignancies of the gastrointestinal system and who are actively involved intranslational and clinical research. Our clinical services also include hyperthermicintraperitoneal chemotherapy and management of neuro-oncology cancers.

Our team’s mission is to provide top-notch cancer care to our patients using themost advanced medical therapies, and providing opportunities for our patient toparticipate in clinical trials, with the ultimate aim of prolonging survival andimproving quality of life. Core to this is our emphasis on doing research to developnew therapies for patients and to enhance our understanding of GI cancers andinvolvement in education of doctors, nurses, allied health and the public.

Our GI cancer database links high quality clinical data to patient clinical samples,allowing us fruitful collaborations with laboratory scientists to answer key scientificquestions in GI oncology and develop a better understanding of GI cancers inour population.

We have numerous investigator-initiated and pharmaceutical-sponsored clinicaltrials investigating novel therapeutics and treatment approaches. We have at least20 ongoing trials at any point in time. We also have special interests inimmunotherapy and cancer genetics.

Two examples of our Bench-to-Bedside Research projects that are activelyrecruiting patients include:

1) Phase II study of Genomic-guided standard-of-care chemotherapy for advancedgastric cancer. This is a proof of concept study based on our laboratorycolleagues’ preclinical work demonstrating that gastric cancer cell linesstratified by their molecular signature exhibited differential sensitivity tooxaliplatin and cisplatin. This trial is done in collaboration with NationalUniversity Hospital and Yonsei Cancer Centre Korea.

2) A phase I/II study of AZD6244 in combination with Sorafenib in AdvancedHepatocellular Carcinoma. The rationale from this study came about frompre-clinical work with our laboratory collaborators which showed that theaddition of AZD6244 enhanced the anti-tumour effect of sorafenib in HCCxenograft models. This trial also involves National University Hospital and isa joint collaboration with Astra-Zeneca.

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Soon Thye LIMSenior Consultant & Deputy

Head, Department of MedicalOncology

MBBS, MRCP(UK)[email protected]

Lymphoma Oncology Research


Miriam TAOKevin TAYRichard QUEK

The Lymphoma Translational Research Laboratory:

Our laboratory is focused on the molecular mechanisms of lymphoid malignancies.

Currently, epidemiological, clinical and molecular data on malignant lymphomas

among Asians is limited and an increasing body of information from our center

and others suggest that geographic localities as well as ethnicity are important

factors in lymphomagenesis. The main aims of this laboratory are:

1. To exhaustively evaluate the molecular characteristics of lymphoma, particularly

subtypes that occur at higher frequencies in Asians.

2. To develop new biomarkers, treatment targets and novel treatment strategies,

particularly against lymphoma subtypes uniqueto Asians.

3. To provide molecular correlation to lymphoma clinical trials.

Our laboratory takes advantage of the large clinical and pathological data and

material available to our researchers. Integrating the clinical and pathological data

of our patients together with the molecular and genomic information derived from

this laboratory, it allows us to identify predictive and prognostic biomarkers as

well as potential therapeutic targets for novel treatment.

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Eng Huat TANSenior Consultant,

Department of MedicalOncology

MBBS, MMed(InternalMedicine), MRCP(UK), FAMS

[email protected]

Thoracic and Head & Neck Oncology Research


Mei-Kim ANGDarren LIMQuan Sing NGDaniel TAN

Thoracic and Head & Neck Oncology ResearchThe thoracic and head/ neck oncology team has maintained a strong track recordin running clinical trials from phase I to III. Initial epidemiologic studies establishedthe unique clinical phenotype of our lung cancer patients, and the group hassubsequently developed trials aimed at defining new treatment standards forspecific clinical subgroups. With improved delineation of distinct molecularsubtypes of cancer, our research efforts are focused at understanding the biologyof each tumour to enable development of rational therapeutic strategies. This isespecially true in the era of targeted therapeutics and the more widespreadapplication of genomics in the clinic.

One of the current challenges is the implementation of molecular tests that definepatient populations that may be more amenable to specific treatments – rangingfrom EGFR mutations and ALK translocations in lung cancer to HPV positive ornegative oropharyngeal cancers, and XRCC1 status in head and neck cancers.These efforts are being developed in conjunction with the Pathology Department(Tan PH, Takano A, Hwang J) and will enable more directed strategies that addressunderlying disease biology. Similarly one of the areas of interest is the developmentof approaches to overcome resistance to EGFR TKIs, where novel agents targetingHGF-Met axis and PI3K inhibitors are now specifically set up for this patientgroup.

Biomarkers that provide earlier readouts of drug effect are also increasinglyapplied to clinical trials, such as the use of functional imaging in a pazopanibmonotherapy trial in nasopharyngeal cancer, and examining circulating endothelialprogenitor cells and functional imaging in a lung cancer trial combining sorafeniband metronomic vinorelbine (PI: Tan EH). Future directions include developingreal time electronic capture of clinical information at point of care, and incorporatingmedium throughput screening for somatic mutations using the Sequenom platformand minimally invasive biomarker platforms like circulating tumour cells.


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Min-Han TANConsultant, Department of

Medical OncologyMBBS (Singapore),

MRCP (UK)[email protected]

Urologic Oncology Research


Noan-Minh CHAU

The National Cancer Centre Singapore is an international centre for research inprostate, renal, testicular and bladder cancer. Many leading trials in genitourinarycancer are conducted here, which allow us to apply novel leading anti-cancercompounds for the immediate use of our patients in a research setting. Forexample, cabazitaxel, newly approved by the FDA in late 2010 for its effectivenessin prostate cancer, was available to our patients on a research basis at the NCCSsince 2006. Many such novel agents are in clinical research settings for ourpatients.

In addition to trials, our extensive translational research activities in urologiconcology also focuses on molecular correlates, such as circulating tumor cells,high-throughput expression and single nucleotide polymorphism genomic profilesand candidate predictive serum proteins. Specific outcomes of interest includedrug response and prognostic outcomes (in collaboration with Prof Tan PuayHoon, Prof Christopher Cheng and Prof Weber Lau of SGH, Prof Teh Bin Teanand Prof Balram Chowbay of NCC, Prof. Lim Chwee Teck and Dr. Sng Jen Hweiof NUS). These studies are only possible with extensive collaborations andcombined databases between the disciplines of urology, pathology, medicaloncology and radiation oncology.

The NCCS has a group of clinicians and researchers focusing on cancer genetics,in terms of clinical care and basic research. Patients with hereditary cancersyndromes receive specialized clinical care, and are involved in translationalresearch. The NCCS hosts a von Hippel-Lindau Clinical Care Center of Excellence.Additionally, epidemiologic research on statistical modelling of prognostic outcomesin urologic cancers is also conducted.

Memberships/Affiliations:a) Dr. Tan Min-Han is a member of the International Metastatic Renal Cell

Carcinoma Consortium since 2009.b) Dr. Tan Min-Han is a member of the Cochrane Prospective Meta-Analysis

Methods Group (Prostatic Diseases and Urologic Cancers Group).c) Dr. Tan Min-Han leads the von Hippel-Lindau Clinical Care Center of Excellence.

ECRU Workgroups/Collaborators:

Noan Minh CHAU (Urologic)

Su Pin CHOO (Director, Gastrointestinal)

Quan Sing NG (Functional Imaging)

Richard QUEK (Sarcoma/Rare Tumours)

Daniel TAN (Lung/ Head/Neck)

Eng Huat TAN (Director of Research, DMO)

Nan Soon WONG (Breast/ Gynae)

Chowbay BALRAM (PK/PD lab)

Samantha LEE (Administrative coordinator)

Lan Ying WANG (CRC Team Leader)

Lishan LOW

Zhong Li LIZ

Zin MA

Sook Kwan YEO

ECRU is a unit within the department of Medical Oncology that was officially established on 16th October 2009.

The unit was formed with an academic focus to enhance support for early phase (Phase 0/1/2) clinical trials

and investigator-initiated trials. ECRU provides a one-stop-shop for the conduct of early phase clinical trials

with a core team of clinical research coordinators (CRC) and assistant research coordinators. It works in close

collaboration with other clinicians and research laboratories to consolidate capabilities and ensure seamless

trial conduct with an emphasis on accelerating throughput of correlatives studies by matching investigator with

collaborators.

The mission of ECRU is to bring new and novel agents to the patient’s bedside and develop new therapeutic

options for cancer patients through investigator-initiated scientifically driven research.

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EARLY CLINICAL RESEARCH UNIT (ECRU)


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Selected PublicationsExamples of current ECRU studies include:

1) A Prospective Study of Metronomic Oral Vinorelbine in Combination

with Sorafenib in Advanced Non-small Cell Lung (PI: Dr Tan Eng Huat)

a) A phase I dose-finding study of the combination of metronomic

oral vinorelbine and sorafenib

b) Pharmacokinetics profiling of the combination of metronomic

oral vinorelbine and sorafenib at maximum-tolerated dose (MTD)

2) A Safety and Tolerability Study of RAD001 (mTOR inhibitor) in Combination

with Two Dosing Schedules of LBH589B (histone deacetylase inhibitor)

in Solid Tumors/Lymphomas with Enrichment for EBV-Driven Tumors

(PI: Dr Daniel Tan)

3) A Phase 2 Study of trastuzumab in Combination with TS-ONE and

cisplatin in first-line human epidermal growth factor receptor 2 (HER2)-

positive advanced gastric cancer (PI: Dr Choo Su Pin)

4) A Phase 1 Study of Oral Vinorelbine in Combination with Erlotinib in

Advanced Non-Small Cell Lung Cancer (NSCLC) (PI: Dr Darren Lim)

5) Aspirin for Dukes C and high risk Dukes B colorectal cancers: an

international, multi-centre, double blind, randomised placebo controlled

phase III trial (PI: Dr John Chia)

6) Clinical Validation of a Microfluidic Device for Isolation and Molecular

Characterization of Circulating Tumor Cells (CTC) (PI: Dr Darren Lim)

7) CYP2D6 Pharmacogenetics and Its Influence on Tamoxifen

Pharmacokinetics and Clinical Outcome in Asian Breast Cancer Patients

(PI: Dr Wong Nan Soon)

Tan MH, Mester J, Peterson C, Yiran Y,Chen J, Rybicki LA, Milas K, PedersonH, Orloff MS, Eng CA proposed clinical scoring system forselection of patients for PTEN mutationtesting based on prospective cohortanalysis of 3,042 probands.Am J Hum Genet (2011) In press.

Heng DYC, Park T, Bjarnason GA,Vaishampayan U, Tan MH, Knox J, NorthS, Kollmannsberger C, McDermott DF,Rini BI, Choueiri DProgression-free survival (PFS) as apredictor of overall survival (OS) inmetastatic renal cell carcinoma (mRCC)treated with contemporary targetedtherapy.Cancer (2010) In press.

Ngeow J, Lim WT, Leong SS et al.Docetaxel is effective in heavily pretreatedpatients with disseminated nasopharyngealcarcinoma.Ann. Oncol. (2010) Epub ahead of print.

Huynh H, Ngo VC, Koong HN, Poon D,Choo SP, Toh HC, Thng CH, Chow P,Ong HS, Chung A, Goh BC, Smith PD,Soo KCAZD6244 enhances the anti-tumor activityof sorafenib in ectopic and orthotopicmodels of human hepatocellular carcinoma(HCC).J. Hepatol. (2010) 52(1):79-87.

Lim WT, Tan EH, Toh CK et al.Phase I pharmacokinetic study of a weeklyliposomal paclitaxel formulation (Genexol-PM) in patients with solid tumors.Ann. Oncol. (2010) 21(2):382-388.

Tan IB, Ang KK, Ching BC, Mohan C,Toh CK, Tan MHTesticular microlithiasis predicts concurrenttesticular germ cell tumors and intratubulargerm cell neoplasia of unclassified typein adults : a meta-analysis and systematicreview.Cancer (2010) 116(19):4520-32.

Tan EH, Ramlau R, Pluzanska A et al. A multicentre phase II gene expressionprofiling study of putative relationshipsbetween tumour biomarkers and clinicalresponse with erlotinib in non-small-celllung cancer.Ann. Oncol. (2010) 21(2):193-4.

Tham CK, Choo SP, Poon DY, Toh HC,Ong SY, Tan SH, Wang ML, Foo KFCapecitabine with radiation is an effectiveadjuvant therapy in gastric cancers.World J. Gastroenterol. (2010)16(29):3709-15.

Toh CK, Ahmad B, Soong R et al.Correlation between epidermal growthfactor receptor mutations and expressionof female hormone receptors in East-Asianlung adenocarcinomas.J. Thorac. Onco. (2010) 5(1):17-22.

Toh HC, Wang WW, Chia WK, KvistborgP, Sun L, Teo K, Phoon YP, Soe Y, TanSH, Hee SW, Foo KF, Ong S, Koo WH,Zocca MB, Claesson MHClinical Benefit of Allogeneic MelanomaCell Lysate-Pulsed Autologous DendriticCell Vaccine in MAGE-Positive ColorectalCancer Patients.Clin. Cancer Res. (2009) 15(24):7726-7736.

DEPARTMENT OFSURGICAL ONCOLOGY

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The Department of Surgical Oncology was established as part of NCCS’ strategicvision to be the premier academic surgical center in the Outram campus to deliverspecialized cancer surgery. The surgical services are divided into well-establishedsub-specialities with specific focus on hepatobiliary, thoracic, breast, head andneck, colorectal and upper GI malignancies. Apart from providing site-specificexpertise, the department is also committed to the other two pillars of NCCS,i.e. teaching and research.

Our research activities include clinical and laboratory-based projects. Clinicalresearch runs the gamut from data audits, retrospective analyses and clinicaltrials to multi-centre phase III trials. Laboratory-based investigations are focusedon translational research initiatives, either headed by surgeon-investigators inthe department or in collaboration with scientists in NCCS or in other institutesat the Outram Campus.

Heng Nung KOONGSenior Consultant &Head, Department ofSurgical OncologyMBBS, MMed (Surgery),FRCSEd, [email protected]

N Gopalakrishna IYERAssociate Consultant,Department of SurgicalOncology

Principal Investigator,Wee Kim Wee Laboratoryof Surgical OncologyMBBS(Hons),FRCS(Gen), FAMS, PhD(Cambridge)[email protected]

Kong Wee ONGConsultant, Departmentof Surgical OncologyMBBS, FRCS(Edinburgh),PhD(Bristol), [email protected]

Hiang Khoon TANSenior Consultant,Department of SurgicalOncology

Co-Investigator, Wee KimWee Laboratory ofSurgical OncologyMBBS(Singapore),FRCS(Edin), [email protected]

Melissa TEOConsultant, Departmentof Surgical OncologyMBBS, MMed (Surg),FRCS (Edinburgh), FAMS,MPH (Johns Hopkins)[email protected]



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NG Iyer, A Kumar, I Nixon, F Palmer, MWhitcher, SG Patel, RM Tuttle, AR ShahaIncidence and Significance of Delphiannode metastasis in papillary thyroid cancer.Ann Surg (2010) In press.

Iyer NG, Clark JR, Singham S, Zhu JRole of pretreatment 18FDG-PET/CT insurgical decision-making for head andneck cancers.Head Neck (2010) 32(9):1202-8.

Tan HK, Giger R, Auperin A, Bourhis J,Janot F, Temam SSalvage surgery after concomitantchemoradiation in head and necksquamous cell carcinomas - stratificationfor postsalvage survival.Head Neck (2010) 32(2):139-47.

Ong KW, Teo M, Lee V, Ong D, Lee A,Tan CS, Vathsala A, Toh HCExpression of EBV latent antigens,mammalian target of rapamycin, and tumorsuppression genes in EBV-positive smoothmuscle tumors: clinical and therapeuticimplications.Clin. Cancer Res. (2009) 15(17):5350-8.

Tan BK, Tan LK, Yu K, Tan PH, Lee M,Sii LH, Wong CY, Ho GH, Yeo AW, ChowPK, Koong HN, Yong WS, Lim DT, OoiLL, Soo KC, Tan PClinical validation of a customized multiplesignature microarray for breast cancer.Clin. Cancer Res. (2008) 14(2):461-9.

Teo MC, Tan YM, Chung AY, Chow PK,Cheow PC, Soo KC, Hee SW, Ooi LLMetastectomy for non-colorectal, non-neuroendocrine liver secondaries.ANZ J. Surg. (2006) 76(7):575-8.

Clinical and translational research initiatives:

1. Head and neck squamous cell carcinoma and nasopharyngeal cancers(led by Dr Gopal Iyer and Dr Tan Hiang Khoon)

Clinical research includes establishment of the head and neck cancerdatabase, retrospective analyses of outcome and factors predictive ofoutcome in our patients with head and neck cancer and clinical trials.We have recently initiated a phase 3 multi-centre trial that includeparticipants formed over 20 institutions in 11 countries (Phase III, double-blind, placebo-controlled study of post-operative adjuvant concurrentchemo-radiotherapy with or without nimotuzumab for stage III/IV headand neck squamous cell cancer). The translational research program forthis section is led by Dr Gopal Iyer in the Wee Kim Wee Laboratory ofSurgical Oncology.

2. Peritoneal metastases program (led by Dr Melissa Teo)This is a niche research area as there are few institutions locally orregionally with the surgical expertise to perform peritonectomies. Apartfrom surgical expertise, together with the department of medical oncologywe have ample clinical experience on the subject and have an interestto identify prognostic markers, carcinogenic pathways and noveltherapeutic targets that can be used for these cancers. Our researchfocus is targeted towards peritoneal metastases from ovarian, colorectalor primary peritoneal origin.

Our research activities include:

a. Clinical database for patients who undergo metastatectomy for peritonealmetastases

b. Retrospective analyses to identify factors that predict outcome andprognosis for peritoneal metastases based on clinico-pathologic andimaging criteria

c. Molecular profiling of these tumors to identify potential biomarkers andtherapeutic targets (in collaboration with Prof Teh Bin Tean)

d. Establishment of cell-line and xenograft models to understand the biologyof disease (in collaboration with Prof Teh Bin Tean and Prof Huynh TheHung)

3. Soft-tissue sarcoma (led by Dr Melissa Teo)These projects have been driven by our increasing volumes of patientswith soft-tissue sarcomas, especially patients with central/trunk soft-tissue sarcomas. They include:

a. Clinical database for patients who undergo surgery for soft-tissue sarcomasand retrospective analyses to identify factors that predict outcome andprognosis for peritoneal metastases based on clinico-pathologic andimaging criteria (Dr Lee Ser Yee)

b. Molecular profiling of these tumors to identify potential biomarkers andtherapeutic targets (in collaboration with Drs Richard Quek and Prof TehBin Tean)

4. Breast cancer (led by Dr Ong Kong Wee)Breast cancer is one of the commonest malignancies treated at NCCS,with increasing incidence in our population. Furthermore, there aredifferences in the epidemiology of these disease not seen in the Westernpopulation, which have led many to believe that the “Asian breast cancer’may be a variant, with differing outcome and response to therapy. Ourresearch activities complement the various initiatives in the center,principally through meticulous collection of tumor tissue during surgerywith matched and annotated databases, updated during themultidisciplinary tumor board meetings held weekly.

Other projects include:

a. Retrospective analyses to identify factors that predict outcome andprognosis for peritoneal metastases based on clinico-pathologic andimaging criteria

b. Molecular profiling of these tumors to identify potential biomarkers andtherapeutic targets (in collaboration with Drs Benita Tan and Prof PatrickTan)

DEPARTMENT OFRADIATION ONCOLOGY

Radiation Oncology (then Therapeutic Radiology) was the first department to beformed as the backbone to cancer care in the Singapore General Hospital. It hassince then grown and established itself as an integral part of the National CancerCentre Singapore.

Traditionally seen as a busy service orientated department, the changing landscapeof medicine and evolution of NCCS into an academic centre has seen researchand teaching emerge to take an important role in our department today.

Radiation Oncology is pursuing research on multiple fronts looking into variousaspects such as Radiation technology, Radiobiology and Clinical trials.

Eu Tiong CHUASenior Consultant and Head, Departmentof Radiation OncologyMBBS,DMRT,FRCR,[email protected]

Clinician Scientists:Francis CHINKam Weng FONGJames LEESusan LOONGYoke Lim SOONGTerence TANRichard YEOJoseph WEEFuh Yong WONG

Selected Clinical trials:

A randomised phase II/III study of concurrent cisplatin-radiotherapy with or without induction chemotherapy using

Gemcitabine, Carboplatin and Paclitaxel (GCP) in locally advanced nasopharyngeal cancer (NPC)

The objective of this trial is to assess the 5 year overall survival in patients with locally advanced NPC treated with

concurrent cisplatin - RT with or without induction Gemcitabine, Carboplatin and Paclitaxel (GCP). It seeks to build on

the results of the Intergroup 00-99 as well as our own SQ NP01 trials where the benefit of radiotherapy with concurrent

& adjuvant cisplatin & 5-fluorouracil for locally advanced NPC was established, by using a novel 3-drug combination

used in an adjuvant setting in addition to concurrent chemo-radiotherapy. It started as a randomised phase II study

(NCC 0302) studying the differences in disease-free survival curves and 2-year disease-free survival rates and has now

been expanded into a phase II/III trial.

Phase 1/2 randomised study of concurrent low dose metronomic cyclophosphamide and intensity modulated radiotherapy

in stage 2 Nasopharyngeal Cancer

Concurrent chemo radiation has been shown to improve cure rates in patients with stage III and IV NPC. However, the

chemotherapy regiment has significant toxicities. In a bid to improve on the cure rates, while minimizing extra toxicities

in patients with stage II NPC, we embarked on a Phase I/II trial to test the use of low dose daily (metronomic)

cyclophosphamide chemotherapy concurrently with radiotherapy. This trial also seeks to look at the anti-angiogenic

effect of metronomic cyclophosphamide using functional MRI scans.

Phase 3 trial to assess the role of chest wall irradiation in intermediate risk breast cancer patients following mastectomy

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Postoperative radiotherapy is routinely given to patients at higher risk ofrecurrence (tumour size > 5cm or 4 or more lymph nodes are involved). Inpatients with less than four involved axillary lymph nodes or in those withoutlymph node involvement but have other features which increase the recurrencerisks, it is not clear whether postoperative radiotherapy is needed. TheSUPREMO trial aims to establish the benefits of postoperative radiotherapyto the chest wall in these patients who are at intermediate risk of recurrence.Through this randomized controlled trial, we aim to provide level I evidenceto offer post mastectomy radiotherapy to all patients at intermediate risk ofrecurrence or not at all, thence sparing women the time and expense of anunnecessary treatment and avoid the potential hazards from radiation exposure.

Feasibility study using Intensity Modulated Radiation Therapy (IMRT) withconcurrent use of temozolomide for Glioblastoma Multiforme (GBM)

Glioblastoma Multiforme (GBM) is the most commonly occurring primarybrain tumour in adults. Post-operative radiotherapy to the tumour bed followinggross total resection of GBM improves local control and survival. However,local recurrence remains the most common pattern of failure. Because of thelarge volume of brain irradiated, escalation of radiation doses beyond 60Gyis fraught with severe neuro-cognitive toxicity. The advent of highly conformalradiotherapy technique such as IMRT allows dose sculpting to restrict highdoses to residual tumour/tumour bed while preserving as much uninvolvednormal tissue as possible. Temozolomide has been demonstrated to improvesurvival beyond that achieved with radiotherapy alone in phase III trials. Weaim to test the feasibility of the combination of IMRT and temozolomide inpatients following gross tumour debulking in this single arm Phase II study.

Selected Radiation technology research:

Atlas Based Auto contouring of Radiation Structures.

We started a research project to develop a customised atlas using our historicalpatient data sets to create a local atlas for site specific automatic contouringfor patients slated for radiation therapy. Patients are scanned and image datasets compared with our historical patients to find a similar patient for use asa starting point for the algorithm to contour normal organs and fusion of MRI.This project has practical clinical application of greatly reducing the timerequired for contouring and fusion and the doctor needs only to review andadjust the contours for subsequent planning.

Electron dosimetry and evaluation of the Monte Carlo algorithm at extendeddistances

Electron dosimetry at extended distances is a challenge due to enhancedscattering conditions that may affect the accuracy of dose calculation.Extensive measurements were done to obtain relative output factors ateffective source surface distances of 105cm to 120cm. This will be incorporatedinto a common physics database for monitor unit calculation. Work is alsounderway to verify a Monte Carlo algorithm against the measurement dataat extended SSDs.

Study of Maximum Intensity Projection (MIP) errors in 4D ComputerisedTomography (CT) planning

4D CT is used in radiotherapy for tracking tumour motion. The breath cycleof each patient is unique and varied. Work is underway to understand theeffects of various parameters in each breath cycle that will affect the acquisitionof 4D images. In particular, the uncertainty in maximum intensity projectionimages will be studied using a 4D phantom.

Selected Radiobiology Research:

See “Laboratory of Genome Maintenance - Dr Susan Loong’s Laboratory”.


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Tham IW, Hee SW, Yeo RM, Salleh PB,Lee J, Tan TW, Fong KW, Chua ET, WeeJTTreatment of nasopharyngeal carcinomausing intensity-modulated radiotherapy-the national cancer centre Singaporeexperience.Int. J. Radiat. Oncol. Biol. Phys. (2009)75(5):1481-6.

Wee JT, Anderson BO, Corry J, D'CruzA, Soo KC, Qian CN, Chua DT, HicksRJ, Goh CH, Khoo JB, Ong SC,Forastiere AA, Chan ATManagement of the neck after chemoradiotherapy for head and neck cancersin Asia: consensus statement from theAsian Oncology Summit 2009.Lancet Oncol. (2009) 10 (11): 1086 – 92.

Chua ML, Ong SC, Wee JT, Ng DC, GaoF, Tan TW, Fong KW, Chua ET, Khoo JB,Low JSComparison of 4 modalities for distantmetastasis staging in endemicnasopharyngeal carcinoma.Head Neck (2009) 31(3):346-54.

Loong SL, Hwang JS, Li HH, Wee JT,Yap SP, Chua ML, Fong KW, Tan TWWeak expression of cyclooxygenase-2 isassociated with poorer outcome inendemic nasopharyngeal carcinoma:analysis of data from randomized trialbetween radiation alone versus concurrentchemo-radiation (SQNP-01).Radiat. Oncol. (2009) 4:23.

Tan JSP, Chan LL, Tan KL, Lee JCL, WanCM, Leong JLComparison of radiation dose to the eyelens delivered by a 16-slice and 64-slicemulti-detector CT (MDCT): Implicationsfor improving patient careAm. J. Neuroradiol. (2009) 30(2):373-377.

Tan WM, Paterson MC, Koo GC, Li HH,Price A, Loong SLIncreased but error-prone nonhomologousend joining in immortalized lymphoblastoidcell extracts from adult cancer patientswith late radionecrosis.Int. J. Radiat. Oncol. Biol. Phys. (2008)72(1):178-85.

Low WK, Toh ST, Wee J, Fook-ChongSM, Wang DYSensorineural hearing loss afterradiotherapy and chemo radiotherapy: asingle, blinded, randomized study.J. Clin. Oncol. (2006) 24(12): 1904-9.

Wee J, Tan EH, Tai BC, Wong HB, LeongSS, Tan T, Chua ET, Yang E, Lee KM,Fong KW, Tan HS, Lee KS, Loong S,Sethi V, Chua EJ, Machin DRandomized trial of radiotherapy versusconcurrent chemo radiotherapy followedby adjuvant chemotherapy in patients withAmerican Joint Committee on Cancer/International Union against cancer stageIII and IV nasopharyngeal cancer of theendemic variety.J. Clin. Oncol. (2005) 23 (27): 6730-38.

DEPARTMENT OFPALLIATIVE MEDICINE

The Department of Palliative Medicine was established in 1999 as part of NCCS’vision to provide holistic care for cancer from prevention and diagnosis to terminaldisease. Palliative care provides expertise in symptom management andpsychosocial support for patients and their families as part of the continuum ofcancer care.

The department provides clinical services to patients at NCCS, Singapore GeneralHospital, and other Singhealth institutions. It also provides visiting consultantservices to hospice organisations in the community.

Our research interests include validation of quality of life instruments, clinicaltrials, health service research and laboratory-based research. We welcomecollaboration that is relevant to our current projects as well as new researchprojects relevant to Palliative Medicine.

Cynthia GOHSenior Consultant &Head, Department ofPalliativeMedicine,NCCS,

Director, Lien Centre forPalliative CarePhD, FAMS, FRCPE,FRCP, [email protected]

Research StaffLalit KRISHNASeok Hui NEOGrace PANGLimin QUDeborah WATKINSONYin Yee WONGAlethea YEE

Current Research Projects:Care of the Dying Coordinated Clinical Pathway (CDP)

Provision of quality end-of-life care has gained prominence worldwide in recent years. The Liverpool Care Pathway for

the Dying Patient has been recognised as the gold standard for end-of-life care for dying patients in UK. In a pilot project,

the pathway was adapted for use in an oncology ward in SGH to improve care of the dying. Preliminary results of the

pre- and post-implementation audit (n=60) show improved end-of-life care in terms of symptom control, documentation

of end-of-life care as well as increased consideration towards discontinuation of non-essential monitoring prior to death.

These findings were presented at the European Society of Medical Oncology Congress 2008 and the poster was accorded

best poster award for its category. We have now extended the project to cover dying renal patients. Results from this

are pending.

Pharmacogenetics of Opioid Receptor Genes

It is clinically well established that patients respond differently to opioid analgesics such as morphine and fentanyl.

Genetic variants such as single nucleotide polymorphisms (SNPs) can contribute to these differences. Establishing the

molecular mechanisms underpinning the effects of genetic variants in opioid receptor genes on differences in opioid

response, may help develop better opioid analgesics with maximum efficacy and minimum side effects. It may also

aid clinicians in identifying patients at risk of serious or burdensome side effects so that alternative opioids may be used

for these patients. These are the aims underlying the concept of personalised drug therapy for our patients.

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Selected PublicationsIn collaboration with the Laboratory of Liver Cancer Functional Genomics and

KKH, we aim to correlate the SNPs in the opioid receptor genes with the

occurrence of opioid-related phenotypes (eg morphine-induced nausea and

vomiting). We have selected out potentially functional SNPs in the opioid

receptor genes for further experimental validation to correlations that we may

observe between the opioid receptor gene SNPs and opioid related phenotypes.

Parts of these findings were presented in a poster entitled: Signature of recent

positive selection at the G-allele of the “E1/A118G non-synonymous single

nucleotide polymorphism in the mu opioid receptor gene” at the 5th Biologie

International Pharmacogenomics Meeting in Greece 2008.

Health-related quality of life, functional status and survivalof high risk End-Stage Renal Disease (ESRD) patients

Little is known about the health-related quality of life (HRQoL) and functional

status in our local end stage renal disease (ESRD) patients. A prospective

observational study of all incident high-risk ESRD patients on dialysis or on

conservative management was initiated. Outcome measures using the Kidney

Disease and Quality of life (KDQoL) instrument and the Karnofsky Performance

Status (KPS) were taken at intervals till 2 years post recruitment or death.

Interim analysis was done on 54 patients who completed 6 months follow-

up by 31/10/08. Results showed that for high risk ESRD patients, those who

embarked on renal replacement therapy appears to have less symptoms and

better overall health compared to those who chose conservative management,

but there was no difference in the summary SF-36 physical or mental

functioning scores. A longer period of follow-up is needed to see if these

observations persist beyond 6 months. Of those who have died by 6 months,

most did so within 3 months, and had a lower baseline KPS, physical functioning

score and haematocrit. Forty-two (78%) patients received input from palliative

care services, majority (93%) of which is hospice homecare. Of the 9 who

have died by 6 months, majority passed away in hospital. However the

numbers are too small to draw any conclusions at the moment. The study is

expected to complete in March 2011, and final analysis of results will be done

then.

Breakthrough Opioid Study

Patients who take regular opioids such as morphine to relieve pain, frequently

experience episodes of pain between their regular doses of medication. This

is called breakthrough pain for which immediate release opioids are used. No

one has defined the optimal dose of this breakthrough in relation to the

background analgesia being used. Hence in collaboration with Flinders

University, Australia, a double-blind, dose-ranging study was initiated to

determine the optimal dose of oral morphine needed to treat breakthrough

pain for people on regular opioids in the palliative care setting. The results

from this study will provide an evidence base for a core element of pain

management which is currently lacking.

Yee A, Seow YY, Tan Slt, Qu LM, GohC, Lee GWhat do renal healthcare professionals inSingapore think of advance care planningfor patients with endstage renal disease?.Nephrology (2010) Epub ahead of print.

Krishna L, Goh COpioid use amongst cancer patients atthe end of life.Ann. Acad. Med. Singapore (2010)39:790-97.

Pang GS, Wang J, Wang Z, Goh C, LeeCGThe G allele of SNP E1/A118G at the mu-opioid receptor gene locus shows genomicevidence of recent positive selection.Pharmacogenomics (2009) 10(7):1101-9.

Pang GS, Wang J, Wang Z, Lee CGPredicting potentially functional SNPs indrug-response genes.Pharmacogenomics (2009) 10(4):639-53.

Gao F, Ng GY, Cheung YB, Thumboo J,Pang G, Koo WH, Sethi VK, Wee J, GohCThe Singaporean English and Chineseversions of the EQ-5D achievedmeasurement equivalence in cancerpatients.J. Clin. Epidemiol. (2009) 62(2):206-13.

Cheung YB, Thumboo J, Gao F, Ng GY,Pang G, Koo WH, Sethi VK, Wee J, GohCMapping the English and Chinese Versionsof the Functional Assessment of CancerTherapy-General to the EQ-5D UtilityIndex.Value Health (2009) 12(2):371-6.

Cheung YB, Goh C, Thumboo J, KhooKS, Wee JVariability and sample size requirementsof quality-of-life measures: a randomizedstudy of three major questionnaires.J. Clin. Oncol. (2005) 23(22):4936-4944.

Cheung YB, Khoo KS, Thumboo J, NgGY, Wee J, Goh CValidation of the English and Chineseversions of the Quick- FLIC quality of lifequestionnaire.Br. J. Cancer (2005) 92(4):668-672.


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DEPARTMENT OFONCOLOGIC IMAGING

The Department of Oncologic Imaging is leading angiogenesis imaging researchin two grants, one funded by the Singapore Cancer Syndicate (SCS-CS-0072)and another by the Biomedical Research Council (BMRC 08/1/31/19/577) to yieldinformation about cancer blood circulation from routine CT and MRI scans.

Choon Hua THNGSenior Consultant, Department ofOncologic ImagingMBBS, [email protected]

Tong San KOHPrincipal Research [email protected]

Anti-angiogenic agents are new anticancer agents that prevent tumour growth by suppressing the growth new vessels

stimulated by the cancer (angiogenesis). They often do not result in a decrease in tumour size even though the drug

is efficacious. Dynamic contrast-enhanced MR imaging (DCE MRI) and computed tomography (DCE CT) have emerged

as methods that can assess tumour angiogenesis and hence show drug activity. They can be performed by currently

available scanners used for routine patient scanning.

We hope to discover a more sensitive and accurate way of non-invasively assessing the degree of angiogenesis with

the eventual goal of showing that DCE MRI and DCE CT is a biomarker of angiogenic activity. We hope to show that

early assessment by DCE MRI and DCE CT after a single dose of anti-angiogenic agent, would allow clinicians to predict

whether the patient would benefit from a full course. This would save patients who would not benefit from therapy the

high financial costs of the new drug.

We have validated blood flow calculations from our unique model (Distributed Parameter model) and have shown that

parameters calculated from our model show better correlation with drug exposure of various anti-angiogenic agents.

They also show promise in predicting patient outcome.

Applying our model to the liver, we were able to reflect the normal as well as the tumour-induced changes in the blood

circulation. The grant from BMRC focuses our research effort on the liver to try to proof that our calculated measures

of blood flow and capillary permeability are accurate and to apply our model to routine day-to-day scanning so as to

provide additional information about tumour circulation. The grant also allows us to apply our technique to drug trials

involving liver cancer to determine if the cancer blood circulation calculations from our model can predict response

early in the course of therapy.

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Koh TS, Thng CH, Hartono S, Kwek JW,Khoo JB, Miyazaki K, Collins DJ, OrtonMR, Leach MO, Lewington V, Koh DMDynamic contrast-enhanced MRI ofneuroendocrine hepatic metastases: Afeasibility study using a dual-input two-compartment model.Magn. Reson. Med. (2010) Epub aheadof print.

Thng CH, Koh TS, Collins DJ, Koh DMPerfusion magnetic resonance imaging ofthe liver.World J. Gastroenterol. (2010)16(13):1598-609.

Wong CI, Koh TS, Soo R, Hartono S,Thng CH, McKeegan E, Yong WP, ChenCS, Lee SC, Wong J, Lim R, Sukri N,Lim SE, Ong AB, Steinberg J, Gupta N,Pradhan R, Humerickhouse R, Goh BCPhase I and biomarker study of ABT-869,a multiple receptor tyrosine kinase inhibitor,in patients with refractory solidmalignancies.J. Clin. Oncol. (2009) 27(28):4718-26.

Koh TS, Thng CH, Hartono S, Lee PS,Choo SP, Poon DY, Toh HC, Bisdas SDynamic contrast-enhanced CT imagingof hepatocellular carcinoma in cirrhosis:feasibility of a prolonged dual-phaseimaging protocol with tracer kineticsmodeling.Eur. Radiol. (2009) 19(5):1184-96.

Bisdas S, Rumboldt Z, Wagenblast J,Baghi M, Koh TS, Hambek M, Vogl TJ,Mack MGResponse and progression-free survivalin oropharynx squamous cell carcinomaassessed by pretreatment perfusion CT:comparison with tumor volumemeasurements.AJNR Am. J. Neuroradiol. (2009)30(4):793-9.

Bisdas S, Donnerstag F, Berding G, VoglTJ, Thng CH, Koh TSComputed tomography assessment ofcerebral perfusion using a distributedparameter tracerkinetics model: validation with H(2)((15))Opositron emission tomographymeasurements and initial clinicalexperience in patients with acute stroke.J. Cereb. Blood Flow Metab. (2008)28(2):402-11.

Koh TS, Thng CH, Lee PS, Hartono S,Rumpel H, Goh BC, Bisdas SHepatic metastases: in vivo assessmentof perfusion parameters at dynamiccontrast-enhanced MR imaging with dual-input two-compartment tracer kineticsmodel.Radiology (2008) 249(1):307-20.

Our model can potentially be applied to other cancers such as lymphoma,

head and neck cancers and breast cancer.


Figure 1: Permeability Surface Area Product

> 79

Publications

Highlighted Publications for 2007:

> 82

The Extracellular Matrix Protein TGFBI Induces Microtubule Stabilization and Sensitizes OvarianCancers to PaclitaxelAhmed AA, Mills AD, Ibrahim AE, Temple J, Blenkiron C, Vias M, Massie CE, Iyer NG, McGeoch A, Crawford

R, Nicke B, Downward J, Swanton C, Bell SD, Earl HM, Laskey RA, Caldas C, Brenton JD

Cancer Cell. 2007 Dec;12(6):514-27.

AbstractThe extracellular matrix (ECM) can induce chemotherapy resistance via AKT-mediated inhibition of

apoptosis. Here, we show that loss of the ECM protein TGFBI (transforming growth factor beta induced)

is sufficient to induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer

cells. Paclitaxel-resistant cells treated with recombinant TGFBI protein show integrin-dependent restoration

of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules. Immunohistochemical

staining for TGFBI in paclitaxel-treated ovarian cancers from a prospective clinical trial showed that

morphological changes of paclitaxel-induced cytotoxicity were restricted to areas of strong expression

of TGFBI. These data show that ECM can mediate taxane sensitivity by modulating microtubule stability.

Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectivelyinduces apoptosis in cancer cellsTan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan P, Liu ET, Yu Q

Genes Dev. 2007 May 1;21(9):1050-63.

AbstractPolycomb-repressive complex 2 (PRC2)-mediated histone methylation plays an important role in aberrant

cancer gene silencing and is a potential target for cancer therapy. Here we show that S-adenosylhomocysteine

hydrolase inhibitor 3-Deazaneplanocin A (DZNep) induces efficient apoptotic cell death in cancer cells

but not in normal cells. We found that DZNep effectively depleted cellular levels of PRC2 components

EZH2, SUZ12, and EED and inhibited associated histone H3 Lys 27 methylation (but not H3 Lys 9

methylation). By integrating RNA interference (RNAi), genome-wide expression analysis, and chromatin

immunoprecipitation (ChIP) studies, we have identified a prominent set of genes selectively repressed by

PRC2 in breast cancer that can be reactivated by DZNep. We further demonstrate that the preferential

reactivation of a set of these genes by DZNep, including a novel apoptosis affector, FBXO32, contributes

to DZNep-induced apoptosis in breast cancer cells. Our results demonstrate the unique feature of DZNep

as a novel chromatin remodeling compound and suggest that pharmacologic reversal of PRC2-mediated

gene repression by DZNep may constitute a novel approach for cancer therapy.

Cancer-derived p53 mutants suppress p53-target gene expression--potential mechanism for gainof function of mutant p53Vikhanskaya F, Lee MK, Mazzoletti M, Broggini M, Sabapathy K

Nucleic Acids Res. 2007;35(6):2093-104.

AbstractTumour-derived p53 mutants are thought to have acquired 'gain-of-function' properties that contribute

to oncogenicity. We have tested the hypothesis that p53 mutants suppress p53-target gene expression,

leading to enhanced cellular growth. Silencing of mutant p53 expression in several human cell lines was

found to lead to the upregulation of wild-type p53-target genes such as p21, gadd45, PERP and PTEN.

The expression of these genes was also suppressed in H1299-based isogenic cell lines expressing various

hot-spot p53 mutants, and silencing of mutant p53, but not TAp73, abrogated the suppression. Consistently,

these hot-spot p53 mutants were able to suppress a variety of p53-target gene promoters. Analysis using

the proto-type p21 promoter construct indicated that the p53-binding sites are dispensable for mutant

p53-mediated suppression. However, treatment with the histone deacetylase inhibitor trichostatin-A

resulted in relief of mutant p53-mediated suppression, suggesting that mutant p53 may induce hypo-

acetylation of target gene promoters leading to the suppressive effects. Finally, we show that stable down-

regulation of mutant p53 expression resulted in reduced cellular colony growth in human cancer cells,

which was found to be due to the induction of apoptosis. Together, the results demonstrate another

mechanism through which p53 mutants could promote cellular growth.


> 83

An Efficient and Safe Herpes Simplex Virus Type 1 Amplicon Vector for Transcriptionally TargetedTherapy of Human Hepatocellular CarcinomasLam PY, Sia KC, Khong JH, De Geest B, Lim KS, Ho IA, Wang GY, Miao LV, Huynh H, Hui KM

Mol Ther. 2007 Jun;15(6):1129-36.

AbstractOur previous studies have shown that transgene expression could be targeted to proliferating cells when

cell cycle transcriptional regulatory elements were incorporated into herpes simplex virus type 1 (HSV-

1) amplicon backbone vectors. In the study reported here, we further demonstrated the transcriptional

activation of transgene expression in association with the onset of cellular proliferation using the mouse

partial hepatectomy model. Moreover, transcriptional regulation could be rendered specific to human

hepatocellular carcinoma (HCC) cells by inserting the chimeric gene Gal4/NF-YA under the regulation of

the HCC-specific hybrid promoter. The hybrid promoter, which consists of four copies of the apolipoprotein

E (ApoE) enhancer element inserted upstream of the human alpha1-antitrypsin(hAAT) promoter, induced

an higher level of transcription than other liver-specific promoters such as alpha-fetoprotein (AFP) and

albumin (Alb) promoter. As a consequence, the enhancement of tissue-specific expression in the context

of Gal4/NF-YA fusion proteins enabled the monitoring of transgene expression using a bioluminescence

imaging system. Furthermore, these vectors have been shown to be non-toxic and exhibited potent

infectivity for proliferating primary HCC cells and HCC cell lines. Together, these results demonstrated

that the new hybrid vectors could provide options for the design of safe and efficient systemic gene

therapeutic strategies for human HCC.

BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensivestrategyAng P, Lim IH, Lee TC, Luo JT, Ong DC, Tan PH, Lee AS

Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2276-84.

AbstractBackground and Objective: Genetic testing for germ line mutations in the BRCA1 and BRCA2 genes

for some families at high risk for breast and/or ovarian cancer may yield negative results due to unidentified

mutations or mutations with unknown clinical significance. We aimed to accurately determine the prevalence

of mutations in these genes in an Asian clinic-based population by using a comprehensive testing strategy.

Materials and Methods: Ninety-four subjects from 90 families were accrued from risk assessment clinics.

In addition to conventional mutational screening of BRCA1 and BRCA2, multiplex ligation-dependent

probe amplification for the detection of large genomic rearrangements, evaluation of splice site alterations

using transcript analysis and SpliceSiteFinder prediction, and analysis of missense mutations of unknown

significance by multiple sequence alignment, PolyPhen analysis, and comparison of Protein Data Bank

structures were incorporated into our testing strategy.

Results: The prevalence rates for clearly deleterious BRCA1 and BRCA2 mutations were 6.7% (6 of 90)

and 8.9% (8 of 90), respectively, or 7.8% (7 of 90) and 11.1% (10 of 90), respectively, by including missense

mutations predicted to be deleterious by computational analysis. In contrast to observations from European

and American populations, deleterious mutations in BRCA2 (10 families) were more common than for

BRCA1 (7 families). Overall, the frequency of mutations was 12.2% (n=11) by conventional screening.

However, by including deleterious mutations detected using multiplex ligation-dependent probe amplification

(n=1), transcript analysis (n=2), and computational evaluation of missense mutations (n=3), the frequency

increased substantially to 18.9%. This suggests that the comprehensive strategy used is effective for

identifying deleterious mutations in Asian individuals at high risk for breast and/or ovarian cancer.

> 84

1. Vikhanskaya F, Toh WH, Dulloo I, Wu Q, Boominathan L, Ng HH, Vousden KH, Sabapathy K (2007)

p73 supports cellular growth through c-Jun-dependent AP-1 transactivation . Nat Cell Biol 9(6): 698-705

2. Grundy RG, Wilne SA, Weston CL, Robinson K, Lashford LS, Ironside J, Cox T, Chong WK,

Campbell RH, Bailey CC, Gattamaneni R, Picton S, Thorpe N, Mallucci C, English MW, Punt JA,

Walker DA, Ellison DW (2007) Primary postoperative chemotherapy without radiotherapy forintracranial ependymoma in children: the UKCCSG/SIOP prospective study . Lancet Oncol 8(8): 696-705

3. Thong PS, Ong KW, Goh NS, Kho KW, Manivasager V, Bhuvaneswari R, Olivo M, Soo KC (2007)

Photodynamic-therapy-activated immune response against distant untreated tumours inrecurrent angiosarcoma . Lancet Oncol 8(10) : 950-952

4. Wong MC, ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A (2007)

Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial originESPRIT: a randomised controlled trial . Lancet Neurol 6(2) : 115-24

5. Hettinger K, Vikhanskaya F, Poh MK, Lee MK, de Belle I, Zhang JT, Reddy SA, Sabapathy K (2007)

c-Jun promotes cellular survival by suppression of PTEN . Cell Death Differ 14(2) : 218-229

6. Wang Z, Wang J, Tantoso E, Wang B, Tai AY, Ooi LL, Chong SS, Lee CG (2007) Signatures ofrecent positive selection at the ATP-binding cassette drug transporter superfamily gene loci. Hum Mol Genet 16(11) : 1367-1380

7. Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG, Jordan SC, Yap HK (2007) Overexpressionof interleukin-13 induces minimal-change-like nephropathy in rats . J Am Soc Nephrol 18(5): 1476-1485

8. Iyer NG, Xian J, Chin SF, Bannister AJ, Daigo Y, Aparicio S, Kouzarides T, Caldas C (2007) p300is required for orderly G1/S transition in human cancer cells . Oncogene 26(1) : 21-29

9. Furge KA, Tan MH, Dykema K, Kort E, Stadler W, Yao X, Zhou M, Teh BT (2007) Identificationof deregulated oncogenic pathways in renal cell carcinoma: an integrated oncogenomicapproach based on gene expression profiling . Oncogene 26(9) : 1346-1350

10. Leong CT, Ong CK, Tay SK, Huynh H (2007) Silencing expression of UO-44 (CUZD1) usingsmall interfering RNA sensitizes human ovarian cancer cells to cisplatin in vitro . Oncogene 26(6): 870-880

11. Ong CK, Leong C, Tan PH, Van T, Huynh H (2007) The role of 5' untranslated region intranslational suppression of OKL38 mRNA in hepatocellular carcinoma . Oncogene 26(8) :1155-1165

12. Chin SF, Wang Y, Thorne NP, Teschendorff AE, Pinder SE, Vias M, Naderi A, Roberts I, Barbosa-

Morais NL, Garcia MJ, Iyer NG, Kranjac T, Robertson JF, Aparicio S, Tavaré S, Ellis I, Brenton JD,

Caldas C (2007) Using array-comparative genomic hybridization to define molecular portraitsof primary breast cancers . Oncogene 26(13) : 1959-1970

13. Phang BH, Sabapathy K (2007) The codon 72 polymorphism-specific effects of human p53are absent in mouse cells: implications on generation of mouse models . Oncogene 26(21): 2964-2974

14. Lau WM, Ho TH, Hui KM (2007) p16INK4A-silencing augments DNA damage-induced apoptosisin cervical cancer cells . Oncogene 26(41) : 6050-6060


> 85

15. Lim SK, Gopalan G (2007) Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A . Oncogene 26(46) : 6593-6603

16. De Silva DA, Woon FP, Lee MP, Chen CP, Chang HM, Wong MC (2007) South Asian patientswith ischemic stroke: intracranial large arteries are the predominant site of disease . Stroke 38(9) : 2592-2594

17. Yao X, Qian CN, Zhang ZF, Tan MH, Kort EJ, Yang XJ, Resau JH, Teh BT (2007) Two distincttypes of blood vessels in clear cell renal cell carcinoma have contrasting prognosticimplications . Clin Cancer Res 13(1) : 161-169

18. Wang SM, Ooi LL, Hui KM (2007) Identification and validation of a novel gene signatureassociated with the recurrence of human hepatocellular carcinoma . Clin Cancer Res 13(21): 6275-6283

19. Tan EK, Prakash KM, Fook-Chong S, Yih Y, Chua E, Lum SY, Wong MC, Pavanni R, Zhao Y (2007)

DRD3 variant and risk of essential tremor . Neurology 68(10) : 790-791

20. Tan EK, Tong J, Fook-Chong S, Yih Y, Wong MC, Pavanni R, Zhao Y (2007) Glucocerebrosidasemutations and risk of Parkinson disease in Chinese patients . Arch Neurol 64(7) : 1056-1058

21. Lee MK, Sabapathy K (2007) Phosphorylation at carboxyl-terminal S373 and S375 residuesand 14-3-3 binding are not required for mouse p53 function . Neoplasia 9(9) : 690-698

22. Gough DJ, Sabapathy K, Ko EY, Arthur HA, Schreiber RD, Trapani JA, Clarke CJ, Johnstone RW

(2007) A novel c-Jun-dependent signal transduction pathway necessary for the transcriptionalactivation of interferon gamma response genes . J Biol Chem 282(2) : 938-946

23. Li YF, Tang RH, Puan KJ, Law SK, Tan SM (2007) The cytosolic protein talin induces anintermediate affinity integrin alphaLbeta2 . J Biol Chem 282(33) : 24310-24319

24. Kho KW, Shen ZX, Lei Z, Watt F, Soo KC, Olivo M (2007) An Investigation into a SurfacePlasmon Related Heating Effect in Surface Enhanced Raman Spectroscopy . Anal Chem 79(23): 8870-8882

25. Du HY, Olivo M, Mahendran R, Huang Q, Shen HM, Ong CN, Bay BH (2007) Hypericinphotoactivation triggers down-regulation of matrix metalloproteinase-9 expression in well-differentiated human nasopharyngeal cancer cells . Cell Mol Life Sci 64(7-8) : 979-988

26. Tan K, Cheang P, Ho IA, Lam PY, Hui KM (2007) Nanosized bioceramic particles could functionas efficient gene delivery vehicles with target specificity for the spleen . Gene Ther 14(10) :828-835

27. Huynh H, Soo KC, Chow PK, Tran E (2007) Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment ofhepatocellular carcinoma . Mol Cancer Ther 6(1) : 138-146

28. Huynh H (2007) Bevacizumab plus 5-fluorouracil induce growth suppression in the CWR-22 and CWR-22R prostate cancer xenografts . Mol Cancer Ther 6(8) : 2149-2157

29. Huynh H, Chow PK, Soo KC (2007) AZD6244 and doxorubicin induce growth suppressionand apoptosis in mouse models of hepatocellular carcinoma . Mol Cancer Ther 6(9) : 2468-2476

30. Huynh H, Teo CC, Soo KC (2007) Bevacizumab and rapamycin inhibit tumor growth inperitoneal model of human ovarian cancer . Mol Cancer Ther 6(11) : 2959-2966

> 86

31. Ha TC, Li H (2007) Meta-analysis of clodronate and breast cancer survival . Br J Cancer 96(12): 1796-1801

32. Oh WK, Tay MH, Huang J (2007) Is there a role for platinum chemotherapy in the treatmentof patients with hormone-refractory prostate cancer? . Cancer 109(3) : 477-86

33. Chen W, Salto-Tellez M, Palanisamy N, Ganesan K, Hou Q, Tan LK, Sii LH, Ito K, Tan B, Wu J, Tay

A, Tan KC, Ang E, Tan BK, Tan PH, Ito Y, Tan P (2007) Targets of genome copy number reductionin primary breast cancers identified by integrative genomics . Genes Chromosomes Cancer 46(3): 288-301

34. Yu XY, Lin SG, Zhou ZW, Chen X, Liang J, Liu PQ, Duan W, Chowbay B, Wen JY, Li CG, Zhou SF

(2007) Role of P-Glycoprotein in the Intestinal Absorption of Tanshinone IIA, a Major ActiveIngredient in the Root of Salvia miltiorrhiza Bunge . Curr Drug Metab 8(4) : 325-340

35. Yu XY, Lin SG, Chen X, Zhou ZW, Liang J, Duan W, Chowbay B, Wen JY, Chan E, Cao J, Li CG,

Zhou SF (2007) Transport of cryptotanshinone, a major active triterpenoid in salvia miltiorrhizabunge widely used in the treatment of stroke and Alzheimer's disease, across the blood-brain barrier . Curr Drug Metab 8(4) : 365-378

36. Wang XD, Li JL, Su QB, Deng XY, Lu Y, Chen J, Zhang JX, Zhao LZ, Zuo Z, Chan E, Chen X,

Chowbay B, Xue CC, Huang M, Zhou SF (2007) A pharmacogenetic study of pregnane Xreceptor (NR1I2) in Han Chinese . Curr Drug Metab 8(8) : 778-786

37. Capra M, Hewitt M, Radford M, Hayward J, Weston CL, Machin D, Children's Cancer and Leukaemia

Group (2007) Long-term outcome in children with Hodgkin's lymphoma: the United KingdomChildren's Cancer Study Group HD82 trial . Eur J Cancer 43(7) : 1171-1179

38. Ho KY, Cheng J, Wee A, Soo KC (2007) Primary malignant melanoma of the esophagus withmultiple esophageal lesions . Nat Clin Pract Gastroenterol Hepatol 4(3) : 171-174

39. Gao F, Tan SB, Machin D, Wong NS (2007) Confirmation of double-peaked time distributionof mortality for Asian breast cancer patients in a population-based study . Breast Cancer

Res 9(2) : R21

40. Wang GY, Ho IA, Sia KC, Miao L, Hui KM, Lam PY (2007) Engineering An Improved Cell Cycle-Regulatable Herpes Simplex Virus Type 1 Amplicon Vector with Enhanced TransgeneExpression in Proliferating Cells Yet Attenuated Activities in Resting Cells . Hum Gene

Ther 18(3) : 222-231

41. Shim WS, Ho IA, Wong PE (2007) Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis .Mol Cancer Res 5(7) : 655-665

42. Goh AS, Chung AY, Lo RH, Lau TN, Yu SW, Chng M, Satchithanantham S, Loong SL, Ng DC, Lim

BC, Connor S, Chow PK (2007) A novel approach to brachytherapy in hepatocellular carcinomausing a phosphorous(32) ((32)P) brachytherapy delivery device-a first-in-man study . Int J

Radiat Oncol Biol Phys 67(3 : 786-792

43. Kang KB, Wang TT, Woon CT, Cheah ES, Moore XL, Zhu C, Wong MC (2007) Enhancement ofglioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: Inhibition of tumorangiogenesis with extensive tumor necrosis . Int J Radiat Oncol Biol Phys 67(3) : 888-896


> 87

44. Whiteman M, Chu SH, Siau JL, Rose P, Sabapathy K, Schantz JT, Cheung NS, Spencer JP,

Armstrong JS (2007) The pro-inflammatory oxidant hypochlorous acid induces Bax-dependentmitochondrial permeabilisation and cell death through AIF-/EndoG-dependent pathways .Cell Signal 19(4) : 705-714

45. Lim SK, Gopalan G (2007) Aurora-A kinase interacting protein 1 (AURKAIP1) promotesAurora-A degradation through an alternative ubiquitin-independent pathway . Biochem

J 403(1) : 119-127

46. Tan EK, Zhao Y, Skipper L, Tan MG, Di Fonzo A, Sun L, Fook-Chong S, Tang S, Chua E, Yuen Y,

Tan L, Pavanni R, Wong MC, Kolatkar P, Lu CS, Bonifati V, Liu JJ (2007) The LRRK2 Gly2385Argvariant is associated with Parkinson's disease: genetic and functional evidence . Hum Genet

120(6) : 857-863

47. Lian D, Cheah E, Tan PH, Thng CH, Tan SM (2007) Phyllodes tumour with intraductal growth:a rare cause of nipple discharge . Histopathology 50(5) : 666-669

48. Li XM, Li CC, Yu SS, Chen JT, Sabapathy K, Ruan DY (2007) JNK1 contributes to metabotropicglutamate receptor-dependent long-term depression and short-term synaptic plasticity inthe mice area hippocampal CA1 . Eur J Neurosci 25(2) : 391-396

49. Toh CK, Gao F, Lim WT, Leong SS, Fong KW, Yap SP, Hsu AA, Eng P, Koong HN, Thirugnanam

A, Tan EH (2007) Differences between small-cell lung cancer and non-small-cell lung canceramong tobacco smokers . Lung Cancer 56(2) : 161-166

50. Yu XY, Lin SG, Zhou ZW, Chen X, Liang J, Yu XQ, Chowbay B, Wen JY, Duan W, Chan E, Li XT,

Cao J, Li CG, Xue CC, Zhou SF (2007) Role of P-glycoprotein in limiting the brain penetrationof glabridin, an active isoflavan from the root of Glycyrrhiza glabra . Pharm Res 24(9) : 1668-1690

51. Chin WW, Lau W, Ramaswamy B, Heng PW, Olivo M (2007) Chlorin e6-polyvinylpyrrolidoneas a fluorescent marker for fluorescence diagnosis of human bladder cancer implanted onthe chick chorioallantoic membrane model . Cancer Lett 245(1-2) : 127-133

52. Wee HL, Li SC, Xie F, Zhang XH, Luo N, Feeny D, Cheung YB, Machin D, Fong KY, Thumboo J

(2007) Validity, feasibility and acceptability of time trade-off and standard gamble assessmentsin health valuation studies: a study in a multiethnic Asian population in Singapore . Value

Health 11 Suppl 1 : S3-S10

53. Wee HL, Machin D, Loke WC, Li SC, Cheung YB, Luo N, Feeny D, Fong KY, Thumboo J (2007)

Assessing differences in utility scores: a comparison of four widely used preference-basedinstruments . Value Health 10(4) : 256-265

54. Lal S, Wong ZW, Jada SR, Xiang X, Chen Shu X, Ang PC, Figg WD, Lee EJ, Chowbay B (2007)

Novel SLC22A16 polymorphisms and influence on doxorubicin pharmacokinetics in Asianbreast cancer patients . Pharmacogenomics 8(6) : 567-575

55. Yoong JK, Chew LC, Quek R, Lim CH, Zai JQ, Fong KY, Thumboo J (2007) Cardiac lymphomain primary Sjogren syndrome: a novel case established by targeted imaging and pericardialwindow . J Thorac Cardiovasc Surg 134(2) : 513-514

56. Puan KJ, Jin C, Wang H, Sarikonda G, Raker AM, Lee HK, Samuelson MI, Märker-Hermann E,

Pasa-Tolic L, Nieves E, Giner JL, Kuzuyama T, Morita CT (2007) Preferential recognition of amicrobial metabolite by human Vgamma2Vdelta2 T cells . Int Immunol 19(5) : 657-673

> 88

57. Tan EK, Tong J, Pavanni R, Wong MC, Zhao Y (2007) Genetic analysis of SCA 2 and 3 repeatexpansions in essential tremor and atypical Parkinsonism . Mov Disord 22(13) : 1971-1974

58. Chia SY, Chua R, Lo YL, Wong MC, Chan LL, Tan EK (2007) Acute ataxia, Graves' disease, andstiff person syndrome . Mov Disord 22(13) : 1969-1971

59. Tan EK, Zhao Y, Tan L, Lim HQ, Lee J, Yuen Y, Pavanni R, Wong MC, Fook-Chong S, Liu JJ (2007)

Analysis of LRRK2 Gly2385Arg genetic variant in non-Chinese Asians . Mov Disord 22(12) :1816-1818

60. Jada SR, Lim R, Wong CI, Shu X, Lee SC, Zhou Q, Goh BC, Chowbay B (2007) Role of UGT1A1*6,UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asiancancer patients . Cancer Sci 98(9) : 1461-1467

61. Thong PS, Olivo M, Kho KW, Zheng W, Mancer K, Harris M, Soo KC (2007) Laser ConfocalEndomicroscopy as a Novel Technique for Fluorescence Diagnostic Imaging of the OralCavity . J Biomed Opt 12(1) : 014007

62. Lee AT, Lee CG (2007) Oncogenesis and transforming viruses: the hepatitis B virus andhepatocellularcarcinoma--the etiopathogenic link . Front Biosci 12 : 234-245

63. Sun YJ, Lee AS, Wong SY, Paton NI (2007) Analysis of the role of Mycobacterium tuberculosiskasA gene mutations in isoniazid resistance . Clin Microbiol Infect 13(8) : 833-835

64. Wang XD, Li JL, Lu Y, Chen X, Huang M, Chowbay B, Zhou SF (2007) Rapid and simultaneousdetermination of nifedipine and dehydronifedipine in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical herb-drug interaction study . J Chromatogr

B Analyt Technol Biomed Life Sci 852(1-2) : 534-544

65. Sun HY, Guan S, Bi HC, Su QB, Huang WL, Chowbay B, Huang M, Chen X, Li CG, Zhou SF (2007)

Determination of CH330331, a novel 4-anilinoquinazoline inhibitor of epidermal growth factorreceptor tyrosine kinase, in human Caco-2 monolayers by high performance liquidchromatography with ultraviolet detection . J Chromatogr B Analyt Technol Biomed Life

Sci 854(1-2) : 320-327

66. Su QB, He F, Guan S, Lu YJ, Gu LQ, Huang ZS, Chen X, Huang M, Li CG, Chowbay B, Zhou SF

(2007) High performance liquid chromatography with ultraviolet detection for the determinationof SYUIQ-5, a novel telomerase inhibitor for cancer therapy: Application to an enzyme kineticstudy in rat liver microsomes . J Chromatogr B Analyt Technol Biomed Life Sci 854(1-2) : 332-337

67. Yip JL, Aung T, Wong TY, Machin D, Khaw PT, Khaw KT, Seah S, Foster PJ (2007) Socioeconomicstatus, systolic blood pressure and intraocular pressure: the Tanjong Pagar Study . Br J

Ophthalmol 91(1) : 56-61

68. Yeo W, Boyer M, Chung HC, Ong SY, Lim R, Zee B, Ma B, Lam KC, Mo FK, Ng EK, Ho R, Clarke

S, Roh JK, Beale P, Rha SY, Jeung HC, Soo R, Goh BC, Chan AT, Cancer Therapeutics Research

Group (CTRG) (2007) Irofulven as first line therapy in recurrent or metastatic gastric cancer:a phase II multicenter study by the Cancer Therapeutics Research Group (CTRG) . Cancer

Chemother Pharmacol 59(3) : 295-300

69. Gao F, Chia KS, Machin D (2007) On the evidence for seasonal variation in the onset of acutelymphoblastic leukemia (ALL) . Leuk Res 31(10) : 1327-1338


> 89

70. Bisdas S, Konstantinou GN, Lee PS, Thng CH, Wagenblast J, Baghi M, Koh TS (2007) Dynamiccontrast-enhanced CT of head and neck tumors: perfusion measurements using a distributed-parameter tracer kinetic model. Initial results and comparison with deconvolution-basedanalysis . Phys Med Biol 52(20) : 6181-6196

71. Hui KM (2007) Current approaches in the transcriptional-guided gene therapy of humanhepatocellular carcinoma . Curr Opin Mol Ther 9(4) : 378-384

72. Toh CK, Lim WT (2007) Lung cancer in never-smokers . J Clin Pathol 60(4) : 337-340

73. Goh BK, Tan YM, Cheow PC, Chung AY, Chow PK, Wong WK, Ooi LL (2007) Solid pseudopapillaryneoplasms of the pancreas: An updated experience . J Surg Oncol 95(8) : 640-644

74. CL Saw, M Olivo, T Wohland, CY Fu, KW Kho, KC Soo, PW Heng (2007) Effects of N-MethylPyrrolidone on the Uptake of Hypericin in Human Bladder Carcinoma and Co-staining withDAPI Investigated by Confocal Microscopy . Technol Cancer Res Treat 6(5) : 383-394

75. Goh BK, Tan YM, Chung AY, Chow PK, Cheow PC, Thng CH, Mesenas S, Wong WK, Ooi LL (2007)

Pancreatic cysts: a proposed management algorithm based on current evidence . Am J

Surg 193(6) : 749-755

76. Goh BK, Teo MC, Chng SP, Soo KC (2007) Right-sided Bochdalek's hernia in an adult . Am

J Surg 194(3) : 390-391

77. Goh C (2007) The Asia pacific hospice palliative care network: supporting individuals anddeveloping organizations . J Pain Symptom Manage 33(5) : 563-567

78. De Silva DA, Woon FP, Pin LM, Chen CP, Chang HM, Wong MC (2007) Intracranial large arterydisease among OCSP subtypes in ethnic South Asian ischemic stroke patients . J Neurol

Sci 260(1-2) : 147-149

79. Olivo M, Ali SM (2007) Apoptosis signalling mechanisms in human cancer cells induced byCalphostin-PDT . Int J Oncol 30(3) : 537-548

80. Fu CY, Ng BK, Razul SG, Chin WW, Tan PH, Lau WK, Olivo M (2007) Fluorescence detectionof bladder cancer using urine cytology . Int J Oncol 31(3) : 525-530

81. Quek R, Lim WT, Foo KF, Koo WH, A-Manaf A, Toh HC (2007) Capecitabine and oxaliplatin(XELOX) is safe and effective in patients with advanced gastric cancer . Acta Oncol 46(7) :1032-1034

82. Toh CK, Lee P, Chowbay B, Goh JW, Mancer K, Tan PH (2007) An inflammatory response withworsening of pleural effusion on treatment with erlotinib in non-small cell lung cancer . Acta

Oncol 46(2) : 256-258

83. Thia TJ, Lui HF, Ooi LL, Chung AY, Chow PK, Cheow PC, Tan YM, Chow WC (2007) A study intothe risk of exacerbation of chronic hepatitis B after liver resection for hepatocellular carcinoma. J Gastrointest Surg 11(5) : 612-618

84. Thumboo J, Wee HL, Cheung YB, Machin D, Luo N, Feeny D, Fong KY (2007) Computerizedadministration of health-related quality of life instruments compared to intervieweradministration may reduce sample size requirements in clinical research: a pilot randomizedcontrolled trial among rheumatology patients . Clin Exp Rheumatol 25(4) : 577-583

> 90

85. Sun YJ, Lee AS, Wong SY, Heersma H, Kremer K, Van Soolingen D, Paton NI (2007) Genotypeand Phenotype Relationships and Transmission Analysis of Drug-resistant Tuberculosis inSingapore . Int J Tuberc Lung Dis 11(4) : 436-442

86. Bhuvaneswari R, Gan YY, Soo KC, Olivo M (2007) Hypericin-mediated photodynamic therapyin combination with Avastin (Bevacizumab) improves tumor response by downregulatingangiogenic proteins . Photochem Photobiol Sci 6(12) : 1275-1283

87. Jada SR, Xiaochen S, Yan LY, Xiaoqiang X, Lal S, Zhou SF, Ooi LL, Chowbay B (2007)

Pharmacogenetics of SLCO1B1: haplotypes, htSNPs and hepatic expression in three distinctAsian populations . Eur J Clin Pharmacol 63(6) : 555-563

88. Lim ST, Gao F, Quek R, Lim LC, Lai LH, Yap SP, Loong SL, Tao M (2007) The relationship ofhepatitis B virus infection and non-Hodgkins Lymphoma and its impact on clinicalcharacteristics and prognosis . Eur J Haematol 79(2) : 132-137

89. Yu XY, Lin SG, Zhou ZW, Chen X, Liang J, Duan W, Yu XQ, Wen JY, Chowbay B, Li CG, Sheu FS,

Chan E, Zhou SF (2007) Tanshinone IIB, a primary active constituent from Salvia miltiorrhza,exhibits neuro-protective activity in experimentally stroked rats . Neurosci Lett 417(3) : 261-265

90. Sia KC, Wang GY, Ho IA, Khor HY, Miao L, Hui KM, Lam PY (2007) Optimal purification methodfor Herpes-based viral vectors that confers minimal cytotoxicity for systemic route of vectoradministration . J Virol Methods 139(2) : 166-174

91. Liu HB, Gong HQ, Ramalingam N, Jiang Y, Dai CC, Hui KM (2007) Micro Air bubble formationand its control during Polymerase Chain Reaction (PCR) in polydimethylsiloxane (PDMS)microreactors . J Micromech Microeng 17(10) : 2055-2064

92. Saw CL, Olivo M, Chin WW, Soo KC, Heng PW (2007) Superiority of N-methyl pyrrolidone overalbumin with hypericin for fluorescence diagnosis of human bladder cancer cells implantedin the chick chorioallantoic membrane model . J Photochem Photobiol B 86(3) : 207-218

93. VITATOPS Trial Study Group, Hankey GJ, Algra A, Chen C, Wong MC, Cheung R, Wong L, Divjak

I, Ferro J, de Freitas G, Gommans J, Groppa S, Hill M, Spence D, Lees K, Lisheng L, Navarro J,

Ranawaka U, Ricci S, Schmidt R, Slivka A, Tan K, Tsiskaridze A, Uddin W, Vanhooren G, Xavier

D, Armitage J, Hobbs M, Le M, Sudlow C, Wheatley K, Yi Q, Bulder M, Eikelboom JW, Loh K, Ho

WK, Jamrozik K, Klijn K, Koedam E, Langton P, Nijboer E, Tuch P, Pizzi J, Tang M, Antenucci M,

Chew Y, Chinnery D, Cockayne C, Chen C, McMullin L, Smith F, Wong MC, Loh K (2007) VITATOPS,the VITAmins TO prevent stroke trial: rationale and design of a randomised trial of B-vitamintherapy in patients with recent transient ischaemic attack or stroke (NCT00097669)(ISRCTN74743444). . Int J Stroke 2(2) : 144-150

94. Bisdas S, Baghi M, Wagenblast J, Knecht R, Thng CH, Koh TS, Vogl TJ (2007) Differentiationof benign and malignant parotid tumors using deconvolution-based perfusion CT imaging:feasibility of the method and initial results . Eur J Radiol 64(2) : 258-265

95. Bhuvaneswari R, Gan YY, Yee KK, Soo KC, Olivo M (2007) Effect of hypericin-mediatedphotodynamic therapy on the expression of vascular endothelial growth factor in humannasopharyngeal carcinoma . Int J Mol Med 20(4) : 421-428

96. Shen Y, Wilder-Smith E, Yu E, Ng YK, Ling EA, Spence I, Wong MC (2007) A novel methodologyto probe endothelial differential gene expression profile reveals novel genes . Endothelium 14(6): 303-314


> 91

97. Wong CW, Choo SP, Foo KF (2007) The not so innocuous abdominal tap . Palliat Med

21(1) : 62

98. Lim WT, Zhang WH, Miller CR, Watters JW, Gao F, Viswanathan A, Govindan R, McLeod HL (2007)

PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-smallcell lung cancer . Oncol Rep 17(4) : 853-857

99. Huynh H, Servant N, Chalifour LE (2007) The ubiquinol-cytochrome-c reductase 7.2kD proteinof mitochondria complex III is steroid responsive and increased in cardiac hypertrophy andhypertension . Can J Physiol Pharmacol 85(10) : 986-96

100. Verma S, Wong NS, Trudeau M, Joy A, Mackey J, Dranitsaris G, Clemons M (2007) Survivaldifferences observed in metastatic breast cancer patients treated with capecitabine whencompared with vinorelbine after pretreatment with anthracycline and taxane . Am J Clin

Oncol 30(3) : 297-302

101. Tan SB, Machin D (2007) Letter to the Editor: Phase II trial designs in the presence ofstratification . Stat Med 25(18) : 3220-3222

102. Lim ST, Fayad L, Tulpule A, Modiano M, Cabanillas F, Laffranchi B, Allievi C, Bernareggi A, Levine

AM (2007) A phase I/II trial of pixantrone (BBR2778), methylprednisolone, cisplatin,and cytosine arabinoside (PSHAP) in relapsed/refractory aggressive non-Hodgkin'slymphoma . Leuk Lymphoma 48(2) : 374-380

103. Leong SS, Toh CK, Lim WT, Lin X, Tan SB, Poon D, Tay MH, Foo KF, Ho J, Tan EH (2007) Arandomized phase II trial of single-agent gemcitabine, vinorelbine, or docetaxel in patientswith advanced non-small cell lung cancer who have poor performance status and/or areelderly . J Thorac Oncol 2(3) : 230-236

104. Lim EH, Zhang SL, Yu K, Nga ME, Ahmed DA, Agasthian T, Wong PS, Chua GC, Wong D, Tan L,

Seto KY, Yap WS, Low SP, Khoo KL, Chang A, Ng A, Tan P (2007) An alternative approach todetermining therapeutic choices in advanced non-small cell lung carcinoma (NSCLC):maximizing the diagnostic procedure and the use of low-volume lung biopsies . J Thorac

Oncol 2(5) : 387-396

105. Leong SS, Fong KW, Lim WT, Toh CK, Yap SP, Tan EH (2007) Combined modality treatmentusing a non-platinum-containing regimen and concurrent radiotherapy in the treatment oflocally-advanced non-small cell lung cancer . J Thorac Oncol 2(8) : S649

106. Tan EH, Grodzki T, Schneider CP, Zatloukal P, Reck M, Aitini E, Rolski J (2007) Global LungOncology Branch trial 3 (Glob 3): final results of a randomised multinational Phase III studyof oral and i.v. vinorelbine (NVB) plus cisplatin (CDDP) versus docetaxel (DTX) plus CDDPas first-line treatment for advanced NSCLC . J Thorac Oncol 2(8) : S451

107. Lim EH, Tan P (2007) Molecular diagnostics in advanced NSCLC: trying to maximize a non-ideal situation . J Thorac Oncol 2(8) : 782

108. Lim WT, Chuah KL, Agasthian T, Chowbay B, Eng P, Leong SS, Tan EH, Hee SW, Koong HN, Toh

CK (2007) Phenotypic differences between sexes and absence of human papillomavirusand Epstein-Barr virus in non-smokers with lung adenocarcinoma in Singapore: P3-011 . JThorac Oncol 2(8) Suppl4 : S503-S511

109. Goh BK, Chen JJ, Tan HK, Yong WS, Chan WH (2007) Acute variceal bleed in a patient withidiopathic myelofibrosis successfully treated with endoscopic variceal band ligation . Dig

Dis Sci 52(1) : 173-175

> 92

110. Chung AY, Chui CH, Tan YM, Kwek BH, Tan HW, Thng CH, Toh HC (2007) Giant Cystic ColorectalLiver Metastasis: An Unusual Presentation . Dig Dis Sci 52(9) : 2333-2335

111. Choo SP, Venook AP (2007) An alternative therapy for patients with hepatic impairment? .Onkologie 30(10) : 474-475

112. Lye KW, Wee J, Gao F, Neo PS, Soong YL, Poon CY (2007) The effect of prior radiation therapyfor treatment of nasopharyngeal cancer on wound healing following extractions: incidenceof complications and risk factors . Int J Oral Maxillofac Surg 36(4) : 315-320

113. Koo SH, Ong TC, Chong KT, Lee CG, Chew FT, Lee EJ (2007) Multiplexed genotyping of ABCtransporter polymorphisms with the Bioplex suspension array . Biol Proced Online 9 : 27-42

114. Teo HE, Peh WC, Akhilesh M, Tan SB, Ishida T (2007) Congenital osteofibrous dysplasiaassociated with pseudoarthrosis of the tibia and fibula . Skeletal Radiol 36(Supplement 1) :7-14

115. Chew MH, Khoo JB, Chong VF, Tai BC, Soo KC, Lim DT (2007) Significance of tumour volumemeasurements in tongue cancer: a novel role in staging . ANZ J Surg 77(8) : 632-637

116. Soon JL, Poopalalingam R, Lim CH, Koong HN, Agasthian T (2007) Peripheral cardiopulmonarybypass-assisted thymoma resection . J Cardiothorac Vasc Anesth 21(6) : 867-869

117. Toh CK, Hee SW, Lim WT, Leong SS, Fong KW, Yap SP, Hsu AA, Eng P, Koong HN, Agasthian T,

Tan EH (2007) Survival of small-cell lung cancer and its determinants of outcome in Singapore. Ann Acad Med Singapore 36(3) : 181-188

118. Kang GC, Soo KC, Lim DT (2007) Extracranial non-vestibular head and neck schwannomas:a ten-year experience . Ann Acad Med Singapore 36(4) : 233-238

119. See SJ, Ty A, Wong MC (2007) Salvage chemotherapy in progressive high-grade astrocytoma. Ann Acad Med Singapore 36(5) : 343-346

120. Wee HL, Loke WC, Li SC, Fong KY, Cheung YB, Machin D, Luo N, Thumboo J (2007)

Cross-Cultural Adaptation and Validation of Singapore Malay and Tamil Versions of the EQ-5D . Ann Acad Med Singapore 36(6) : 403-406

121. Low JS, Koh WY, Yap SP, Fong KW (2007) Radical Radiotherapy in Stage I Non-small CellLung Cancer (NSCLC) - Singapore National Cancer Centre Experience . Ann Acad Med

Singapore 36(9) : 778-783

122. Ngo LS, Yeo A, Wong AS, Tay MH (2007) Efficacy of Low-dose Ketoconazole in HormoneRefractory Prostate Cancer Patients at the National Cancer Centre and The Cancer Institute,Singapore . Ann Acad Med Singapore 36(10) : 811-814

123. Wijaya R, Yong WS, Yeo AW, See DT (2007) Managing breast cancer diagnosed in first trimesterpregnancy: a case report . Ann Acad Med Singapore 36(12) : 1024-1027

124. De Silva DA, Ong SH, Elumbra D, Wong MC, Chen CL, Chang HM (2007) Timing of hospitalpresentation after acute cerebral infarction and patients' acceptance of intravenousthrombolysis . Ann Acad Med Singapore 36(4) : 244-246

125. Chandran NS, Greaves M, Gao F, Lim L, Cheng BC (2007) Psoriasis and the eye: prevalenceof eye disease in Singaporean Asian patients with psoriasis . J Dermatol 34(12) : 805-810


> 93

126. Goh BK, Yeo AW, Koong HN, Ooi LL, Wong WK (2007) Laparotomy for Acute Complicationsof Gastrointestinal Metastases from Lung Cancer: Is it a Worthwhile or Futile Effort? . Surg

Today 37(5) : 370-374

127. Zhou JY, Chong VF, Khoo JB, Chan KL, Huang J (2007) The relationship between nasopharyngealcarcinoma tumor volume and TNM T-classification: a quantitative analysis . Eur Arch

Otorhinolaryngol 264(2) : 169-174

128. Yeow VK, Lee ST, Cheng JJ, Koh A, Wong HB, Machin D (2007) Randomised clinical trials inplastic surgery: Survey of output and quality of reporting . J Plast Reconstr Aesthet Surg 60(8): 965-966

129. Kah JC, Kho KW, Lee CG, Sheppard CJ, Shen ZX, Soo KC, Olivo M (2007) Early diagnosis oforal cancer based on the surface plasmon resonance of gold nanoparticles . Int J

Nanomedicine 2(4) : 785-798

130. Machin D, Tan SB (2007) Biometrical aspects of drug development . Ernst Schering Res Found

Workshop (59) : 195-207

131. Machin D, Tan SB (2007) Biometrical aspects of drug development . Appropriate Dose

Selection: How to optimize clinical drug development Chapt 15 : 195-208

132. Wang Z, Chong SS, Lee CG (2007) Characterization of Single Nucleotide Polymorphisms in13 Members of the ABC Drug Transporter Genes in Three Different Populations . The Open

Pharmacol J 1 : 1-12

133. Chin WW, Heng PW, Olivo M (2007) Chlorin e6 - polyvinylpyrrolidone mediated photosensitizationis effective against human non-small cell lung carcinoma compared to small cell lungcarcinoma xenografts . BMC Pharmacol 7(1) : 15

134. Ha TC (2007) Genetic Epidemiology of Cancer . SGH Proceedings 16(3) : 148-151

135. Xu Y, Singh J, Teo HS, Ramakrishna K, Premchandran CS, Chen WS, Kuan CT, Chen NK, Olivo

M, Sheppard CJR (2007) MEMS-based non-rotatory circumferential scanning optical probefor endoscopic optical coherence tomography . Proc SPIE 6627 : 662715

136. Olivo M (2007) New endoscopic technology to detect cancer. The latest confocalendomicroscopy allows early cancer diagnosis at high resolution . Innovations 7(1) : 27-28

137. Huynh H, Tai ES, Gillies PJ (2007) Nutrigenomics-Opportunities in Asia . Forum Nutr 60 : 146-157

138. Chin WW, Ramaswamy B, Thong PS, Heng PW, Gan YY, Olivo M, Soo KC (2007) Preclinical andPilot Clinical Cancer Studies Using Fluorescence-guided Photodynamic Therapy with Chlorine6-polyvinylpyrrolidone and Hypericin . SGH Proceedings 16(3) : 118-126

139. Singh J, Chan CH, Teo HS, Chen NK, Premachandran CS, Sheppard C, Olivo M (2007) Opticalcoherent tomography (OCT) bio-imaging using 3D scanning micromirror . Proc SPIE 6432 :12.702279

140. Mashfiqul MA, Tan YM, Thng CH, Cheow PC, Chung AY, Chow PK, Ooi LL (2007) PedunculatedHCC or adrenal metastasis: a diagnostic conundrum . Singapore Med J 48(2) : e50-2

141. Kho KW, Kah JC, Lee CG, Sheppard CJ, Shen ZX, Soo KC, Olivo M (2007) Applications of goldnanoparticles in the early detection of oral cancer . J Mech Med Biol 7(1) : 19 - 35

> 94

142. Thong PS, Kho KW, Zheng W, Harris M, Soo KC, Olivo M (2007) Development of a LaserConfocal Endomicroscope for In Vivo Fluorescence Imaging . J Mech Med Biol 7(1) : 11-18

143. Sreedharan S, Tan YM, Tan SG, Soo KC, Wong WK (2007) Clinical spectrum and surgicalmanagement of acute mesenteric ischaemia in Singapore . Singapore Med J 48(4) : 319-323

144. Tan HH, Ooi LL, Tan D, Tan CK (2007) Recurrent abdominal pain in a woman with a wanderingspleen . Singapore Med J 48(4) : e122-124

145. Goh BK, Chung AY, Ng DC, Selvarajan S, Soo KC (2007) Positron emission tomography with2-deoxy-2-[18f] fluoro-D-glucose in the detection of malignancy in intraductal papillarymucinous neoplasms of the pancreas . J Pancreas 8(3) : 350-354

146. Zhou SF, Chowbay B (2007) Clinical Significance of Thiopurine S-Methyltransferase GenePolymorphisms . Curr Pharmacogenomics 5(2) : 103-115

147. Mashfiqul MA, Tan YM, Chintana CW (2007) Endometriosis of the inguinal canal mimickinga hernia . Singapore Med J 48(6) : e157-159

148. Zhou SF, Chowbay B, Xue CC (2007) Pharmacogenetics of oxazaphosphorines and the clinicalapplications . Curr Pharmacogenomics 5(2) : 143-156

149. Sreedharan S, Pang CE, Chan GS, Soo KC, Lim DT (2007) Follicular thyroid carcinomapresenting as axial skeletal metastases . Singapore Med J 48(7) : 640-644

150. Soo KC (2007) Voice Conservation Surgery For Laryngeal And Hypopharyngeal Cancer .Singapore Med J 48(7) : 701

151. Choo SP, Lal S, Chowbay B (2007) Pharmacogenetics and ethnicity: An Asian perspective .Pharmacogenomics in Admixed Populations.URL: http://www.landesbioscience.com/books/iu/id/959 9 : 133-152

152. Huynh H (2007) Dietary quercetin inhibits proliferation of lung carcinoma cells . Forum

Nutr 60 : 146-157

153. Ong JC, Chow PK, Chan WH, Chung AY, Thng CH, Wong WK (2007) Hepatocellular carcinomamasquerading as a bleeding gastric ulcer: A case report and a review of the surgicalmanagement . World J Gastroenterol 13(33) : 4523-4525

154. Chang AY, Lopes G, Koo WH, Lim R, Fong FK, Wong JS (2007) Phase II Trial of 5-Fluorouracil/Leucovorin/Gemcitabine/Cisplatin as Second-Line Treatment in Patients withMetastatic or Recurrent Colorectal Carcinoma: A Cancer Therapeutics Research GroupStudy . Clin Colorectal Cancer 6(9) : 646-651

155. Khor TH, Tuan JK, Hee SW, Tham IW (2007) Radical radiotherapy with high-dose rate (HDR)brachytherapy for uterine cervix cancer - long term results . Australas Radiol 51(6)-7 : 570-577

156. Ho SY, Choo SP (2007) Oncological Emergencies: An Overview and Approach . SGH

Proceedings 16(2) : 63-71


> 95

157. De Silva DA, Wong MC, Lee MP, Chen CL, Chang HM (2007) Amphetamine-associated ischemicstroke: clinical presentation and proposed pathogenesis . J Stroke Cerebrovasc Dis 16(4) :185-186

158. De Silva DA, Woon FP, Xie XY, Li Hsian Chen C, Chang HM, Wong MC (2007) Metabolic syndrome

among ethnic South Asian patients with ischemic stroke and comparison with ethnic Chinesepatients: the Singapore General Hospital experience . J Stroke Cerebrovasc Dis 16(3) : 119-121

> 96


Somatic pairing of chromosome 19 in renal oncocytoma is associated with deregulated ELGN2-mediated oxygen-sensing responseKoeman JM, Russell RC, Tan MH, Petillo D, Westphal M, Koelzer K, Metcalf JL, Zhang Z, Matsuda D,

Dykema KJ, Houseman HL, Kort EJ, Furge LL, Kahnoski RJ, Richard S, Vieillefond A, Swiatek PJ, Teh

BT, Ohh M, Furge KA

PLoS Genet. 2008 Sep 5;4(9):e1000176.

AbstractChromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence

in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed

somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences

of somatic pairing have not been established. Gene expression profiling studies revealed that somatic

pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of

the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the

paired regions and resulted in the deregulation of the prolyl-hydroxylase EGLN2 [corrected] a key protein

that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of

EGLN2 [corrected] in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly

suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The

transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional

changes that occur following DNA amplification. Therefore, in addition to numerical and structural

chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic

events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated

gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing

network to the biology of renal oncocytoma.

Integrative genomics identifies RAB23 as an invasion mediator gene in diffuse-type gastric cancerHou Q, Wu YH, Grabsch H, Zhu Y, Leong SH, Ganesan K, Cross D, Tan LK, Tao J, Gopalakrishnan V, Tang

BL, Kon OL, Tan P

Cancer Res. 2008 Jun 15;68(12):4623-30.

AbstractRecurrent genomic amplifications and deletions are frequently observed in primary gastric cancers (GC).

However, identifying specific oncogenes and tumor suppressor genes within these regions can be

challenging, as they often cover tens to hundreds of genes. Here, we combined high-resolution array-

based comparative genomic hybridization (aCGH) with gene expression profiling to target genes within

focal high-level amplifications in GC cell lines, and identified RAB23 as an amplified and overexpressed

Chr 6p11p12 gene in Hs746T cells. High RAB23 protein expression was also observed in some lines

lacking RAB23 amplification, suggesting additional mechanisms for up-regulating RAB23 besides gene

amplification. siRNA silencing of RAB23 significantly reduced cellular invasion and migration in Hs746T

cells, whereas overexpression of RAB23 enhanced cellular invasion in AGS cells. RAB23 amplifications

in primary gastric tumors were confirmed by both fluorescence in situ hybridization and genomic qPCR,

and in two independent patient cohorts from Hong Kong and the United Kingdom RAB23 expression was

significantly associated with diffuse-type GC (dGC) compared with intestinal-type GC (iGC). These results

provide further evidence that dGC and iGC likely represent two molecularly distinct tumor types, and

show that investigating focal chromosomal amplifications by combining high-resolution aCGH with

expression profiling is a powerful strategy for identifying novel cancer genes in regions of recurrent

chromosomal aberration.


> 97

Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancercellsZhao Y, Hamza MS, Leong HS, Lim CB, Pan YF, Cheung E, Soo KC, Iyer NG

Oncogene. 2008 Jan 3;27(1):1-8.

AbstractAlthough Kruppel-like factor 5 (KLF5) is a transcription factor that has been implicated in pathways critical

to carcinogenesis, controversy persists as to whether it functions as a tumor suppressor or as an oncogene.

Here, we describe a novel role for KLF5 in a p53-independent apoptotic pathway. Using RNA-interference

technology, we show that cells deficient in KLF5 have increased sensitivity to DNA damage, regardless

of p53 status. Both p53 and p53-dependent factors are unaffected by KLF5 depletion. Instead, the

apoptotic phenotype consequent to damage is associated with reduced bad phosphorylation, and

downregulation of Pim1. Consistently, transfection of wild-type Pim1 is sufficient to rescue this phenotype.

Previous data have shown a number of putative Sp1-binding consensus sequences on the Pim1 promoter.

Remarkably, chromatin immunoprecipitation studies show that KLF5 binds to the Pim1 promoter, and that

binding increases soon after damage. These results identify a novel, p53-independent apoptotic pathway

through which KLF5 functions in response to DNA damage. Therapeutic deregulation of this pathway

could be used to modulate chemosensitivity.

Clinical validation of a customized multiple signature microarray for breast cancerTan BK, Tan LK, Yu K, Tan PH, Lee M, Sii LS, Wong CY, Ho GH, Yeo AW, Chow PK, Koong HN, Yong WS,

Lim DT, Ooi LL, Soo KC, Tan P

Clin Cancer Res. 2008 Jan 15;14(2):461-9.

AbstractPurpose: Current histopathologic systems for classifying breast tumors require evaluation of multiple

variables and are often associated with significant interobserver variability. Recent studies suggest that

gene expression profiles may represent a promising alternative for clinical cancer classification. Here, we

investigated the use of a customized microarray as a potential tool for clinical practice.

Experimental Design We fabricated custom 188-gene microarrays containing expression signatures for

three breast cancer molecular subtypes [luminal/estrogen receptor (ER) positive, human epidermal growth

factor receptor 2 (HER2), and "basaloid"], the Nottingham prognostic index (NPI-ES), and low histologic

grade (TuM1). The reliability of these multiple-signature arrays (MSA) was tested in a prospective cohort

of 165 patients with primary breast cancer.

Results: The MSA-ER signature exhibited a high concordance of 90% with ER immunohistochemistry

reported on diagnosis (P < 0.001). This remained unchanged at 89% (P < 0.001) when the

immunohistochemistry was repeated using current laboratory standards. Expression of the HER2 signature

showed a good correlation of 76% with HER2 fluorescence in situ hybridization (FISH; ratio > or =2.2; P

< 0.001), which further improved to 89% when the ratio cutoff was raised to > or =5. A proportion of low-

level FISH-amplified samples (ratio, 2.2-5) behaved comparably to FISH-negative samples by HER2

signature expression, HER2 quantitative reverse transcription-PCR, and HER2 immunohistochemistry.

Luminal/ER+ tumors with high NPI-ES expression were associated with high NPI scores (P = 0.001), and

luminal/ER+ TuM1-expressing tumors were significantly correlated with low histologic grade (P = 0.002)

and improved survival outcome in an interim analysis (hazard ratio, 0.2; P = 0.019).

Conclusion: The consistency of the MSA platform in an independent patient population suggests that

custom microarrays could potentially function as an adjunct to standard immunohistochemistry and FISH

in clinical practice.

> 98

PXR pharmacogenetics: association of haplotypes with hepatic CYP3A4 and ABCB1 messengerRNA expression and doxorubicin clearance in Asian breast cancer patientsSandanaraj E, Lal S, Selvarajan V, Ooi LL, Wong ZW, Wong NS, Ang PC, Lee EJ, Chowbay B

Clin Cancer Res. 2008 Nov 1;14(21):7116-26.

AbstractPurpose: To characterize pregnane X receptor (PXR) polymorphic variants in healthy Asian populations

[Chinese, Malay and Indian (n=100 each)], and to investigate the association between PXR haplotypes

and hepatic mRNA expression of PXR and its downstream target genes, CYP3A4 and ABCB1, as well

as their influence on the clearance of doxorubicin in Asian breast cancer patients.

Experimental Design: PXR genotyping was done by direct DNA sequencing, and PXR haplotypes and

haplotype clusters were derived by expectation-maximization algorithm. Genotype-phenotype correlations

were done using Mann-Whitney U test and Kruskal-Wallis test.

Results: Significant interethnic variations were observed in PXR pharmacogenetics among the three Asian

ethnic groups. The expression of PXR mRNA in liver tissues harboring the PXR*1B haplotype clusters was

4-fold lower compared with the non-PXR*1B (*1A + *1C) haplotype clusters [PXR*1B versus PXR*1A;

P=0.015; PXR*1B versus PXR*1C; P=0.023]. PXR*1B-bearing liver tissues were associated with significantly

lower expression of CYP3A4 (PXR*1B versus non-PXR*1B, P=0.030) and ABCB1 (PXR*1B versus non-

PXR*1B, P=0.060) compared with non-PXR*1B-bearing liver tissues. Doxorubicin clearance in breast

cancer patients harboring the PXR*1B haplotypes was significantly lower compared with patients carrying

the non-PXR*1B haplotypes [PXR*1B versus non-PXR*1B, CL/BSA (L h(-1) m(-2)): 20.84 (range, 8.68-

29.24) versus 24.85 (range, 13.80-55.66), P=0.022].

Conclusions: This study showed that PXR*1B was associated with reduced hepatic mRNA expression

of PXR and its downstream targets, CYP3A4 and ABCB1. Genotype-phenotype correlates in breast cancer

patients showed PXR*1B to be significantly associated with lower doxorubicin clearance, suggesting that

PXR haplotype constitution could be important in influencing interindividual and interethnic variations in

disposition of its putative drug substrates.


> 99

1. Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers

GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlö B, De Keyser J, Donnan GA, Estol

C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R,

Skvortsova V, Teal P, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW, Wong MC, PRoFESS

Study Group (2008) Aspirin and extended-release dipyridamole versus clopidogrel forrecurrent stroke . New Eng J Med 359(12) : 1238-1251

2. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers

GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlö'f6f B, De Keyser J, Donnan GA, Estol


Skvortsova V, Teal P, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW, Wong MC, PRoFESS

Study Group (2008) Telmisartan to prevent recurrent stroke and cardiovascular events. .New Eng J Med 359(12) : 1225-1237

3. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X,

Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C, Lonigro RJ, Palanisamy

N, Maher CA, Chinnaiyan AM (2008) Genomic loss of microRNA-101 leads to overexpressionof histone methyltransferase EZH2 in cancer . Science 322(5908) : 1695-1699

4. Lee AS, Ang P (2008) CHEK2*1100delC screening of Asian women with a family history ofbreast cancer is unwarranted . J Clin Oncol 26(14) : 2419-2420

5. Diener HC, Sacco RL, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers

GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlö B, De Keyser J, Donnan GA, Estol


Skvortsova V, Teal P, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW, Wong MC (Prevention

Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group) (2008) Effects ofaspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disabilityand cognitive function after recurrent stroke in patients with ischaemic stroke in thePrevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind,active and placebo-controlled study . Lancet Neurol 7(10) : 875-84

6. Soo KC (2008) Role of comprehensive cancer centres during economic and disease transition:National Cancer Centre, Singapore--a case study . Lancet Oncol 9(8) : 796-802

7. Toh CK (2008) Refining the bipartite model of lung cancer . Lancet Oncol 9(10) : 918-919

8. Pietersen AM, Evers B, Prasad AA, Tanger E, Cornelissen-Steijger P, Jonkers J, van Lohuizen M

(2008) Bmi1 regulates stem cells and proliferation and differentiation of committed cellsin mammary epithelium . Curr Biol 18(14) : 1094-1099

9. Sim SH, Yu Y, Lin CH, Karuturi RK, Wuthiekanun V, Tuanyok A, Chua HH, Ong C, Paramalingam

SS, Tan G, Tang L, Lau G, Ooi EE, Woods D, Feil E, Peacock SJ, Tan P (2008) The core andaccessory genomes of Burkholderia pseudomallei: implications for human melioidosis .PLoS Pathog 4(10) : e1000178

10. Yu K, Ganesan K, Tan LK, Laban M, Wu J, Zhao XD, Li H, Leung CH, Zhu Y, Wei CL, Hooi SC,

Miller L, Tan P (2008) A precisely regulated gene expression cassette potently modulatesmetastasis and survival in multiple solid cancers . PLoS Genet 4(7) : e1000129

11. Sabapathy K, Nam SY (2008) Defective MHC class I antigen surface expression promotescellular survival through elevated ER stress and modulation of p53 function . Cell Death

Differ 15(9) : 1364-1374

> 100

12. Ganesan K, Ivanova T, Wu Y, Rajasegaran V, Wu J, Lee MH, Yu K, Rha SY, Chung HC, Ylstra B,

Meijer G, Kon OL, Grabsch H, Tan P (2008) Inhibition of gastric cancer invasion and metastasisby PLA2G2A, a novel beta-catenin/TCF target gene . Cancer Res 68(11) : 4277-4286

13. Kort EJ, Farber L, Tretiakova M, Petillo D, Furge KA, Yang XJ, Cornelius A, Teh BT (2008) TheE2F3-Oncomir-1 axis is activated in Wilms' tumor . Cancer Res 68(11) : 4034-4038

14. Huang D, Ding Y, Luo WM, Bender S, Qian CN, Kort E, Zhang ZF, VandenBeldt K, Duesbery NS,

Resau JH, Teh BT (2008) Inhibition of MAPK kinase signaling pathways suppressed renalcell carcinoma growth and angiogenesis in vivo . Cancer Res 68(1) : 81-88

15. Lin CH, Bourque G, Tan P (2008) A comparative synteny map of burkholderia species links large-

scale genome rearrangements to fine-scale nucleotide variation in prokaryotes . Mol Biol Evol 25(3)

: 549-558

16. Liu BH, Goh CH, Ooi LL, Hui KM (2008) Identification of unique and common low abundancetumour-specific transcripts by suppression subtractive hybridization and oligonucleotideprobe array analysis . Oncogene 27(29) : 4128-4136

17. Huynh H, Chow PK, Palanisamy N, Salto-Tellez M, Goh BC, Lee CK, Somani A, Lee HS, Kalpana

R, Yu K, Tan PH, Wu J, Soong R, Lee MH, Hor H, Soo KC, Toh HC, Tan P (2008) Bevacizumaband rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Hepatol 49(1) : 52-60

18. Toh WH, Logette E, Corcos L, Sabapathy K (2008) TAp73beta and DNp73beta activate theexpression of the pro-survival caspase-2S . Nucleic Acids Res 36(13) : 4498-4509

19. De Silva DA, Wong TY, Chang HM, Ng BF, Tikellis G, Saw SM, Woon FP, Chen CP, Wong MC

(2008) Is routine retinal examination useful in patients with acute ischemic stroke? . Stroke 39(4) : 1352-1354

20. De Silva DA, Woon FP, Chen CPLH, Chang HM, Wong MC (2008) Response to Letter by Sheik. Stroke 39(1): : e2

21. Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, Ong HS, Chung AY, Chow

PK, Pollock P, Byron S, Tran E (2008) Brivanib alaninate, a dual inhibitor of vascular endothelialgrowth factor receptor and fibroblast growth factor receptor tyrosine kinases, inducesgrowth inhibition in mouse models of human hepatocellular carcinoma . Clin Cancer Res 14(19): 6146-6153

22. Peacock SJ, Schweizer HP, Dance DA, Smith TL, Gee JE, Wuthiekanun V, DeShazer D, Steinmetz

I, Tan P, Currie BJ (2008) Management of accidental laboratory exposure to Burkholderiapseudomallei and B. mallei . Emerg Infect Dis 14(7) : e2

23. Lee MK, Sabapathy K (2008) The R246S hot-spot p53 mutant exerts dominant-negativeeffects in embryonic stem cells in vitro and in vivo . J Cell Science 121(Pt 11) : 1899-1906

24. Sarikonda G, Wang H, Puan KJ, Liu XH, Lee HK, Song Y, Distefano MD, Oldfield E, Prestwich GD,

Morita CT (2008) Photoaffinity antigens for human gammadelta T cells . J Immunol 181(11): 7738-7750

25. Koh TS, Thng CH, Lee PS, Hartono S, Rumpel H, Goh BC, Bisdas S (2008) Hepatic metastases:in vivo assessment of perfusion parameters at dynamic contrast-enhanced MR imagingwith dual-input two-compartment tracer kinetics model . Radiology 249(1) : 307-320


> 101

26. Tan KC (2008) The right posterior hepatic notch sign . Radiology 248(1) : 317-318

27. Wang P, Bowl MR, Bender S, Peng J, Farber L, Chen J, Ali A, Zhang Z, Alberts AS, Thakker RV,

Shilatifard A, Williams BO, Teh BT (2008) Parafibromin, a component of the human PAFcomplex, regulates growth factors and is required for embryonic development and survivalin adult mice . Mol Cell Biol 28(9) : 2930-2940

28. Bisdas S, Donnerstag F, Berding G, Vogl TJ, Thng CH, Koh TS (2008) Computed tomographyassessment of cerebral perfusion using a distributed parameter tracer kinetics model:validation with H(2)((15))O positron emission tomography measurements and initial clinicalexperience in patients with acute stroke . J Cereb Blood Flow Metab 28(2) : 402-411

29. Meng W, Zhang H, Guo T, Pandey C, Zhu Y, Kon OL, Sze SK (2008) One-Step Procedure forPeptide Extraction from In-Gel Digestion Sample for Mass Spectrometric Analysis . Anal

Chem 80(24) : 9379-9851

30. Ou K, Yu K, Kesuma D, Hooi M, Huang N, Chen W, Lee SY, Goh XP, Tan LK, Liu J, Soon SY, Bin

Abdul Rashid S, Putti TC, Jikuya H, Ichikawa T, Nishimura O, Salto-Tellez M, Tan P (2008) Novelbreast cancer biomarkers identified by integrative proteomic and gene expression mapping. J Proteome Res 7(4) : 1518-1528

31. Guo T, Gan CS, Zhang H, Zhu Y, Kon OL, Sze SK (2008) Hybridization of Pulsed-Q Dissociationand Collision-Activated Dissociation in Linear Ion Trap Mass Spectrometer for iTRAQQuantitation . J Proteome Res 7(11) : 4831-4840

32. Teo CR, Wang W, Yang Law H, Lee CG, Chong SS (2008) Single-step scalable-throughputmolecular screening for Huntington disease . Clin Chem 54(6) : 964-972

33. Wang Y, Lee AT, Ma JZ, Wang J, Ren J, Yang Y, Tantoso E, Li KB, Ooi LL, Tan P, Lee CG (2008)

Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target . J Biol Chem 283(19): 13205-13215

34. Sandanaraj E, Jada SR, Shu X, Lim R, Lee SC, Zhou Q, Zhou S, Goh BC, Chowbay B (2008)

Influence of UGT1A9 intronic I399C>T polymorphism on SN-38 glucuronidation in Asiancancer patients . Pharmacogenomics J 8(3) : 174-185

35. Bhuvaneswari R, Gan YY, Lucky SS, Chin WW, Ali SM, Soo KC, Olivo M (2008) Molecularprofiling of angiogenesis in hypericin mediated photodynamic therapy . Mol Cancer 7 : 56

36. Leong SS, Wee J, Rajan S, Toh CK, Lim WT, Hee SW, Tay MH, Poon D, Tan EH (2008) Tripletcombination of gemcitabine, paclitaxel, and carboplatin followed by maintenance 5-fluorouracil and folinic acid in patients with metastatic nasopharyngeal carcinoma . Cancer 113(6) : 1332-1337

37. Lee HH, Zhu Y, Govindasamy KM, Gopalan G (2008) Downregulation of aurora-A overridesestrogen-mediated growth and chemoresistance in breast cancer cells . Endocr Relat

Cancer 15(3) : 765-775

38. Pietersen AM, Horlings HM, Hauptmann M, Langerød A, Ajouaou A, Cornelissen-Steijger P, Wessels

LF, Jonkers J, van de Vijver MJ, van Lohuizen M (2008) EZH2 and BMI1 inversely correlatewith prognosis and TP53 mutation in breast cancer . Breast Cancer Res 10(6) : R109

> 102

39. Ryan G, Martinelli G, Kuper-Hommel M, Tsang R, Pruneri G, Yuen K, Roos D, Lennard A, Devizzi

L, Crabb S, Hossfeld D, Pratt G, Dell'olio M, Choo SP, Bociek RG, Radford J, Lade S, Gianni AM,

Zucca E, Cavalli F, Seymour JF (2008) Primary diffuse large B-cell lymphoma of the breast:prognostic factors and outcomes of a study by the International Extranodal LymphomaStudy Group . Ann Oncol 19(2) : 233-241

40. Boyle P, Anderson BO, Andersson LC, Ariyaratne Y, Auleley GR, Barbacid M, Bartelink H, Baselga

J, Behbehani K, Belardelli F, Berns A, Bishop J, Brawley O, Burns H, Clanton M, Cox B, Currow

D, Dangou JM, de Valeriola D, Dinshaw K, Eggermont A, Fitzpatrick J, Forstmane M, Garaci E,

Gavin AT, Kakizoe T, Kasler M, Keita N, Kerr D, Khayat D, Khleif S, Khuhaprema T, Knezevic T,

Kubinova R, Mallath M, Martin-Moreno J, McCance D, McVie JG, Merriman A, Ngoma T, Nowacki

M, Orgelbrand J, Park JG, Pierotti M, Ashton LP, Puska P, Escobar CV, Rajan B, Rajkumar T,

Ringborg U, Robertson C, Rodger A, Roovali L, Santini LA, Sarhan M, Seffrin J, Semiglazov V,

Shrestha BM, Soo KC, Stamenic V, Tamblyn C, Thomas R, Tuncer M, Tursz T, Vaitkiene R, Vallejos

C, Veronesi U, Wojtyla A, Yach D, Yoo KY, Zatonski W, Zaridze D, Zeng YX, Zhao P, Zheng T (2008)

Need for global action for cancer control . Ann Oncol 19(9) : 1519-1521

41. Lum SS, Chua HW, Li H, Li WF, Rao N, Wei J, Shao Z, Sabapathy K (2008) MDM2 SNP309 Gallele increases risk but the T allele is associated with earlier onset-age of sporadic breastcancers in the Chinese population . Carcinogenesis 29(4) : 754-761

42. Tan HK, Saulnier P, Auperin A, Lacroix L, Casiraghi O, Janot F, Fouret P, Temam S (2008)

Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas . Br J Cancer 99(2): 357-363

43. Morris MR, Gentle D, Abdulrahman M, Clarke N, Brown M, Kishida T, Yao M, Teh BT, Latif F, Maher

ER (2008) Functional epigenomics approach to identify methylated candidate tumoursuppressor genes in renal cell carcinoma . Br J Cancer 98(2) : 496-501

44. Tan WM, Paterson MC, Koo GC, Li HH, Price A, Loong SL (2008) Increased but error-pronenonhomologous end joining in immortalized lymphoblastoid cell extracts from adult cancerpatients with late radionecrosis . Int J Radiat Oncol Biol Phys 72(1) : 178-185

45. Nam SY, Lee MK, Sabapathy K (2008) The tumour-suppressor p53 is not required for pancreaticß cell death during diabetes and upon irradiation . J Physiol-London 586(2) : 407-417

46. Phang BH, Linn YC, Li H, Sabapathy K (2008) MDM2 SNP309 G allele decreases risk but doesnot affect onset age or survival of Chinese leukaemia patients . Eur J Cancer 44(5) : 760-766

47. Goh BK, Tan YM, Chung AY, Cheow PC, Ong HS, Chan WH, Chow PK, Soo KC, Wong WK, Ooi

LL (2008) Critical appraisal of 232 consecutive distal pancreatectomies with emphasis onrisk factors, outcome, and management of the postoperative pancreatic fistula: a 21-yearexperience at a single institution . Arch Surg 143(10) : 956-965

48. Lee TC, Lee AS, Li KB (2008) Incorporating the amino acid properties to predict the significanceof missense mutations . Amino Acids 35(3) : 615-626

49. Tan SY, Ye H, Liu H, Lim KH, Toh HC, Ng CF, Chung AY, Wotherspoon AC, Du MQ (2008)

t(11;18)(q21;q21)-positive transformed MALT lymphoma . Histopathology 52(6) : 777-780

50. Phonthammachai N, Kah JC, Jun G, Sheppard CJ, Olivo M, Mhaisalkar SG, White TJ (2008)

Synthesis of contiguous silica-gold core-shell structures: critical parameters and processes. Langmuir 24(9) : 5109-5112


> 103

51. Yang XJ, Zhou M, Hes O, Shen S, Li R, Lopez J, Shah RB, Yang Y, Chuang ST, Lin F, Tretiakova

MM, Kort EJ, Teh BT (2008) Tubulocystic carcinoma of the kidney: clinicopathologic andmolecular characterization . Am J Surg Pathol 32(2) : 177-187

52. Camparo P, Vasiliu V, Molinie V, Couturier J, Dykema KJ, Petillo D, Furge KA, Comperat EM, Lae

M, Bouvier R, Boccon-Gibod L, Denoux Y, Ferlicot S, Forest E, Fromont G, Hintzy MC, Laghouati

M, Sibony M, Tucker ML, Weber N, Teh BT, Vieillefond A (2008) Renal translocation carcinomas:clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 caseswith a review of the literature . Am J Surg Pathol 32(5) : 656-670

53. Chuang ST, Patton KT, Schafernak KT, Papavero V, Lin F, Baxter RC, Teh BT, Yang XJ (2008)

Over expression of insulin-like growth factor binding protein 3 in clear cell renal cell carcinoma. J Urology 179(2) : 445-449

54. Tan KD, Zhu Y, Tan HK, Rajasegaran V, Aggarwal A, Wu J, Wu HY, Hwang J, Lim DT, Soo KC, Tan

P (2008) Amplification and overexpression of PPFIA1, a putative 11q13 invasion suppressorgene, in head and neck squamous cell carcinoma . Genes Chromosomes Cancer 47(4) : 353-362

55. Goh BK, Tan YM, Thng CH, Cheow PC, Chung AY, Chow PK, Wong WK, Ooi LL (2008) Howuseful are clinical, biochemical, and cross-sectional imaging features in predicting potentiallymalignant or malignant cystic lesions of the pancreas? Results from a single institutionexperience with 220 surgically treated patients . J Am Coll Surg 206(1) : 17-27

56. Bisdas S, Medov L, Baghi M, Konstantinou GN, Wagenblast J, Thng CH, Vogl TJ, Koh TS (2008)

A comparison of tumour perfusion assessed by deconvolution-based analysis of dynamiccontrast-enhanced CT and MR imaging in patients with squamous cell carcinoma of theupper aerodigestive tract . 18(4) : 843-850

57. Bisdas S, Rumboldt Z, Surlan K, Koh TS, Deveikis J, Spampinato MV (2008) Perfusion CTmeasurements in healthy cervical spinal cord: feasibility and repeatability of the study aswell as interchangeability of the perfusion estimates using two commercially availablesoftware packages . Eur Radiol 18(10) : 2321-2328

58. Kah JC, Wan RC, Wong KY, Mhaisalkar S, Sheppard CJ, Olivo M (2008) Combinatorial treatmentof photothermal therapy using gold nanoshells with conventional photodynamic therapy toimprove treatment efficacy: an in vitro study . Lasers Surg Med 40(8) : 584-589

59. Tan DS, Eng PC, Lim ST, Tao M (2008) Primary tracheal lymphoma causing respiratory failure. J Thorac Oncol 3(8) : 929-930

60. Matsuda D, Khoo SK, Massie A, Iwamura M, Chen J, Petillo D, Wondergem B, Avallone M, Kloostra

SJ, Tan MH, Koeman J, Zhang Z, Kahnoski RJ; French Kidney Cancer Study Group, Baba S, Teh

BT (2008) Identification of copy number alterations and its association with pathologicalfeatures in clear cell and papillary RCC . Cancer Lett 272(2) : 260-267

61. Lal S, Sandanaraj E, Wong ZW, Ang PC, Wong NS, Lee EJ, Chowbay B (2008) CBR1 and CBR3pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancerpatients. . Cancer Sci 99(10) : 2045-2054

62. Lal S, Wong ZW, Sandanaraj E, Xiang X, Ang PC, Lee EJ, Chowbay B (2008) Influence of ABCB1and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients .Cancer Sci 99(4) : 816-823

> 104

63. Ma B, Goh BC, Tan EH, Lam KC, Soo R, Leong SS, Wang LZ, Mo F, Chan AT, Zee B, Mok T (2008)

A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP,Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokineticevaluation using peripheral blood mononuclear cells . Invest New Drugs 26(2) : 169-173

64. Sarquis MS, Silveira LG, Pimenta FJ, Dias EP, Teh BT, Friedman E, Gomez RS, Tavares GC, Eng

C, De Marco L (2008) Familial hyperparathyroidism: surgical outcome after 30 years offollow-up in three families with germline HRPT2 mutations . Surgery 143(5) : 630-640

65. Chin WW, Heng PW, Thong PS, Bhuvaneswari R, Hirt W, Kuenzel S, Soo KC, Olivo M (2008)

Improved formulation of photosensitizer chlorin e6 polyvinylpyrrolidone for fluorescencediagnostic imaging and photodynamic therapy of human cancer . Eur J Pharm Biopharm 69(3): 1083-1093

66. Wong WY, Wong JS (2008) Uptake of Tc-99m Methylene Diphosphonate in PeritonealMetastases From Breast Cancer . Clin Nucl Med 33(3) : 218-219

67. Kolomeichuk SN, Terrano DT, Lyle CS, Sabapathy K, Chambers TC (2008) Distinct signalingpathways of microtubule inhibitors - vinblastine and Taxol induce JNK-dependent cell deathbut through AP-1-dependent and AP-1-independent mechanisms, respectively . FEBS

J 275(8) : 1889-1899

68. Lal S, Sandanaraj E, Jada SR, Kong MC, Lee LH, Goh BC, Lee SC, Chowbay B (2008) Influenceof APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients.. Br J Clin Pharmacol 65(2) : 260-264

69. Cao S, Ho GH, Lin VC (2008) Tetratricopeptide repeat domain 9A is an interacting proteinfor tropomyosin Tm5NM-1 . BMC Cancer 8 : 231

70. Yap KY, Chui WK, Chan A (2008) Drug interactions between chemotherapeutic regimensand antiepileptics . Clin Ther 30(8) : 1385-1407

71. Teo FS, Hsu AA, Agasthian T (2008) Recurrent foreign body granuloma with airway obstruction:is there a role for steroids? . J Thorac Cardiovasc Surg 136(1) : 224-225

72. Wee HL, Cheung YB, Loke WC, Tan CB, Chow MH, Li SC, Fong KY, Feeny D, Machin D, Luo N,

Thumboo J (2008) The association of body mass index with health-related quality of life:an exploratory study in a multiethnic Asian population . Value Health 11 Suppl 1 : S105-S114

73. Ho IA, Chan KY, Miao L, Shim WS, Guo CM, Cheang P, Hui KM, Lam PY (2008) HSV-1 ampliconviral vector-mediated gene transfer to human bone marrow-derived mesenchymal stemcells . Cancer Gene Ther 15(9) : 553-562

74. Kah JC, Lau WK, Tan PH, Sheppard CJ, Olivo M (2008) Endoscopic image analysis ofphotosensitizer fluorescence as a promising noninvasive approach for pathological gradingof bladder cancer in situ . J Biomed Opt 13(5) : 054022

75. Kho KW, Qing KZ, Shen ZX, Ahmad IB, Lim SS, Mhaisalkar S, White TJ, Watt F, Soo KC, Olivo

M (2008) Polymer-based microfluidics with surface-enhanced Raman-spectroscopy-activeperiodic metal nanostructures for biofluid analysis . J Biomed Opt 13(5) : 054026

76. Tsao CC, Teh BT, Jonasch E, Shreiber-Agus N, Efstathiou E, Hoang A, Czerniak B, Logothetis C,

Corn PG (2008) Inhibition of Mxi1 suppresses HIF-2alpha-dependent renal cancertumorigenesis . Cancer Biol Ther 7(10) : 1619-1627


> 105

77. Lim WT, Baggstrom MQ, Read W, Fracasso PM, Govindan R (2008) A Phase I trial of weeklydocetaxel and topotecan for solid tumors . Acta Oncol 47(2) : 311-315

78. Ngeow JY, Prakash KM, Chowbay B, Quek ST, Choo SP (2008) Capecitabine-inducedoromandibular dystonia: A case report and literature review . Acta Oncol 447(6) : 1161-1165

79. De Silva DA, Woon FP, Gan HY, Cameron J, Kingwell B, Koh TH, Chen C, Chang HM, Wong MC

(2008) Arterial stiffness, metabolic syndrome and inflammation amongst Asian ischaemicstroke patients . Eur J Neurol 15(8) : 872-875

80. De Silva D, Woon FP, Chen C, Chang HM, Kingwell B, Cameron J, Wong MC (2008) Profile andassociations of central pulse wave velocity and central pulse pressure among ischemicstroke patients . Eur J Neurol 15(2) : 196-198

81. Moe KT, Woon FP, De Silva DA, Wong P, Koh TH, Kingwell B, Chin-Dusting J, Wong MC (2008)

Association of acute ischemic stroke with the MTHFR C677T polymorphism but not withNOS3 gene polymorphisms in a Singapore population . Eur J Neurol 15(12) : 1309-1314

82. Bisdas S, Baghi M, Wagenblast J, Vogl TJ, Thng CH, Koh TS (2008) Gadolinium-enhancedecho-planar T2-weighted MRI of tumors in the extracranial head and neck: Feasibility studyand preliminary results using a distributed-parameter tracer kinetic analysis . J Magn Reson

Imaging 27(5) : 963-969

83. Koh TS, Thng CH, Ho JT, Tan PH, Rumpel H, Khoo JB (2008) Independent component analysisof dynamic contrast-enhanced magnetic resonance images of breast carcinoma: A feasibilitystudy . J Magn Reson Imaging 28(1) : 271-277

84. Chew MH, Chan G, Siddiqui MM, Tai BC, Sivanandan R, Soo KC, Lim DT (2008) Risk-stratifiedManagement of Well-differentiated Thyroid Cancers: A Review of Experience from a SingleInstitution, 1990-2003 . World J Surg 32(3) : 386-394

85. Tan EK, Sie L, Loong SL (2008) Growth rate of patient-derived lymphoblastoid cells withLRRK2 mutations . Mol Genet Metab 95(1-2) : 113

86. Tan CY, Ho JF, Yap SC, Loganath A, Chan YH, Jeganathan R, Lee CG, Chong SS (2008) Paternalcontribution of HLA-G*0106 significantly increases risk for pre-eclampsia in multigravidpregnancies . Mol Hum Reprod 14(5) : 317-234

87. Koh TS (2008) On the a priori identifiability of the two-compartment distributed parametermodel from residual tracer data acquired by dynamic contrast-enhanced imaging . IEEE

Trans Biomed Eng 55(1) : 340-344

88. Goh BK, Chow PK, Kesavan S, Yap WM, Wong WK (2008) Outcome after surgical treatmentof suspected gastrointestinal stromal tumors involving the duodenum: is limited resectionappropriate? . J Surg Oncol 97(5) : 388-391

89. Zhang ZF, Matsuda D, Khoo SK, Buzzitta K, Block E, Petillo D, Richard S, Anema J, Furge KA,

Teh BT (2008) A comparison study reveals important features of agreement and disagreementbetween summarized DNA and RNA data obtained from renal cell carcinoma. . Mutat Res-

Gen Tox En 657(1) : 77-83

90. Selvarajan S, Sii LH, Lee A, Yip G, Bay BH, Tan MH, Teh BT, Tan PH (2008) Parafibrominexpression in breast cancer: a novel marker for prognostication? . J Clin Pathol 61(1) : 64-67

> 106

91. Soon SR, Yong WS, Ho GH, Wong CY, Ho BC, Tan PH (2008) Adenoid cystic breast carcinoma:a salivary gland-type tumour with excellent prognosis and implications for management .Pathology 40(4) : 413-415

92. Goh BK, Chow PK, Kesavan S, Yap WM, Ong HS, Song IC, Eu KW, Wong WK (2008) Intraabdominalschwannomas: a single institution experience. . J Gastrointest Surg 12(4) : 756-760

93. Wong CM, Ko Y, Chan A (2008) Clinically significant drug-drug interactions between oralanticancer agents and nonanticancer agents: profiling and comparison of two drug compendia. Ann Pharmacother 42(12) : 1737-1748

94. Ramalingam M, Lau W, Tan T, Fook S, Ngoi F, Cheng C (2008) Asians with localized prostatecancer treated with 3-dimensional conformal radiation therapy and adjuvant hormonaltherapy: comparing Phoenix and American Society of Therapeutic Radiology and Oncology(ASTRO) definitions in an Asian population . Urology 71(3) : 506-510

95. Lim ST, Hee SW, Quek R, Lim LC, Yap SP, Loong SL, Sng I, Tan LH, Ang MK, Ngeow JY, Tham

CK, Ngo L, Tan MH, Tao M (2008) Comparative analysis of extra-nodal NK/T-cell lymphomaand peripheral T-cell lymphoma: significant differences in clinical characteristics andprognosis . Eur J Haematol 80(1) : 55-60

96. Xu Y, Singh J, Premachandran CS, Khairyanto A, Chen KWS, Chen N, Sheppard CJR, Olivo M

(2008) Design and development of a 3D scanning MEMS OCT probe using a novel SiOBpackage assembly . J Micromech Microeng 18(12) : 125005

97. Singh J, Teo JHS, Xu Y, Premachandran CS, Chen N, Kotlanka R, Olivo M, Sheppard CJR (2008)

A two axes scanning SOI MEMS micromirror for endoscopic bioimaging . J Micromech

Microeng 18(2) : 025001

98. Kah JC, Olivo M, Lee CG, Sheppard CJ (2008) Molecular contrast of EGFR expression usinggold nanoparticles as a reflectance-based imaging probe . Mol Cell Probe 22(1) : 14-23

99. Ho J, Tan PH, Hee SW, Wong JS (2008) Underestimation of malignancy of atypical ductalhyperplasia diagnosed on 11-gauge stereotactically guided Mammotome breast biopsy: AnAsian breast screen experience . Breast 17(4) : 401-406

100. Wong ZW, Ang PC, Chowbay B, Wong NS, See HT, Khoo KS (2008) Phase I/II study ofgemcitabine with pegylated liposomal doxorubicin as first-line therapy in Asian women withmetastatic breast cancer . Breast 17(5) : 517-522

101. Shord SS, Chew L, Villano J (2008) Evaluation of opioid induced nausea and vomiting insickle cell disease . Am J Hematol 83(3) : 196-199

102. Chua C, Zaiden N, Chong KH, See SJ, Wong MC, Ang BT, Tang C (2008) Characterization ofa side population of astrocytoma cells in response to temozolomide . J Neurosurg 109(5) :856-866

103. Tai BC, De Stavola BL, de Gruttola V, Gebski V, Machin D (2008) First-event or marginalestimation of cause-specific hazards for analysing correlated multivariate failure-time data?. Stat Med 27(6) : 922-936

104. Hughes S, Barbachano Y, Ashley S, Yap YS, Popat S, Allen M, Della-Rovere UQ, Johnston S,

Smith I, O'Brien M (2008) Time trends in the outcome of elderly patients with breast cancer. Breast J 14(2) : 158-163


> 107

105. De Silva DA, Woon FP, Gan HY, Chen C, Chang HM, Cameron J, Kingwell B, Wong MC (2008)

Arterial stiffness is associated with raised levels of the inflammatory marker erythrocytesedimentation rate among ischaemic stroke patients . Intern Med J 38(12) : 918-920

106. Kah JC, Phonthammachai N, Wan RC, Song J, White TJ, Mhaisalkar S, Ahmad IB, Sheppard CJ,

Olivo M (2008) Synthesis of gold nanoshells using precursor seed particles prepared froma deposition-precipitation process . Gold Bulletin 41(1) : 23-36

107. Lindley RI, Wong MC, Multi-Centre Retinal Stroke Study Collaborative Group (2008) Retinalmicrovascular signs: a key to understanding the underlying pathophysiology of differentstroke subtypes? . Int J Stroke 3(4) : 297-305

108. Lim ST, Hee SW, Quek R, Tao M (2008) Performance status is the single most importantprognostic factor in lymphoma patients aged greater than 75 overriding other prognosticfactors such as histology . Leuk Lymphoma 49(1) : 149-151

109. Ngo L, Hee SW, Lim LC, Tao M, Quek R, Yap SP, Loong SL, Sng I, Hwan-Cheong TL, Ang MK,

Ngeow JY, Tham CK, Tan MH, Lim ST (2008) Prognostic factors in patients with diffuse largeB cell lymphoma: Before and after the introduction of rituximab . Leuk Lymphoma 49(3) :462-469

110. Tham CK, Tao M, Quek R, Yap SP, Loong SL, Sng I, Tan LHC, Li HH, Lim ST (2008) Clinicalcharacteristics, prognostic factors and outcomes of Burkitt lymphoma in adult Asians . Leuk

Lymphoma 49(4) : 824-827

111. Loong SL, Hwang JS, Lim ST, Yap SP, Tao M, Chong TW, Tan LH, Huynh H (2008) An Epstein-Barr virus positive natural killer lymphoma xenograft derived for drug testing . Leuk

Lymphoma 49(6) : 1161-1167

112. Wang XD, Deng XY, Chen J, Li JL, Chen X, Zhao LZ, Lu Y, Chowbay B, Su QB, Huang M, Zhou

SF (2008) Single nucleotide polymorphisms of the pregnane x receptor gene in Han Chineseand a comparison with other ethnic populations . Pharmacology 81(4) : 350-354

113. Sarraf-Yazdi S, Mi J, Moeller BJ, Niu X, White RR, Kontos CD, Sullenger BA, Dewhirst MW, Clary

BM (2008) Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of anangiopoietin 2-specific RNA aptamer . J Surg Res 146(1) : 16-23

114. Williams RS, Casey PJ, Kamei RK, Buckley EG, Soo KC, Merson MH, Krishnan RK, Dzau VJ

(2008) A global partnership in medical education between Duke University and the NationalUniversity of Singapore . Acad Med 83(2) : 122-127

115. Wee HL, Fong KY, Tse C, Machin D, Cheung YB, Luo N, Thumboo J (2008) Optimizing thedesign of visual analogue scales for assessing quality of life: a semi-qualitative study amongChinese-speaking Singaporeans . J Eval Clin Pract 14(1) : 121-125

116. Ilangovan KR, Yeo R (2008) Unusual presentation of metastatic Crohn's disease . Eur J

Obstet Gynecol Reprod Biol 137(2) : 259

117. Thong PS, Olivo M, Kho KW, Bhuvaneswari R, Chin WW, Ong KW, Soo KC (2008) ImmuneResponse against Angiosarcoma following Lower Fluence Rate Clinical PhotodynamicTherapy . J Environ Pathol Toxicol Oncol 27(1) : 35-42

118. Saw CL, Heng PW, Olivo M (2008) Potentiation of the Photodynamic Action of Hypericin .J Environ Pathol Toxicol Oncol 27(1) : 23-33

> 108

119. Lau LC, Lim P, Lim YC, Teng LM, Lim TH, Lim LC, Tan SY, Lim ST, Sanger WG, Tien SL (2008)

Occurrence of trisomy 12, t(14;18)(q32;q21), and t(8;14)(q24.1;q11.2) in a patient with B-cellchronic lymphocytic leukemia . Cancer Genet Cytogenet 185(2) : 95-101

120. Tan SB, Wee J, Wong HB, Machin D (2008) Can external and subjective information ever beused to reduce the size of randomised controlled trials? . Contemp Clin Trials 29(2) : 211-219

121. Chuwa EW, Tan VH, Tan PH, Yong WS, Ho GH, Wong CY (2008) Treatment for ductal carcinomain situ in an Asian population: outcome and prognostic factors . ANZ J Surg 78(1-2) : 42-48

122. Chan WH, Cheow PC, Chung AY, Ong HS, Koong HN, Wong WK (2008) Pancreaticoduodenectomyfor locally advanced stomach cancer: preliminary results . ANZ J Surg 78(9) : 767-770

123. Goh BK, Tan YM, Cheow PC, Chung AY, Chow PK, Wong WK, Ooi LL (2008) Outcome of DistalPancreatectomy for Pancreatic Adenocarcinoma . Dig Surg 25(1) : 32-38

124. Ong LC, Jin Y, Song IC, Yu S, Zhang K, Chow PK (2008) 2-[18F]-2-deoxy-D-glucose (FDG)uptake in human tumor cells is related to the expression of GLUT-1 and hexokinase II . Acta

Radiol 49(10) : 1145-1153

125. Tan JS, Thng CH, Tan PH, Cheng CW, Lau WK, Tan T, Ho JTs, Ching BC (2008) Local experienceof endorectal magnetic resonance imaging of prostate with correlation to radical prostatectomyspecimens . Ann Acad Med Singapore 37(1) : 40-44

126. Soon JL, Jeyaraj PR, Agasthian T (2008) Thoracic complications of radiofrequency ablationof recurrent hepatoma . Ann Acad Med Singapore 37(1) : 75-76

127. Yap SP, Lim WT, Foo KF, Hee SW, Leong SS, Fong KW, Eng P, Hsu AA, Wee J, Agasthian T, Koong

HN, Tan EH (2008) Induction concurrent chemoradiotherapy using Paclitaxel and Carboplatincombination followed by surgery in locoregionally advanced non-small cell lung cancer -asian experience . Ann Acad Med Singapore 37(5) : 377-382

128. Chia WK, Ong SY, Toh HC, Hee SW, Choo SP, Poon D, Tay MH, Tan CK, Koo WH, Foo KF (2008)

Phase II trial of gemcitabine in combination with cisplatin in inoperable or advancedhepatocellular carcinoma . Ann Acad Med Singapore 37(7) : 554-558

129. Wee J (2008) 4th FY Khoo Memorial Lecture 2008: Nasopharyngeal Cancer Workgroup--thepast, the present and the future. . Ann Acad Med Singapore 37(7) : 606-614

130. Tan MH, Lee Z, Ng B, Sim ES, Chua YY, Tien M, Ooi CJ (2008) The Tao of bao: a randomisedcontrolled trial examining the effect of steamed bun consumption on night-call inpatientcourse and mortality . Ann Acad Med Singapore 37(3) : 255-253

131. De Silva DA, Lee MP, Wong MC, Chang HM, Chen CL (2008) Limb-shaking transient ischemicattack with distal micro-embolic signals and impaired cerebrovascular reactivity usingtranscranial Doppler . Ann Acad Med Singapore 37(7) : 619-620

132. De Silva DA, Woon FP, Moe KT, Chen CL, Chang HM, Wong MC (2008) Concomitant coronaryartery disease among Asian ischaemic stroke patients . Ann Acad Med Singapore 37(7) : 573-575


> 109

133. Yeo TC, Chan YH, Low LP, Venketasubramanian N, Lim SC, Tay JC, Tan RS, Eng P, Lingamanaicker

J, Wong MC, REACH Investigators (2008) Risk factor profile and treatment patterns of patientswith atherothrombosis in Singapore: insight from the REACH Registry . Ann Acad Med

Singapore 37(5) : 365-371

134. Choo SP, Venook AP (2008) Emergence of the Epothilones . Oncology (Williston Park) 22(4) :424-426

135. Goh C, Walsh Declan T (2008) Culture, Ethnicity and Illness . Palliative Medicine. Mosby,

Inc Part 1. Section B. Chapter 10 :

136. Sandanaraj E, Lal S, Xiang XQ, Kong MC, Lee LH, Chowbay B (2008) VKORC1 diplotypes,warfarin disposition and dose requirements in Chinese patients . SGH Proceedings 17(1)Suppl : O-CLI (1215)

137. Chen NK, Wong JS, Kee IH, Lai SH, Thng CH, Ng WH, Ng RT, Tan SY, Lee SY, Tan ME, Sivalingam

J, Chow PK, Kon OL (2008) Nonvirally modified autologous primary hepatocytes correctdiabetes and prevent target organ injury in a large preclinical model . PLoS ONE 3(3) : e1734

138. Goh C (2008) Challenges of Cultural Diversity . Supportive Care In Heart Failure. JamesBeattie and Sarah Goodlin (eds). Oxford University Press Pt3 Chapt 25 : 451-462

139. Balaji R, Khoo JB, Sittampalam K, Soo KC (2008) CT imaging of malignant metastatichemangiopericytoma of the parotid gland with histopathological correlation . Cancer Imaging 8: 186-190

140. Chin WW, Heng PW, Lim Pl, Lau KO, Olivo M (2008) Membrane transport enhancement ofchlorin e6-polyvinylpyrrolidone and its photodynamic efficacy on the chick chorioallantoicmodel . J Biophoto 1(5) : 395-407

141. Kon OL, Yip TT, Ho M, Chan WH, Wong WK, Tan SY, Ng WH, Kam SY, Eng AK, Ho P, Viner R, Ong

HS, Kumarasinghe MP (2008) The distinctive gastric fluid proteome in gastric cancer revealsa multi-biomarker diagnostic profile . BMC Med Genomics 1(1) : 54

142. Lee SY, Goh BK, Tan YM, Chung AY, Cheow PC, Chow PK, Wong WK, Ooi LL (2008) Spleen-preserving distal pancreatectomy. . Singapore Med J 49(11) : 883-885

143. Choo SP, Venook AP (2008) Responding to the rising incidence of hepatocellular carcinomawith targeted therapy . Gastrointest Cancer Res 2(2) : 96-97

144. Chen J, Futami K, Petillo D, Peng J, Wang P, Knol J, Li Y, Khoo SK, Huang D, Qian CN, Zhao P,

Dykyma K, Zhang R, Cao B, Yang XJ, Furge K, Williams BO, Teh BT (2008) Deficiency of FLCNin mouse kidney led to development of polycystic kidneys and renal neoplasia . PLoS

ONE 3(10) : e3581

145. Ha TC, Starmer F (2008) Investigative Methods and Tools: Developing an Integrated Approachto Critical Thinking, Evidence-based Medicine and Biostatistics . SGH Proceedings 17(3) :160-163

146. Choo SP, Venook AP (2008) Hepatic Artery Infusion in the Treatment of Colorectal CancerMetastases . Curr Colorectal Cancer Rep 4(2) : 106-113

> 110

147. Toh ST, Lee CG (2008) Role of the Hepatitis B Virus in Hepatocellular Carcinoma . HumCancer Viruses. Principles of Transformation and Pathogenesis. Transl Res Biomed 1 : 94-107

148. Chia SC, Chau YP, Tan YM (2008) Late-onset post-transplant lymphoproliferative diseasepresenting as massive occult gastrointestinal haemorrhage . Singapore Med J 49(5) : e117-120

149. Morris-Stiff G, Tan YM, Vauthey JN (2008) Hepatic complications following preoperativechemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases . Eur J Surg

Oncol 34(6) : 609-614

150. Chan A, Shih V, Chew L (2008) Evolving roles of oncology pharmacists in Singapore: a surveyon prescribing patterns of antiemetics for chemotherapy induced nausea and vomiting(CINV) at a cancer centre . J Oncol Pharm Pract 14(1) : 23-29

151. Machin D, Campbell M, Tan SB, Tan SH (2008) Sample Size Tables for Clinical Studies . Sample

Size Tables for Clinical Studies. Wiley-Blackwell : 1-264

152. Ayad T, Kolb F, De Monès E, Mamelle G, Tan HK, Temam S (2008) The musculo-mucosal facialartery flap: harvesting technique and indications . Ann Chir Plast Esthet 53(6) : 487-494

153. Sarraf-Yazdi S, Mi J, Dewhirst MW, Clary BM (2008) Use of bioluminescence imaging to detectenhanced hepatic and systemic tumor growth following partial hepatectomy in mice . Eur

J Surg Oncol 34(4) : 476-481


> 111


Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumorsuppressionGenander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, Martling A, Greicius G, Thakar S, Catchpole

T, Chumley MJ, Zdunek S, Wang C, Holm T, Goff SP, Pettersson S, Pestell RG, Henkemeyer M, Frisé'e9n

J

Cell. 2009 Nov 13;139(4):679-92.

AbstractSignaling proteins driving the proliferation of stem and progenitor cells are often encoded by proto-

oncogenes. EphB receptors represent a rare exception; they promote cell proliferation in the intestinal

epithelium and function as tumor suppressors by controlling cell migration and inhibiting invasive growth.

We show that cell migration and proliferation are controlled independently by the receptor EphB2. EphB2

regulated cell positioning is kinase-independent and mediated via phosphatidylinositol 3-kinase, whereas

EphB2 tyrosine kinase activity regulates cell proliferation through an Abl-cyclin D1 pathway. Cyclin D1

regulation becomes uncoupled from EphB signaling during the progression from adenoma to colon

carcinoma in humans, allowing continued proliferation with invasive growth. The dissociation of EphB2

signaling pathways enables the selective inhibition of the mitogenic effect without affecting the tumor

suppressor function and identifies a pharmacological strategy to suppress adenoma growth.

Oncogenic pathway combinations predict clinical prognosis in gastric cancerOoi CH, Ivanova T, Wu J, Lee M, Tan IB, Tao J, Ward L, Koo JH, Gopalakrishnan V, Zhu Y, Cheng LL, Lee

J, Rha SY, Chung HC, Ganesan K, So J, Soo KC, Lim DT, Chan WH, Wong WK, Bowtell D, Yeoh KG,

Grabsch H, Boussioutas A, Tan P

PLoS Genet. 2009 Oct;5(10):e1000676.

AbstractMany solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different

oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant

relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to

map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause

of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB,

and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated

these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway

combinations showed reproducible and significant survival differences in multiple cohorts, suggesting

that pathway interactions may play an important role in influencing disease behavior. Individual GCs can

be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant

subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-

related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by

other platforms.

> 112

Matrix Metalloproteinase 1 Is Necessary for the Migration of Human Bone Marrow-DerivedMesenchymal Stem Cells Toward Human GliomaHo IA, Chan KY, Ng WH, Guo CM, Hui KM, Cheang P, Lam PY

Stem Cells. 2009 Jun;27(6):1366-75.

AbstractHuman mesenchymal stem cells (MSCs) have increasingly been used as cellular vectors for the delivery

of therapeutic genes to tumors. However, the precise mechanism of mobilization remains poorly defined.

In this study, MSCs that expressed similar cell surface markers and exhibited multilineage differentiation

potentials were isolated from various donors. Interestingly, different MSC isolates displayed differential

migration ability toward human glioma cells. We hypothesized that distinct molecular signals may be

involved in the varied tumor tropisms exhibited by different MSC isolates. To test this hypothesis, gene

expression profiles of tumor-trophic MSCs were compared with those of non-tumor-trophic MSCs. Among

the various differentially regulated genes, matrix metalloproteinase one (MMP1) gene expression and its

protein activities were enhanced by 27-fold and 21-fold, respectively, in highly migrating MSCs compared

with poorly migrating MSCs. By contrast, there was no change in the transcriptional levels of other MMPs.

Functional inactivation of MMP1 abrogated the migratory potential of MSCs toward glioma-conditioned

medium. Conversely, the nonmigratory phenotype of poorly migrating MSC could be rescued in the

presence of either recombinant MMP1 or conditioned medium from the highly migrating MSCs. Ectopic

expression of MMP1 in these poorly migrating cells also rendered the cells responsive to the signaling

cues from the glioma cells in vivo. However, blocking the interaction of MMP1 and its cognate receptor

PAR1 effectively diminished the migratory ability of MSCs. Taken together, this study provides, for the first

time, supporting evidence that MMP1 is critically involved in the migration capacity of MSCs, acting

through the MMP1/PAR1 axis.

Prediction of clinical outcome in multiple lung cancer cohorts by integrative genomics: implicationsfor chemotherapy selectionBroët P, Camilleri-Broët S, Zhang S, Alifano M, Bangarusamy D, Battistella M, Wu Y, Tuefferd M, Régnard

JF, Lim E, Tan P, Miller LD

Cancer Res. 2009 Feb 1;69(3):1055-62.

AbstractThe role of adjuvant chemotherapy in patients with stage IB non-small-cell lung cancer (NSCLC) is

controversial. Identifying patient subgroups with the greatest risk of relapse and, consequently, most likely

to benefit from adjuvant treatment thus remains an important clinical challenge. Here, we hypothesized

that recurrent patterns of genomic amplifications and deletions in lung tumors could be integrated with

gene expression information to establish a robust predictor of clinical outcome in stage IB NSCLC. Using

high-resolution microarrays, we generated tandem DNA copy number and gene expression profiles for

85 stage IB lung adenocarcinomas/large cell carcinomas. We identified specific copy number alterations

linked to relapse-free survival and selected genes within these regions exhibiting copy number-driven

expression to construct a novel integrated signature (IS) capable of predicting clinical outcome in this

series (P = 0.02). Importantly, the IS also significantly predicted clinical outcome in two other independent

stage I NSCLC cohorts (P = 0.003 and P = 0.025), showing its robustness. In contrast, a more conventional

molecular predictor based solely on gene expression, while capable of predicting outcome in the initial

series, failed to significantly predict outcome in the two independent data sets. Our results suggest that

recurrent copy number alterations, when combined with gene expression information, can be successfully

used to create robust predictors of clinical outcome in early-stage NSCLC. The utility of the IS in identifying

early-stage NSCLC patients as candidates for adjuvant treatment should be further evaluated in a clinical

trial.


> 113

Deregulated direct targets of the hepatitis B virus (HBV) protein, HBx, identified through chromatinimmunoprecipitation and expression microarray profilingSung WK, Lu Y, Lee CW, Zhang D, Ronaghi M, Lee CG

J Biol Chem. 2009 Aug 14;284(33):21941-54.

AbstractThe hepatitis B-X (HBx) protein is strongly associated with hepatocellular carcinoma. It is implicated not

to directly cause cancer but to play a role in hepatocellular carcinoma as a co-factor. The oncogenic

potential of HBx primarily lies in its interaction with transcriptional regulators resulting in aberrant gene

expression and deregulated cellular pathways. Utilizing ultraviolet irradiation to simulate a tumor-initiating

event, we integrated chip-based chromatin immunoprecipitation (ChIP-chip) with expression microarray

profiling and identified 184 gene targets directly deregulated by HBx. One-hundred forty-four transcription

factors interacting with HBx were computationally inferred. We experimentally validated that HBx interacts

with some of the predicted transcription factors (pTF) as well as the promoters of the deregulated target

genes of these pTFs. Significantly, we demonstrated that the pTF interacts with the promoters of the

deregulated HBx target genes and that deregulation by HBx of these HBx target genes carrying the pTF

consensus sequences can be reversed using pTF small interfering RNAs. The roles of these deregulated

direct HBx target genes and their relevance in cancer was inferred via querying against biogroup/cancer-

related microarray databases using web-based NextBio(TM) software. Six pathways, including the Jak-

STAT pathway, were predicted to be significantly deregulated when HBx binds indirectly to direct target

gene promoters. In conclusion, this study represents the first ever demonstration of the utilization of ChIP-

chip to identify deregulated direct gene targets from indirect protein-DNA binding as well as transcriptional

factors directly interacting with HBx. Increased knowledge of the gene/transcriptional factor targets of

HBx will enhance our understanding of the role of HBx in hepatocellular carcinogenesis and facilitate the

design of better strategies in combating hepatitis B virus-associated hepatocellular carcinoma.

> 114

1. Lindley RI, Wang JJ, Wong MC, Mitchell P, Liew G, Hand P, Wardlaw J, De Silva DA, Baker M,

Rochtchina E, Chen C, Hankey GJ, Chang HM, Fung VS, Gomes L, Wong TY; Multi-Centre Retina

and Stroke Study (MCRS) Collaborative Group (2009) Retinal microvasculature in acute lacunarstroke: a cross-sectional study . Lancet Neurol 8(7) : 628-634

2. Quek R, Morgan JA, George S, Butrynski JE, Polson K, Meyer F, Demetri GD, Block SD (2009)

Small molecule tyrosine kinase inhibitor and depression . J Clin Oncol 27(2) : 312-313

3. Koo YX, Tan DS, Tan IB, Quek R, Tao M, Lim ST (2009) Risk of hepatitis B virus reactivationin patients who are hepatitis B surface antigen negative/antibody to hepatitis B core antigenpositive and the role of routine antiviral prophylaxis . J Clin Oncol 27(15) : 2570-2571

4. Morgan JA, Quek R, George S, Block SD, Demetri GD (2009) Reply to W.F. Pirl et al . J Clin

Oncol 27(23) : e51

5. Tan MH, Tan CS, Lim WY (2009) Race to report: are vascular endothelial growth factor geneticpolymorphisms associated with outcome in advanced breast cancer patients treated withPaclitaxel plus bevacizumab? . J Clin Oncol 27(8) : 1342

6. Wong CI, Koh TS, Soo R, Hartono S, Thng CH, McKeegan E, Yong WP, Chen CS, Lee SC, Wong

J, Lim R, Sukri N, Lim SE, Ong AB, Steinberg J, Gupta N, Pradhan R, Humerickhouse R, Goh BC

(2009) Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor,in patients with refractory solid malignancies . J Clin Oncol 27(28) : 4718-4726

7. Koo YX, Tan DS, Tan IB, Tao M, Lim ST (2009) Hepatitis B virus reactivation in a patient withresolved hepatitis B virus infection receiving maintenance rituximab for malignant B-celllymphoma . Ann Intern Med 150(9) : 655-656

8.

9. Wee J, Anderson BO, Corry J, D'Cruz A, Soo KC, Qian CN, Chua DT, Hicks RJ, Goh CH, Khoo

JB, Ong SC, Forastiere AA, Chan AT (2009) Management of the neck after chemoradiotherapyfor head and neck cancers in Asia: consensus statement from the Asian Oncology Summit2009 . Lancet Oncol 10(11) : 1086-1092

10. Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, Singh H, Chow WC, Ooi LL,

Chow P, Khin MW, Koo WH (2009) Management of hepat ocellular carcinoma in Asia:consensus statement from the Asian Oncology Summit 2009 . Lancet Oncol 10(11) : 1111-1118

11. Soo RA, Anderson BO, Cho BC, Yang CH, Liao M, Lim WT, Goldstraw P, Mok TS (2009) First-line systemic treatment of advanced stage non-small-cell lung cancer in Asia: consensusstatement from the Asian Oncology Summit 2009 . Lancet Oncol 10(11) : 1102-1110

12. Kwong YL, Anderson BO, Advani R, Kim WS, Levine AM, Lim ST (2009) Management of T-celland natural-killer-cell neoplasms in Asia: consensus statement from the Asian OncologySummit 2009 . Lancet Oncol 10(11) : 1093-1101

13. Wong NS, Anderson BO, Khoo KS, Ang PT, Yip CH, Lu YS, Voravud N, Shao ZM, Pritchard KI

(2009) Management of HER2-positive breast cancer in Asia: consensus statement from theAsian Oncology Summit 2009 . Lancet Oncol 10(11) : 1077-1085

14. Yap KY, Chan A, Chui WK (2009) Improving pharmaceutical care in oncology bypharmacoinformatics: the evolving role of informatics and the internet for drug therapy .Lancet Oncol 10(10) : 1011-1019


> 115

15. Narasimhalu K, Ang S, De Silva DA, Wong MC, Chang HM, Chia KS, Auchus AP, Chen C (2009)

Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort .Neurology 73(22) : 1866-1872

16. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Toh HC, Thng CH, Chow P, Ong HS, Chung A,

Goh BC, Smith PD, Soo KC (2009) AZD6244 enhances the anti-tumor activity of sorafenibin ectopic and orthotopic models of human hepatocellular carcinoma (HCC) . J Hepatol 15(24): 7726-7736

17. Chong YK, Toh TB, Zaiden N, Poonepalli A, Leong SH, Ee Ling Ong C, Yu Y, Tan P, See SJ, Ng

WH, Ng I, Hande MP, Kon OL, Ang BT, Tang C (2009) Cryopreservation of Neurospheres derivedfrom Human Glioblastoma Multiforme . Stem Cells 27(1) : 29-39

18. Qian CN, Furge KA, Knol J, Huang D, Chen J, Dykema KJ, Kort EJ, Massie A, Khoo SK, Vanden

Beldt K, Resau JH, Anema J, Kahnoski RJ, Morreau H, Camparo P, Comperat E, Sibony M, Denoux

Y, Molinie V, Vieillefond A, Eng C, Williams BO, Teh BT (2009) Activation of the PI3K/AKTpathway induces urothelial carcinoma of the renal pelvis: identification in human tumorsand confirmation in animal models . Cancer Res 69(21) : 8256-8264

19. Fan HM, Yi JB, Yang Y, Kho KW, Tan HR, Shen ZX, Ding J, Sun XW, Olivo M, Feng YP (2009)

Single-Crystalline MFe(2)O(4) Nanotubes/Nanorings Synthesized by Thermal TransformationProcess for Biological Applications . ACS Nano 3(9) : 2798-2808

20. Baum N, Schiene-Fischer C, Frost M, Schumann M, Sabapathy K, Ohlenschläger O, Grosse F,

Schlott B (2009) The prolyl cis/trans isomerase cyclophilin 18 interacts with the tumorsuppressor p53 and modifies its functions in cell cycle regulation and apoptosis .Oncogene 28(44) : 3915-3925

21. Ong DC, Ho YM, Rudduck C, Chin K, Kuo WL, Lie DK, Chua CL, Tan PH, Eu KW, Seow-Choen

F, Wong CY, Hong GS, Gray JW, Lee AS (2009) LARG at chromosome 11q23 has functionalcharacteristics of a tumor suppressor in human breast and colorectal cancer . Oncogene 28(47): 4189-4200

22. Lee P, Cheah FK, Huang J, Poon D, Loo CM (2009) A suspicious clot . Thorax 64(11) : 1011

23. De Silva DA, Liew G, Wong MC, Chang HM, Chen C, Wang JJ, Baker ML, Hand PJ, Rochtchina

E, Liu EY, Mitchell P, Lindley RI, Wong TY (2009) Retinal vascular caliber and extracranialcarotid disease in patients with acute ischemic stroke: the Multi-Centre Retinal Stroke(MCRS) study . Stroke 40(12) : 3695-3699

24. De Silva DA, Chang HM, Woon FP, Chen CP, Wong MC (2009) Ischemic stroke in ethnic SouthAsians . Stroke 40(10) : e594

25. Kasiman K, Eikelboom JW, Hankey GJ, Lee SP, Lim JP, Lee JH, Chang HM, Wong MC, Chen CP

(2009) Ethnicity does not affect the homocysteine-lowering effect of B-vitamin therapy inSingaporean stroke patients . Stroke 40(6) : 2209-2211

26. Srinivasan BS, Doostzadeh J, Absalan F, Mohandessi S, Jalili R, Bigdeli S, Wang J, Mahadevan

J, Lee CG, Davis RW, William Langston J, Ronaghi M (2009) Whole genome survey of codingSNPs reveals a reproducible pathway determinant of Parkinson disease . Hum Mutat 30(2): 228-238

> 116

27. Ong KW, Teo M, Lee V, Ong D, Lee A, Tan CS, Vathsala A, Toh HC (2009) Expression of EBVLatent Antigens, Mammalian Target of Rapamycin, and Tumor Suppression Genes in EBV-Positive Smooth Muscle Tumors: Clinical and Therapeutic Implications . Clin Cancer Res 15(17): 5350-5358

28. Toh HC, Wang WW, Chia WK, Kvistborg P, Sun L, Teo K, Phoon YP, Soe Y, Tan SH, Hee SW, Foo

KF, Ong SY, Koo WH, Zocca MB, Claesson MH (2009) Clinical Benefit of Allogeneic MelanomaCell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal CancerPatients . Clin Cancer Res 15(24) : 7726-7736

29. Macher-Goeppinger S, Aulmann S, Tagscherer KE, Wagener N, Haferkamp A, Penzel R, Brauckhoff

A, Hohenfellner M, Sykora J, Walczak H, Teh BT, Autschbach F, Herpel E, Schirmacher P, Roth W

(2009) Prognostic value of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)and TRAIL receptors in renal cell cancer . Clin Cancer Res 15(2) : 650-659

30. Chew HC, Lee CH, Cheah FK, Lim ST, Loo CM (2009) Cardiac tumor and renal involvementin a nonsmoker with centrilobular pulmonary nodules . Chest 135(4) : 1102-1106

31. Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge LW, Robinson BG, Teh BT, Gimm

O, Marsh DJ (2009) Accuracy of combined protein gene product 9.5 and parafibromin markersfor immunohistochemical diagnosis of parathyroid carcinoma . J Clin Endocrinol Metab 94(2): 434-441

32. Bhuvaneswari R, Gan YY, Soo KC, Olivo M (2009) The effect of photodynamic therapy ontumor angiogenesis . Cell Mol Life Sci 66(14) : 2275-2283

33. Tan EK, Lee J, Chen CP, Wong MC, Zhao Y (2009) Case control analysis of LRRK2 Gly2385Argin Alzheimer's disease . Neurobiol Aging 30(3) : 501-502

34. Samuel M, Chow PK, Chan SY, Machin D, Soo KC (2009) Neoadjuvant and adjuvant therapyfor surgical resection of hepatocellular carcinoma . Cochrane Database Syst Rev (1) : CD001199

35. Tan EH, Rolski J, Grodzki T, Schneider CP, Gatzemeier U, Zatloukal P, Aitini E, Carteni G, Riska

H, Tsai YH, Abratt R (2009) Global Lung Oncology Branch trial 3 (GLOB3): final results of arandomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatinversus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer. Ann Oncol 20(7) : 1249-1256

36. Ngeow JY, Quek R, Ng DC, Hee SW, Tao M, Lim LC, Tan YH, Lim ST (2009) High SUV uptakeon FDG-PET/CT predicts for an aggressive B-cell lymphoma in a prospective study of primaryFDG-PET/CT staging in lymphoma . Ann Oncol 20(9) : 1543-1547

37. Wong MC, Choo SP, Tan EH (2009) Travel warning with capecitabine . Ann Oncol 20(7) : 1281

38. Shih V, Chiang JY, Chan A (2009) Complementary and alternative medicine (CAM) usage inSingaporean adult cancer patients . Ann Oncol 20(4) : 752-757

39. Koh V, Goh BK, Goh AS, Chow PK (2009) Utility of Positron Emission Tomography/ComputedTomography in the Detection of Malignancy Within a Choledochal Cyst . Clin Gastroenterol

Hepatol 7(4) : e17-e18


> 117

40. Pearson T, Giffard P, Beckstrom-Sternberg S, Auerbach R, Hornstra H, Tuanyok A, Price EP, Glass

MB, Leadem B, Beckstrom-Sternberg JS, Allan GJ, Foster JT, Wagner DM, Okinaka RT, Sim SH,

Pearson O, Wu Z, Chang J, Kaul R, Hoffmaster AR, Brettin TS, Robison RA, Mayo M, Gee JE, Tan

P, Currie BJ, Keim P (2009) Phylogeographic reconstruction of a bacterial species with highlevels of lateral gene transfer . BMC Biol 7 : 78

41. Zhou SF, Liu JP, Chowbay B (2009) Polymorphism of human cytochrome P450 enzymes andits clinical impact. . Drug Metab Rev 41(2) : 89-295

42. Qian CN, Huang D, Wondergem B, Teh BT (2009) Complexity of tumor vasculature in clearcell renal cell carcinoma . Cancer 115(S10) : 2282-2289

43. Atkins MB, Bukowski RM, Escudier BJ, Figlin RA, Hudes GH, Kaelin WG Jr, Linehan WM, McDermott

DF, Mier JW, Pedrosa I, Rini BI, Signoretti S, Sosman JA, Teh BT, Wood CG, Zurita AJ, King L

(2009) Innovations and challenges in renal cancer: summary statement from the ThirdCambridge Conference . Cancer 115(10 Suppl) : 2247-2251

44. Puppe J, Drost R, Liu X, Joosse SA, Evers B, Cornelissen-Steijger P, Nederlof P, Yu Q, Jonkers

J, van Lohuizen M, Pietersen AM (2009) BRCA1-deficient mammary tumor cells are dependenton EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A . Breast Cancer Res 11(4) : R63

45. Tham CK, Poon D, Li HH, Tan MH, Choo SP, Foo KF (2009) Gastrointestinal stromal tumourin the elderly . Crit Rev Oncol Hematol 70(3) : 256-261

46. Huynh H, Chow KH, Soo KC, Toh HC, Choo SP, Foo KF, Poon D, Ngo VC, Tran E (2009) RAD001(everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma. J Cell Mol Med 13(7) : 1371-1380

47. Huynh H, Ngo VC, Koong HN, Poon D, Choo SP, Thng CH, Chow P, Ong HS, Chung A, Soo KC

(2009) Sorafenib and Rapamycin Induce Growth Suppression in Mouse Models ofHepatocellular Carcinoma. . J Cell Mol Med 13(8B) : 2673-2683

48. Wang Y, Lee CG (2009) MicroRNA and cancer - focus on apoptosis. . J Cell Mol Med 13(1) :12-23

49. Huynh H, Ngo VC, Choo SP, Poon D, Koong HN, Thng CH, Toh HC, Zheng L, Ong LC, Jin Y, Song

IC, Chang AP, Ong HS, Chung AY, Chow PK, Soo KC (2009) Sunitinib (SUTENT, SU11248)suppresses tumor growth and induces apoptosis in xenograft models of human hepatocellularcarcinoma . Curr Cancer Drug Targets 9(6) : 738-747

50. De Silva DA, Woon FP, Gan HY, Chen CP, Chang HM, Koh TH, Kingwell BA, Cameron JD, Wong

MC (2009) Arterial stiffness is associated with intracranial large artery disease among ethnicChinese and South Asian ischemic stroke patients . J Hypertens 27(7) : 1453-1458

51. Huynh H, Lee JW, Chow PK, Ngo VC, Lew GB, Lam IW, Ong HS, Chung AY, Soo KC (2009)

Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor. Mol Cancer Ther 8(1) : 152-159

52. Yang S, Ngo VC, Lew GB, Chong LW, Lee SS, Ong WJ, Lam WL, Thng CH, Koong HN, Ong HS,

Chung A, Chow P, Lee J, Soo KC, Huynh H (2009) AZD6244 (ARRY-142886) enhances thetherapeutic efficacy of sorafenib in mouse models of gastric cancer . Mol Cancer Ther 8(9): 2537-2545

> 118

53. Ho YM, Sun YJ, Wong SY, Lee AS (2009) Contribution of dfrA and inhA mutations to thedetection of isoniazid-resistant Mycobacterium tuberculosis isolates . Antimicrob Agents

Chemother 53(9) : 4010-4012

54. Tan FL, Ooi A, Huang D, Wong JC, Qian CN, Chao C, Ooi L, Tan YM, Chung A, Cheow PC, Zhang

Z, Petillo D, Yang XJ, Teh BT (2009) p38delta/MAPK13 as a diagnostic marker forcholangiocarcinoma and its involvement in cell motility and invasion . Int J Cancer 126(10): 2353-2361

55. Tham IW, Hee SW, Yeo R, Salleh PB, Lee J, Tan T, Fong KW, Chua ET, Wee J (2009) Treatmentof Nasopharyngeal Carcinoma Using Intensity-Modulated Radiotherapy-The National CancerCentre Singapore Experience . Int J Radiat Oncol Biol Phys 75(5) : 1481-1486

56. Hui Z, Tretiakova M, Zhang Z, Li Y, Wang X, Zhu JX, Gao Y, Mai W, Furge K, Qian CN, Amato R,

Butler EB, Teh BT, Teh BS (2009) Radiosensitization by inhibiting STAT1 in renal cell carcinoma. Int J Radiat Oncol Biol Phys 73(1) : 288-295

57. Lim EH, Zhang SL, Li JL, Yap WS, Howe TC, Tan BP, Lee YS, Wong D, Khoo KL, Seto KY, Tan L,

Agasthian T, Koong HN, Tam J, Tan C, Caleb M, Chang A, Ng A, Tan P (2009) Using wholegenome amplification (WGA) of low-volume biopsies to assess the prognostic role of EGFR,KRAS, p53, and CMET mutations in advanced-stage non-small cell lung cancer (NSCLC). .J Thorac Oncol 4(1) : 12-21

58. Tham CK, Choo SP, Lim WT, Toh CK, Leong SS, Tan SH, Li HH, Tan EH (2009) Gefitinib inCombination with Gemcitabine and Carboplatin in Never Smokers with Non-small Cell LungCarcinoma: A Retrospective Analysis . J Thorac Oncol 4(8) : 988-993.

59. Pramono ZA, Tan CL, Seah IA, See JS, Kam SY, Lai PS, Yee WC (2009) Identification andcharacterisation of human dysferlin transcript variants: implications for dysferlin mutationalscreening and isoforms. . Hum Genet 125(4) : 413-420

60. Tay WL, Yip GW, Tan PH, Matsumoto K, Yeo R, Ng TP, Kumar SD, Tsujimoto M, Bay BH (2009)

Y-Box-binding protein-1 is a promising predictive marker of radioresistance andchemoradioresistance in nasopharyngeal cancer . Mod Pathol 22(2) : 282-290

61. Thong PS, Olivo M, Chin WW, Bhuvaneswari R, Mancer K, Soo KC (2009) Clinical applicationof fluorescence endoscopic imaging using hypericin for the diagnosis of human oral cavitylesions . Br J Cancer 101(9) : 1580-1584

62. Wang YC, Gallego-Arteche E, Iezza G, Yuan X, Matli MR, Choo SP, Zuraek MB, Gogia R, Lynn FC,

German MS, Bergsland EK, Donner DB, Warren RS, Nakakura EK (2009) Homeodomaintranscription factor NKX2.2 functions in immature cells to control enteroendocrinedifferentiation and is expressed in gastrointestinal neuroendocrine tumors . Endocr Relat

Cancer 16(1) : 267-279

63. Khoo SK, Pendek R, Nickolov R, Luccio-Camelo DC, Newton TL, Massie A, Petillo D, Menon J,

Cameron D, Teh BT, Chan SP (2009) Genome-wide scan identifies novel modifier loci ofacromegalic phenotypes for isolated familial somatotropinoma . Endocr Relat Cancer 16(3): 1057-1063

64. Shin S, Asano T, Yao Y, Zhang R, Claret FX, Korc M, Sabapathy K, Menter DG, Abbruzzese JL,

Reddy SA (2009) Activator Protein-1 Has an Essential Role in Pancreatic Cancer Cells andIs Regulated by a Novel Akt-Mediated Mechanism . Mol Cancer Res 7(5) : 745-754

> 119

65. Kang KB, Zhu CJ, Yong SK, Gao QH, Wong MC (2009) Enhanced sensitivity of celecoxib inhuman glioblastoma cells: Induction of DNA damage leading to p53-dependent G1 cell cyclearrest and autophagy . Mol Cancer 8(1) : 66

66. Bhuvaneswari R, Gan YY, Soo KC, Olivo M (2009) Targeting EGFR with photodynamic therapyin combination with Erbitux enhances in vivo bladder tumor response . Mol Cancer 8(1) : 94

67. Lee SC, Xu X, Lim YW, Iau P, Sukri N, Lim SE, Yap HL, Yeo WL, Tan P, Tan SH, McLeod H, Goh

BC (2009) Chemotherapy-induced tumor gene expression changes in human breast cancers. Pharmacogenet Genomics 19(3) : 181-192

68. Lee SC, Xu X, Chng WJ, Watson M, Lim YW, Wong CI, Iau P, Sukri N, Lim SE, Yap HL, Buhari SA,

Tan P, Guo J, Chuah B, McLeod HL, Goh BC (2009) Post-treatment tumor gene expressionsignatures are more predictive of treatment outcomes than baseline signatures in breastcancer . Pharmacogenet Genomics 19(11) : 833-842

69. Tan P (2009) Germline polymorphisms as modulators of cancer phenotypes . BMC Med 6: 27

70. Tan IB, Padhy AK, Thng CH, Osmany S, Magsombol B, Ho YH, Tham CK, Quek R, Tao M, Lim

ST (2009) Intensely hypermetabolic extra-axial brainstem tumor in Erdheim-chester disease. Clin Nucl Med 34(9) : 604-607

71. Pang GS, Wang J, Wang Z, Lee CG (2009) Predicting potentially functional SNPs in drug-response genes . Pharmacogenomics 10(4) : 639-653

72. Pang GS, Wang J, Wang Z, Goh C, Lee CG (2009) The G allele of SNP E1/A118G at the mu-opioid receptor gene locus shows genomic evidence of recent positive selection .Pharmacogenomics 10(7) : 1101-1109

73. Wang Z, Sew PH, Chong SS, Lee CG (2009) Realtime exonuclease-mediated allelicdiscrimination (READ): a simple homogeneous genotyping assay for SNPs at the ABC geneloci . Pharmacogenomics 10(12) : 1995-2001

74. Toh HC, Sun L, Soe Y, Wu Y, Phoon YP, Chia WK, Wu J, Wong KY, Tan P (2009) G-CSF inducesa potentially tolerant gene and immunophenotype profile in T cells in vivo . Clin Immunol 132(1): 83-92

75. Begum SM, Jara-Lazaro AR, Thike AA, Tse GM, Wong JS, Ho JT, Tan PH (2009) Mucin extravasationin breast core biopsies--clinical significance and outcome correlation . Histopathology 55(5): 609-617

76. Puan KJ, Low JS, Tan T, Wee J, Tan EH, Fong KW, Chua ET, Jin C, Giner JL, Morita CT, Goh CH,

Hui KM (2009) Phenotypic and functional alterations of Vgamma2Vdelta2 T cell subsets inpatients with active nasopharyngeal carcinoma . Cancer Immunol Immunother 58(7) : 1095-1107

77. Hui KM (2009) Human hepatocellular carcinoma: Expression profiles-based molecularinterpretations and clinical applications. . Cancer Lett 286(1) : 96-102

78. Chua TC, Liauw W, Robertson G, Chia WK, Soo KC, Alobaid A, Al-Mohaimeed K, Morris DL (2009)

Towards randomized trials of cytoreductive surgery using peritonectomy and hyperthermicintraperitoneal chemotherapy for ovarian cancer peritoneal carcinomatosis . Gynecol

Oncol 114(1) : 137-139


79. Kvistborg P, Bechmann CM, Pedersen AW, Toh HC, Claesson MH, Zocca MB (2009) Comparisonof monocyte-derived dendritic cells from colorectal cancer patients, non-small-cell-lung-cancer patients and healthy donors . Vaccine 28(2) : 542-547

80. Koh TS, Thng CH, Hartono S, Lee PS, Choo SP, Poon D, Toh HC, Bisdas S (2009) Dynamiccontrast-enhanced CT imaging of hepatocellular carcinoma in cirrhosis: feasibility of aprolonged dual-phase imaging protocol with tracer kinetics modeling . 19(5) : 1184-1196

81. Tan DS, Thomas GV, Garrett MD, Banerji U, de Bono JS, Kaye SB, Workman P (2009) Biomarker-driven early clinical trials in oncology: a paradigm shift in drug development . Cancer J 15(5): 406-420

82. Ramalingam N, Liu HB, Dai CC, Jiang Y, Wang H, Wang Q, Hui KM, Gong HQ (2009) Real-timePCR array chip with capillary-driven sample loading and reactor sealing for point-of-careapplications . Biomed Microdevices 11(5) : 1007-1020

83. Ang P, Lim IH, Yong RY, Lee AS (2009) A molecular approach for identifying individuals withLi-Fraumeni syndrome who have a limited family history. . Clin Genet 75(3) : 294-297

84. Dong H, Gong YD, Paulose V, Shum P, Olivo M (2009) Effect of input states of polarization onthe measurement error of Mueller matrix in a system having small polarization-dependentloss or gain . Opt Express 17(15) : 13017-13030

85. Dong H, Gong YD, Paulose V, Shum P, Olivo M (2009) Optimum input states of polarizationfor Mueller matrix measurement in a system having finite polarization-dependent loss orgain . Opt Express 17(25) : 23044-23057

86. Ranganath SH, Kee I, Krantz WB, Chow PK, Wang CH (2009) Hydrogel Matrix EntrappingPLGA-Paclitaxel Microspheres: Drug Delivery with Near Zero-Order Release and ImplantabilityAdvantages for Malignant Brain Tumour Chemotherapy . Pharmaceut Res 26(9) : 2101-2114

87. Linn YC, Lau SK, Liu BH, Ng LH, Yong HX, Hui KM (2009) Characterization of the recognitionand functional heterogeneity exhibited by cytokine-induced killer cell subsets against acutemyeloid leukaemia target cell . Immunology 126(3) : 423-435

88. Chan A, Tan SH, Wong CM, Yap KY, Ko Y (2009) Clinically significant drug-drug interactionsbetween oral anticancer agents and nonanticancer agents: A delphi survey of oncologypharmacists . Clin Ther 31(Pt2) : 2379-2386

89. Purushotham S, Chang PE, Rumpel H, Kee IH, Ng RT, Chow PK, Tan CK, Ramanujan RV (2009)

Thermoresponsive core-shell magnetic nanoparticles for combined modalities of cancertherapy . Nanotechnology 20(30) : 305101

90. Liu HB, Ramalingam N, Jiang Y, Dai CC, Hui KM, Gong HQ (2009) Rapid distribution of a liquidcolumn into a matrix of nanoliter wells for parallel real-time quantitative PCR . Sens Actuators

B Chem 35(2) : 671-677

91. Cheung YB, Thumboo J, Gao F, Ng GY, Pang G, Koo WH, Sethi VK, Wee J, Goh C (2009) Mappingthe English and Chinese Versions of the Functional Assessment of Cancer Therapy-Generalto the EQ-5D Utility Index . Value Health 12(2) : 371 - 376

92. Sie L, Loong S, Tan EK (2009) Utility of lymphoblastoid cell lines . J Neurosci Res 87(9) : 1953-1959

> 120


93. Gao F, Ng GY, Cheung YB, Thumboo J, Pang G, Koo WH, Sethi VK, Wee J, Goh C (2009) TheSingaporean English and Chinese versions of the EQ-5D achieved measurement equivalencein cancer patients . J Clin Epidemiol 62(2) : 206-213

94. Ang MK, Hee SW, Quek R, Yap SP, Loong SL, Tan L, Tao M, Lim ST (2009) Presence of a high-grade component in gastric mucosa-associated lymphoid tissue (MALT) lymphoma is notassociated with an adverse prognosis . Ann Hematol 88(5) : 417-424

95. Kah JC, Wong KY, Neoh KG, Song JH, Fu JW, Mhaisalkar S, Olivo M, Sheppard CJ (2009) Criticalparameters in the pegylation of gold nanoshells for biomedical applications: An in vitromacrophage study . J Drug Target 17(3) : 181-193

96. Markus HS, Siegel JE, Topakian R, Schaafsma A, Reihill S, Cullinane M, McCorie H, Morgan E,

Kwon S, Jones K, Keating R, Shipley M, Davies A, Qu SB, Czlonkowskia A, Rozenfeld A, Piorkowska

A, Skowronska M, Fitzgerald D, McMahon N, Sitzer M, Singer O, Baskerville P, Deane C, Goss

D, Naylor R, Walker J, Wong L, Fokkens A, Brown M, Hao SQ, Liu R, Lee MP, Streifler J, Sabah

T, Brusa G, Montano V, Ottonello GA, Wong MC, Chen CP (2009) The Asymptomatic CarotidEmboli Study: study design and baseline results . Int J Stroke 4(5) : 398-405

97. Loa J, Chow PK, Zhang K (2009) Studies of structure-activity relationship on plant polyphenol-induced suppression of human liver cancer cells . Cancer Chemother Pharmacol 63(6) : 1007-1916

98. Tan MG, Kumarasinghe MP, Wang SM, Ooi LL, Aw SE, Hui KM (2009) Modulation of iron-regulatory genes in human hepatocellular carcinoma and its physiological consequences .Exp Biol Med (Maywood) 234(6) : 693-702

99. Lai GG, Lim ST, Tao M, Chan A, Li H, Quek R (2009) Late-onset neutropenia following RCHOPchemotherapy in diffuse large B-cell lymphoma . Am J Hematol 84(7) : 414-417

100. Zhu X, Rivera A, Golub MS, Peng J, Sha Q, Wu X, Song X, Kumarathasan P, Ho M, Redman CM,

Lee S (2009) Changes in red cell ion transport, reduced intratumoral neovascularization,and some mild motor function abnormalities accompany targeted disruption of the MouseKell gene (Kel) . Am J Hematol 84(8) : 492-498

101. Sandanaraj E, Lal S, Cheung YB, Xiang X, Kong MC, Lee LH, Ooi LL, Chowbay B (2009) VKORC1diplotype-derived dosing model to explain variability in warfarin dose requirements in Asianpatients . Drug Metab Pharmacokinet 24(4) : 365-375

102. Loong SL, Hwang JS, Li HH, Wee J, Yap SP, Chua ML, Fong KW, Tan T (2009) Negligible orweak expression of cyclooxygenase-2 is associated with poorer outcome in endemicnasopharyngeal carcinoma: analysis of data from randomized trial between radiation aloneversus concurrent chemo-radiation (SQNP-01) . Radiat Oncol 4(1): : 23

103. De Silva DA, Ancalan M, Doshi K, Chang HM, Wong MC, Chen C (2009) Intracranial large arterydisease in Alzheimer's disease and vascular dementia among ethnic Asians . Eur J Neurol 16(5): 643-645

104. Liu J, Saw CL, Olivo M, Sudhaharan T, Ahmed S, Heng PW, Wohland T (2009) Study of interactionof hypericin and its pharmaceutical preparation by fluorescence techniques. . J Biomed

Opt 14(1) : 014003

105. Kah JC, Olivo M, Chow TH, Song KS, Koh KZ, Mhaisalkar S, Sheppard CJ (2009) Control ofoptical contrast using gold nanoshells for optical coherence tomography imaging of mousexenograft tumor model in vivo . J Biomed Opt 14(5) : 054015

> 121

106. Ong LC, Song IC, Jin Y, Kee IH, Siew E, Yu S, Thng CH, Huynh H, Chow PK (2009) Effectiveinhibition of xenografts of hepatocellular carcinoma (HepG2) by rapamycin and bevacizumabin an intrahepatic model . Mol Imaging Biol 11(5) : 334-342

107. Shih V, Wan HS, Chan A (2009) Clinical predictors of chemotherapy-induced nausea andvomiting in breast cancer patients receiving adjuvant doxorubicin and cyclophosphamide. Ann Pharmacother 43(3) : 444-452

108. Tan EH, Chan A (2009) Evidence-Based Treatment Options for the Management of SkinToxicities Associated with Epidermal Growth Factor Receptor Inhibitors . Ann

Pharmacother 43(10) : 1658-1666

109. Petillo D, Kort EJ, Anema J, Furge KA, Yang XJ, Teh BT (2009) MicroRNA profiling of humankidney cancer subtypes . Int J Oncol 35(1) : 109-114

110. Goh BK, Chow PK, Kesavan SM, Yap WM, Chung AY, Wong WK (2009) A Single-InstitutionExperience with Eight CD117-Positive Primary Extragastrointestinal Stromal Tumors: CriticalAppraisal and a Comparison with Their Gastrointestinal Counterparts . J Gastrointest Surg 13(6): 1094-1098

111. Goh BK, Ooi LL, Cheow PC, Tan YM, Ong HS, Chung AY, Chow PK, Wong WK, Soo KC (2009)

Accurate Preoperative Localization of Insulinomas Avoids the Need for Blind Resection andReoperation: Analysis of a Single Institution Experience with 17 Surgically Treated Tumorsover 19 Years . J Gastrointest Surg 13(6) : 1071-1077

112. De Silva DA, Woon FP, Chen CL, Chang HM, Wong MC (2009) Ethnic South Asian ischaemicstroke patients have a higher prevalence of a family history of vascular disease comparedto age, gender and diabetes-matched ethnic Chinese subjects . J Neurol Sci 285(1-2) : 118-120

113. De Silva DA, Woon FP, Chen C, Chang HM, Wong MC (2009) Serum erythrocyte sedimentationrate is higher among ethnic South Asian compared to ethnic Chinese ischemic strokepatients. Is this attributable to metabolic syndrome or central obesity . J Neurol Sci 276(1-2) : 126-129.

114. Tan CY, Chong YS, Loganath A, Chan YH, Ravichandran J, Lee CG, Chong SS (2009) PossibleGene-Gene Interaction of KIR2DL4 With its Cognate Ligand HLA-G in Modulating Risk forPreeclampsia . Reprod Sci 16(12) : 1135-1143

115. Chua ML, Ong SC, Wee J, Ng DC, Gao F, Tan T, Fong KW, Chua ET, Khoo JB, Low JS (2009)

Comparison of 4 modalities for distant metastasis staging in endemic nasopharyngealcarcinoma . Head Neck 31(3) : 346-354

116. Iyer NG, Clark JR, Murali R, Gao K, O'Brien CJ (2009) Outcomes following parotidectomy formetastatic squamous cell carcinoma with microscopic residual disease: implications forfacial nerve preservation . Head Neck 31(1) : 21-27

117. Tham IW, Hee SW, Yap SP, Tuan JK, Wee J (2009) Retropharyngeal nodal metastasis relatedto higher rate of distant metastasis in patients with N0 and N1 nasopharyngeal cancer . Head Neck 31(4) : 468-474

118. Yeo R, Fong KW, Hee SW, Chua ET, Tan T, Wee J (2009) Brachytherapy boost for T1/T2nasopharyngeal carcinoma . Head Neck 31(12) : 1610-1618

> 122


119. Kanesvaran R, Tao M, Tan IB, Tan DS, Ng DCE, Lim ST (2009) Malignant arrhythmia: A casereport of nasal NK/T-cell lymphoma with cardiac involvement . Acta Oncol 48(4) : 637-639

120. Tang T, Tay KY, Chai J, Agarwal A, Low J, Lee EL, Chuah KL, Sittampalan KS, Wong CF, Dalmau

J, Ngeow JY, Soh LT, Tan MH (2009) A multimodality approach to reversible paraneoplasticencephalitis associated with ovarian teratomas . Acta Oncol 48(7) : 1079-1082

121. Koo YX, Tan DS, Tan IB, Quek R, Tao M, Lim ST (2009) "Anti-HBc alone" in humanimmunodeficiency virus-positive and immuno-suppressed lymphoma patients . World J

Gastroenterol 15(30) : 3834-3835

122. Abdullah SA, Gupta T, Jaafar KA, Chung YF, Ooi LL, Mesenas SJ (2009) Ampullary carcinoma:effect of preoperative biliary drainage on surgical outcome . World J Gastroenterol 15(23) :2908-2912

123. Li H, Ha TC, Tai BC (2009) XRCC1 Gene Polymorphisms and Breast Cancer Risk in DifferentPopulations: A Meta-Analysis . Breast 18(3) : 183-191

124. Lambert C, Berlin I, Lee TL, Hee SW, Tan AS, Picard D, Han JS (2009) A StandardizedTranscutaneous Electric Acupoint Stimulation for Relieving Tobacco Urges in DependentSmokers . Evid Based Complement Alternat Med : 1-9

125. Quek R, George S (2009) Gastrointestinal stromal tumor: a clinical overview . Hematol Oncol

Clin North Am 23(1) : 69-78, viii

126. Koh TH, Sng LH, Yuen SM, Thomas CK, Tan PL, Tan SH, Wong NS (2009) Streptococcal CellulitisFollowing Preparation of Fresh Raw Seafood . Zoonoses Public Health 56(4) : 206-208

127. Leong QM, Lai HK, Lo RG, Teo TK, Goh A, Chow PK (2009) Radiation Dermatitis followingRadioembolization for Hepatocellular Carcinoma: A Case for Prophylactic Embolization ofa Patent Falciform Artery . J Vasc Interv Radiol 20(6) : 833-836

128. Pua U, Low SC, Tan YM, Lim KH (2009) Combined hepatocellular and cholangiocarcinomawith sarcomatoid transformation: radiologic-pathologic correlation of a case . Hepatol Int 3(4): 587-592

129. Kho KW, Stoddart PR, Harris M, Mazzolini AP (2009) Confocal fluorescence polarizationmicroscopy for linear unmixing of spectrally similar labels . Micron 40(2) : 212-217

130. Chuwa EW, Yeo AW, Koong HN, Wong CY, Yong WS, Tan PH, Ho JT, Wong JS, Ho GH (2009)

Early detection of breast cancer through population-based mammographic screening inAsian women: a comparison study between screen-detected and symptomatic breast cancers. Breast J 15(2) : 133-139

131. Lim WT, Chuah KL, Leong SS, Tan EH, Toh CK (2009) Assessment of human papillomavirusand Epstein-Barr virus in lung adenocarcinoma . Oncol Rep 21(4) : 971-975

132. Kah JC, Chow TH, Ng BK, Razul SG, Olivo M, Sheppard CJ (2009) Concentration dependenceof gold nanoshells on the enhancement of optical coherence tomography images: a quantitativestudy . Appl Optics 48(10) : D96-D108

133. Iyer NG, Clark JR, Ashford BG (2009) Internal mammary artery perforator flap for head andneck reconstruction . ANZ J Surg 79(11) : 799-803

> 123

134. Bisdas S, Baghi M, Wagenblast J, Bisdas T, Thng CH, Mack MG, Koh TS, Ernemann U (2009)

Tracer kinetics analysis of dynamic contrast-enhanced CT and MR data in patients withsquamous cell carcinoma of the upper aerodigestive tract: comparison of the results . Clin

Physiol Funct Imaging 29(5) : 339-346

135. Yap KY, Tay WL, Chui WK, Chan A (2009) Clinically relevant drug interactions betweenanticancer drugs and psychotropic agents . Eur J Cancer Care (Engl) 2009 Dec 17 : Epubahead of print

136. Cheung YB, Goh C, Wee J, Khoo KS, Thumboo J (2009) Measurement properties of the Chineselanguage version of the functional assessment of cancer therapy-general in a Singaporeanpopulation . Ann Acad Med Singapore 38(3) : 38(3):225-229

137. Ng DZ, Goh BK, Tham EH, Young SM, Ooi LL (2009) Cystic neoplasms of the pancreas: currentdiagnostic modalities and management . Ann Acad Med Singapore 38(3) : 251-259

138. Koong HN, Khoo D, Higbee C, Travers M, Hyland A, Cummings KM, Dresler C (2009) Global airmonitoring study: a multi-country comparison of levels of indoor air pollution in differentworkplaces . Ann Acad Med Singapore 38(3) : 202-206

139. Madhavan K, Vathsala A, Ooi LL (2009) Organ and tissue transplantation . Ann Acad Med

Singapore 38(4) : 289-292

140. Gogna A, Lath N, Chang HM, Tan BS, Wong MC, Koh TH, Lim ST, Htoo MM, Lim WE (2009)

Stent-assisted percutaneous angioplasty for extra-cranial carotid disease:experience atSingapore General Hospital . Ann Acad Med Singapore 38(9) : 756-762

141. Beng AK, Fong CW, Shum E, Goh C, Goh KT, Chew SK (2009) Where the elderly die: theinfluence of socio-demographic factors and cause of death on people dying at home . Ann

Acad Med Singapore 38(8) : 676-683

142. Bisdas S, Foo CZ, Thng CH, Vogl TJ, Koh TS (2009) Optimization of Perfusion CT Protocolfor Imaging of Extracranial Head and Neck Tumors . J Digit Imaging 22(5) : 437-448

143. Lee SY, Pormento JG, Koong HN (2009) Abdominal paracentesis and thoracocentesis . Surg

Laparosc Endosc Percutan Tech 19(2) : e32-e35.

144. Huynh H, Fargnoli J (2009) Brivanib alaninate CYP17 Inhibitor, Oncolytic . Drugs Future 34(11): 861-934

145. Cheong LS, Lin F, Seah HS, Qian K, Zhao F, Thong PS, Soo KC, Olivo M, Kung SY (2009)

Embedded Computing for Fluorescence Confocal Endomicroscopy Imaging . J Signal Process

Syst 55(1-3) : 217-228

146. Boussioutas A, Tan P (2009) Genomic and Proteomic Advances in Gastric Cancer . The

Biology of Gastric Cancers Book Chapt 11 : 285-321

147. Wang ML, Foo KF (2009) Adjuvant chemoradiotherapy for high-risk pancreatic cancer . Singapore Med J 50(1) : 43-48

148. Toh CK (2009) The changing epidemiology of lung cancer . Methods Mol Biol 472 : 397-411

149. Li GD, Luo R, Zhang J, Yeo KS, Xie F, Tan KWE, Caille D, Que J, Kon OL, Salto-Tellez M, Meda

P, Lim SK (2009) Derivation of functional insulin-producing cell lines from primary mouseembryo culture . Stem Cell Res 2(1) : 29-40

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150. Li GD, Luo R, Zhang J, Yeo KS, Lian Q, Xie F, Tan EKW, Caille D, Kon OL, Salto-Tellez M, Meda

P, Lim SK (2009) Generating mESC-derived insulin-producing cell lines through an intermediatelineage-restricted progenitor line . Stem Cell Res 2(1) : 41-55

151. Chin WW, Thong PS, Bhuvaneswari R, Soo KC, Heng PW, Olivo M (2009) In-vivo optical detectionof cancer using chlorin e6--polyvinylpyrrolidone induced fluorescence imaging andspectroscopy . BMC Med Imaging 9 : 1

152. Law YM, Quek ST, Tan PH, Wong JS (2009) Adenoid cystic carcinoma of the breast . Singapore

Med J 50(1) : e8-11

153. Teo TH, Ho GH, Chaturverdi A, Khoo JB (2009) Tuberculosis of the chest wall: unusualpresentation as a breast lump . Singapore Med J 50(3) : e97-e99

154. Wang Z, Wang J, Chong SS, Lee CG (2009) Mining Potential Functional Polymorphisms atthe ATP-Binding Cassette Transporter Family . Curr Pharmacogenomics Person Med 7(1) : 40-58

155. Chan A, Lim LL, Tao M (2009) Utilisation review of epoetin alfa in cancer patients at a cancercentre in Singapore . Singapore Med J 50(4) : 365-370

156. Ching BC, Wong JS, Tan MH, Jara-Lazaro AR (2009) The many faces of intraosseoushaemangioma: a diagnostic headache . Singapore Med J 50(5) : e195-e198

157. Chew L, Shih V (2009) Cutaneous reaction associated with weekly docetaxel administration. J Oncol Pharm Pract 15(1) : 29-34

158. Wong JS, Pang ALM (2009) Magnetic Resonance Imaging of Breast Tumors . Magnetic

Resonance Spectroscopy of Breast Tumors. Nova Science Publishers, Inc. New York Chapt 4 : 61-86

159. Upile T, Jerjes W, Sterenborg HJ, El-Naggar AK, Sandison A, Witjes MJ, Biel MA, Bigio I, Wong

BJ, Gillenwater A, Macrobert AJ, Robinson DJ, Betz CS, Stepp H, Bolotine L, McKenzie G, Mosse

CA, Barr H, Chen Z, Berg K, D'Cruz AK, Stone N, Kendall C, Fisher S, Leunig A, Olivo M, Richards-

Kortum R, Soo KC, Bagnato V, Choo-Smith LP, Svanberg K, Tan IB, Wilson BC, Wolfsen H, Yodh

AG, Hopper C (2009) Head & neck optical diagnostics: vision of the future of surgery . Head

Neck Oncol 1(1) : 25

160. Lim R, Tan PH, Cheng C, Agasthian T, Tan HL, Teh BT, Tan MH (2009) A unique case ofspontaneous regression of metastatic papillary renal cell carcinoma: a case report . Cases

J 2 : 7769

161. Chan A, Leow CY, Hian SM (2009) Patients' perspectives and safe handling of oral anticancerdrugs at an Asian cancer center . J Oncol Pharm Pract 15(3) : 161-165

162. Rogers CG, Ditlev JA, Tan MH, Sugimura J, Qian CN, Cooper J, Lane B, Jewett MA, Kahnoski RJ,

Kort EJ, Teh BT (2009) Microarray gene expression profiling using core biopsies of renalneoplasia . Am J Transl Res 1(1) : 55-61

163. Wong TH, Tan YM (2009) Surgery for the palliation of intestinal obstruction in advancedabdominal malignancy . Singapore Med J 50(12) : 1139-1144

164. De Silva DA, Woon FP, Lee MP, Chen CL, Chang HM, Wong MC (2009) Metabolic syndrome isassociated with intracranial large artery disease among ethnic Chinese patients with stroke. J Stroke Cerebrovasc Dis 18(6) : 424-427

> 125

> 126


Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genesDalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer

C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott

H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko

T, Mulderrig L, Mudie L, O'Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L,

Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J,

Kahnoski RJ, Teh BT, Stratton MR, Futreal PA

Nature. 2010 Jan 21;463(7279):360-3.

AbstractClear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized

by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic

mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101

cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in

two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36

methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as

mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results

highlight the role of mutations in components of the chromatin modification machinery in human cancer.

Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer

genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type

dominated by mutations in a single gene, and that systematic screens will be key to fully determining the

somatic genetic architecture of cancer.

Inflammatory tumor microenvironment is associated with superior survival in hepatocellularcarcinoma patientsChew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, Loh M, Bolze A, Quek R, Lee VK, Lee KH, Abastado

JP, Toh HC, Nardin A

J Hepatol. 2010 Mar;52(3):370-9.

AbstractBackground & Aims: Hepatocellular carcinoma (HCC) is an aggressive malignancy with few treatment

options. As the status of the tumour immune microenvironment can affect progression of established

tumours, we evaluated potential immune mechanisms associated with survival in HCC.

Methods: Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from

resected HCC patients using quantitative PCR and immunohistochemistry. Tumour-infiltrating leukocytes

(TILs) were isolated to verify the expression of immune genes and to identify proliferating TILs. These

parameters were analyzed statistically in relation with patient survival and tumour phenotype (apoptosis

and proliferation).

Results: The immune microenvironment within tumours was found to be heterogeneous, although globally

more inert compared to the adjacent non-tumour liver tissue. Univariate analysis in 61 patients identified

a group of innate immune genes whose expression within tumours is positively associated with patient

survival. TNF, IL6 and CCL2 are the most significant genes, with TNF being an independent predictor of

survival in multivariate analysis. The gene set includes macrophage and NK-associated molecules such

as TLR4, TLR3, CCR2, NCR3. Most of these molecules are expressed by TILs. Importantly, proliferating

immune cells, predominantly NK and T cells, are present in tumours of patients with longer survival, and

exclusively in areas devoid of proliferating tumour cells. NK and CD8(+) T cell densities are correlated

positively with tumour apoptosis, and negatively with tumour proliferation.

Conclusions: Hence, an inflammatory immune microenvironment within HCC tumours could be an

important means to control tumour progression via TIL activation and proliferation.


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Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosisin human hepatocellular carcinoma cellsTan SM, Li F, Rajendran P, Prem Kumar A, Hui KM, Sethi G

J Pharmacol Exp Ther. 2010 Jul;334(1):285-93.

AbstractThe activation of signal transducer and activator of transcription 3 (STAT3) has been linked with the

proliferation, survival, invasion, and angiogenesis of a variety of human cancer cells, including hepatocellular

carcinoma (HCC). Agents that can suppress STAT3 activation have potential for the prevention and

treatment of HCC. In this study, we tested an agent, beta-escin, for its ability to suppress STAT3 activation.

We found that beta-escin, a pentacyclic triterpenoid, inhibited both constitutive and interleukin-6-inducible

STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated

through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-

activated kinase 2. Vanadate treatment reversed the beta-escin-induced down-regulation of STAT3,

suggesting the involvement of a tyrosine phosphatase. Indeed, we found that beta-escin induced the

expression of tyrosine phosphatase Src homology phosphatase 1 that correlated with the down-regulation

of constitutive STAT3 activation. beta-Escin also down-regulated the expression of STAT3-regulated gene

products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, and vascular endothelial growth factor. Finally,

beta-escin inhibited proliferation and also substantially potentiated the apoptotic effects of paclitaxel and

doxorubicin in HCC cells. Overall, these results suggest that beta-escin is a novel blocker of STAT3

activation that may have potential in the suppression of proliferation and chemosensitization in HCC.

Global molecular dysfunctions in gastric cancer revealed by an integrated analysis of thephosphoproteome and transcriptomeGuo T, Lee SS, Ng WH, Zhu Y, Gan CS, Zhu J, Wang H, Huang S, Sze SK, Kon OL

Cell Mol Life Sci. 2010 Oct 16.

AbstractWe integrated LC-MS/MS-based and protein antibody array-based proteomics with genomics approaches

to investigate the phosphoproteome and transcriptome of gastric cancer cell lines and endoscopic gastric

biopsies from normal subjects and patients with benign gastritis or gastric cancer. More than 3,000 non-

redundant phosphorylation sites in over 1,200 proteins were identified in gastric cancer cells. We correlated

phosphoproteome data with transcriptome data sets and reported the expression of 41 protein kinases,

5 phosphatases and 65 phosphorylated mitochondrial proteins in gastric cancer cells. Transcriptional

expression levels of 190 phosphorylated proteins were >2-fold higher in gastric cancer cells compared

to normal stomach tissue. Pathway analysis demonstrated over-presentation of DNA damage response

pathway and underscored critical roles of phosphorylated p53 in gastric cancer. This is the first study to

comprehensively report the gastric cancer phosphoproteome. Integrative analysis of the phosphoproteome

and transcriptome provided an expansive view of molecular signaling pathways in gastric cancer.

> 128

AZD6244 (ARRY-142886) enhances the antitumor activity of rapamycin in mouse models of humanhepatocellular carcinomaHuynh H

Cancer. 2010 Mar 1;116(5):1315-25.

AbstractBackground: The protein kinase B (AKT)/mammalian target of rapamycin (AKT/mTOR) and mitogen

activated protein kinase/extracellular regulated kinase kinase/extracellular regulated kinase (MEK/ERK)

signaling pathways have been shown to play an important role in hepatocellular carcinoma (HCC) growth

and angiogenesis, suggesting that inhibition of these pathways may have therapeutic potential.

Methods: We treated patient-derived HCC xenografts with 1) mTOR inhibitor rapamycin (RAPA); 2) MEK

inhibitor AZD6244 (ARRY-142886); and 3) AZD6244 plus RAPA (AZD6244/RAPA). Western blotting was

used to determine pharmacodynamic changes in biomarkers relevant to angiogenesis, mTOR pathway,

and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by

immunohistochemistry.

Results: We report here that pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced

the antitumor and antiangiogenic activities of mTOR inhibitor RAPA in both orthotopic and ectopic models

of HCC. Such inhibition led to increased apoptosis, decreased angiogenesis and cell proliferation, reduced

expression of positive cell cycle regulators, and increase in proapoptotic protein Bim.

Conclusions: Our findings indicate that the AZD6244/RAPA combination had antitumor and antiangiogenic

effects in preclinical models of human HCC. Given the urgent need for effective therapies in HCC, clinical

evaluating AZD6244/RAPA combination seems warranted.


> 129

1. Wong NS, Buckman RA, Clemons M, Verma S, Dent S, Trudeau ME, Roche K, Ebos J, Kerbel R,

Deboer GE, Sutherland DJ, Emmenegger U, Slingerland J, Gardner S, Pritchard KI (2010) PhaseI/II Trial of Metronomic Chemotherapy With Daily Dalteparin and Cyclophosphamide, Twice-Weekly Methotrexate, and Daily Prednisone As Therapy for Metastatic Breast Cancer UsingVascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor ReceptorLevels As Markers of Response . J Clin Oncol 28(5) : 723-730

2. Tan DS, Ng QS, Tan IB, Lim ST, Lim WT (2010) Truth About ERCC1 in Lung Cancer . J Clin

Oncol 28(10) : e162

3. Tan MH, Leo NQ, Loy EY, Lim WY, Chia KS (2010) Association Between Being Underweightand Outcomes in Breast Cancer: Alternative Explanations . J Clin Oncol 28(11) : e177

4. Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal P, Von Pawel J, Sun X, Bennouna J,

Santoro A, Biesma B, Delgado FM, Salhi Y, Vaissiere N, Hansen O, Tan EH, Quoix E, Garrido P,

Douillard JY (2010) Phase III Trial Comparing Vinflunine With Docetaxel in Second-LineAdvanced Non-Small-Cell Lung Cancer Previously Treated With Platinum-ContainingChemotherapy . J Clin Oncol 28(13) : 2167-2173

5. Furge KA, Mackeigan JP, Teh BT (2010) Kinase targets in renal-cell carcinomas: reassessingthe old and discovering the new . Lancet Oncol 11(6) : 571-578

6. Gough DJ, Messina NL, Hii L, Gould JA, Sabapathy K, Robertson AP, Trapani JA, Levy DE, Hertzog

PJ, Clarke CJ, Johnstone RW (2010) Functional crosstalk between type I and II interferonthrough the regulated expression of STAT1 . PLoS Biol 8(4) : e1000361

7. Dulloo I, Gopalan G, Melino G, Sabapathy K (2010) The antiapoptotic DeltaNp73 is degradedin a c-Jun-dependent manner upon genotoxic stress through the antizyme-mediated pathway. Proc Natl Acad Sci USA 107(11) : 4902-4907

8. Cheung CC, Yang C, Berger T, Zaugg K, Reilly P, Elia AJ, Wakeham A, You-Ten A, Chang N, Li L,

Wan Q, Mak TW (2010) Identification of BERP (brain-expressed RING finger protein) as ap53 target gene that modulates seizure susceptibility through interacting with GABAAreceptors . Proc Natl Acad Sci USA 107(26) : 11883-11888

9. McIlwain DR, Pan Q, Reilly P, Elia AJ, McCracken S, Wakeham AC, Itie-Youten A, Blencowe BJ,

Mak TW (2010) Smg1 is required for embryogenesis and regulates diverse genes viaalternative splicing coupled to nonsense-mediated mRNA decay . Proc Natl Acad Sci

USA 107(27) : 12186-12191

10. Guo T, Zhu Y, Gan CS, Lee SS, Zhu J, Wang H, Li X, Christensen J, Huang S, Kon OL, Sze SK

(2010) Quantitative proteomics discloses MET expression in mitochondria as a direct targetof MET kinase inhibitor in cancer cells . Mol Cell Proteomics 2010 Aug 16 : Epub ahead ofprint

11. Toh WH, Nam SY, Sabapathy K (2010) An essential role for p73 in regulating mitotic cell death. Cell Death Differ 17(5) : 787-800

12. Lee MK, Tong WM, Wang ZQ, Sabapathy K (2010) Serine 312 phosphorylation is dispensablefor wild-type p53 functions in vivo . Cell Death Differ 2010 Jul 30 : Epub ahead of print

13. Fan HM, Olivo M, Shuter B, Yi JB, Bhuvaneswari R, Tan HR, Xing GC, Ng CT, Liu L, Lucky SS,

Bay BH, Ding J (2010) Quantum Dot Capped Magnetite Nanorings as High PerformanceNanoprobe for Multiphoton Fluorescence and Magnetic Resonance Imaging . J Am Chem

Soc 132(42) : 14803-14811

> 130

14. Wang Y, Lu Y, Toh ST, Sung WK, Tan P, Chow P, Chung AY, Jooi LL, Lee CG (2010) Lethal-7 isdown-regulated by the hepatitis B virus x protein and targets signal transducer and activatorof transcription 3 . J Hepatol 53(1) : 57-66

15. Huang D, Ding Y, Li Y, Luo WM, Zhang ZF, Snider J, VandenBeldt K, Qian CN, Teh BT (2010)

Sunitinib acts primarily on tumor endothelium rather than tumor cells to inhibit the growthof renal cell carcinoma . Cancer Res 70(3) : 1053-1062

16. Ranganath SH, Fu Y, Arifin DY, Kee I, Zheng L, Lee HS, Chow PK, Wang CH (2010) The use ofsubmicron/nanoscale PLGA implants to deliver paclitaxel with enhanced pharmacokineticsand therapeutic efficacy in intracranial glioblastoma in mice . Biomaterials 31(19) : 5199-5207

17. Wang J, Ronaghi M, Chong SS, Lee CG (2010) pfSNP: An integrated potentially functionalSNP resource that facilitates hypotheses generation through knowledge syntheses . Hum

Mutat 2010 Jul 29 : Epub ahead of print

18. Ong SJ, Teo M, Lim KH, Choo SP, Toh HC (2010) Rapamycin and Thalidomide Treatment ofa Patient with Refractory Metastatic Gastroesophageal Adenocarcinoma: A Case Report .Oncologist 15(9) : 965-968

19. Chia WK, Wang WW, Lim WT, Tai WM, Sun L, Thng CH, Soe Y, Yap SP, Tan EH, Toh HC (2010)

Nonmyeloablative Allogeneic Stem Cell Transplantation for Nasopharyngeal Carcinoma .Oncologist 2010 Oct 27 : Epub ahead of print

20. Low SY, Takano AM, Devanand A, Ngeow JY (2010) Recurring mouth ulcer and skin rash ina man with abnormal chest radiograph . Chest 137(4) : 983-988

21. Jaichandran S, Krishnan S, Ng WH, Lee SS, Phan TT, Kon OL (2010) Biosafety assessment ofsite-directed transgene integration in human umbilical cord-lining cells . Mol Ther 18(7) :

1346-1356

22. Bhuvaneswari R, Gan YY, Soo KC, Olivo M (2010) Author's reply to comment on "The effectof photodynamic therapy on tumor angiogenesis. Cellular and Molecular Life Sciences, 66,2275-2283" . Cell Mol Life Sci 67(9) : 1561

23. Ang MK, Ooi AS, Thike AA, Tan P, Zhang Z, Dykema K, Furge K, Teh BT, Tan PH (2010) Molecularclassification of breast phyllodes tumors: validation of the histologic grading scheme andinsights into malignant progression . Breast Cancer Res Treat 2010 Oct 14 : Epub ahead ofprint

24. Lim WT, Tan EH, Toh CK, Hee SW, Leong SS, Ang PC, Wong NS, Chowbay B (2010) Phase Ipharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexol-PM) in patientswith solid tumors . Ann Oncol 21(2) : 382-388

25. Tan EH, Ramlau R, Pluzanska A, Kuo HP, Reck M, Milanowski J, Au JS, Felip E, Yang PC, Damyanov

D, Orlov S, Akimov M, Delmar P, Essioux L, Hillenbach C, Klughammer B, McLoughlin P, Baselga

J (2010) A multicentre phase II gene expression profiling study of putative relationshipsbetween tumour biomarkers and clinical response with erlotinib in non-small-cell lungcancer . Ann Oncol 21(2) : 217-222

26. Ngeow J, Lim WT, Leong SS, Ang MK, Toh CK, Gao F, Chowbay B, Tan EH (2010) Docetaxelis effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma .Ann Oncol 2010 Aug 17 : Epub ahead of print


> 131

27. Cho SJ, Ahn YH, Maiti KK, Dinish US, Fu CY, Thoniyot P, Olivo M, Chang YT (2010) Combinatorialsynthesis of a triphenylmethine library and their application in the development of surfaceenhanced Raman scattering (SERS) probes . Chem Commun (Camb) 46(5) : 722-724

28. Tan SJ, Lakshmi RL, Chen P, Lim WT, Yobas L, Lim CT (2010) Versatile label free biochip forthe detection of circulating tumor cells from peripheral blood in cancer patients . Biosens

Bioelectron 2010 Jul 22 : Epub ahead of print

29. Maiti KK, Dinish US, Fu CY, Lee JJ, Soh KS, Yun SW, Bhuvaneswari R, Olivo M, Chang YT (2010)

Development of biocompatible SERS nanotag with increased stability by chemisorption ofreporter molecule for in vivo cancer detection . Biosens Bioelectron 26(2) : 398-403

30. Dinish US, Yaw FC, Agarwal A, Olivo M (2010) Development of highly reproducible nanogapSERS substrates: Comparative performance analysis and its application for glucose sensing. Biosens Bioelectron 2010 Sep 23 : Epub ahead of print

31. Koo YX, Tan DS, Tan IB, Tao M, Chow WC, Lim ST (2010) Hepatitis B virus reactivation androle of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection whoare receiving chemoimmunotherapy . Cancer 116(1) : 115-121

32. Tan IB, Ang KK, Ching BC, Mohan C, Toh CK, Tan MH (2010) Testicular microlithiasis predictsconcurrent testicular germ cell tumors and intratubular germ cell neoplasia of unclassifiedtype in adults: a meta-analysis and systematic review . Cancer 116(19) : 4520-4532

33. Song JY, Han HS, Sabapathy K, Lee BM, Yu E, Choi J (2010) Expression of a homeostaticregulator, Wip1 (wild-type p53-induced phosphatase), is temporally induced by c-Jun andp53 in response to UV irradiation . J Biol Chem 285 : 9067-9076

34. Ngeow JY, Leong SS, Gao F, Toh CK, Lim WT, Tan EH, Poon D (2010) Impact of comorbiditieson clinical outcomes in non-small cell lung cancer patients who are elderly and/or havepoor performance status . Crit Rev Oncol Hematol 76(1) : 53-60

35. Ho IA, Miao L, Sia KC, Wang GY, Hui KM, Lam PY (2010) Targeting human glioma cells usingHSV-1 amplicon peptide display vector . Gene Ther 17(2) : 250-260

36. Chen NK, Tan SY, Udolph G, Kon OL (2010) Insulin expressed from endogenously activeglucose-responsive EGR1 promoter in bone marrow mesenchymal stromal cells as diabetestherapy . Gene Ther 17(5) : 592-605

37. Gao F, Wee J, Wong HB, Machin D (2010) Quality-of-Life-Adjusted Survival Analysis ofConcurrent Chemo Radiotherapy for Locally Advanced (Nonmetastatic) NasopharyngealCancer . Int J Radiat Oncol Biol Phys 78(2) : 454-460

38. Mirzayans R, Andrais B, Scott A, Paterson MC, Murray D (2010) Single-cell analysis of p16(INK4a)and p21(WAF1) expression suggests distinct mechanisms of senescence in normal humanand Li-Fraumeni Syndrome fibroblasts . J Cell Physiol 223(1) : 57-67

39. Toh CK, Ahmad B, Soong R, Chuah KL, Tan SH, Hee SW, Leong SS, Tan EH, Lim WT (2010)

Correlation between Epidermal Growth Factor Receptor Mutations and Expression of FemaleHormone Receptors in East-Asian Lung Adenocarcinomas . J Thorac Oncol 5(1) : 17-22

40. Seet RC, Kasiman K, Gruber J, Tang SY, Wong MC, Chang HM, Chan YH, Halliwell B, Chen CP

(2010) Is uric acid protective or deleterious in acute ischemic stroke? A prospective cohortstudy . Atherosclerosis 209(1) : 215-219

> 132

41. Khoo D, Chiam Y, Ng P, Berrick AJ, Koong HN (2010) Phasing-out tobacco: proposal to denyaccess to tobacco for those born from 2000 . Tob Control 19(5) : 355-360

42. Bai J, Sadrolodabaee L, Ching CB, Chowbay B, Chen WN (2010) A Comparative ProteomicAnalysis of HepG2 cells Incubated by S(-) and R(+) Enantiomers of Anti-coagulating DrugWarfarin . Proteomics 10(7) : 1463-1473

43. Hsu CH, Yang TS, Hsu C, Toh HC, Epstein RJ, Hsiao LT, Chen PJ, Lin ZZ, Chao TY, Cheng AL

(2010) Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy inpatients with advanced hepatocellular carcinoma . Br J Cancer 102(6) : 981-986

44. Hahn MA, Howell VM, Gill AJ, Clarkson A, Weaire-Buchanan G, Robinson BG, Delbridge L, Gimm

O, Schmitt WD, Teh BT, Marsh DJ (2010) CDC73/HRPT2 CpG island hypermethylation andmutation of 5'-untranslated sequence are uncommon mechanisms of silencing parafibrominin parathyroid tumors . Endocr Relat Cancer 17(1) : 273-282

45. Huynh H (2010) Molecularly targeted therapy in hepatocellular carcinoma . Biochem

Pharmacol 80(5) : 550-560

46. Ong DC, Yam WC, Siu GK, Lee AS (2010) Rapid Detection of Rifampicin- and Isoniazid-Resistant Mycobacterium tuberculosis by High-Resolution Melting Analysis . J Clin

Microbiol 48(4) : 1047-1054

47. Ho IA, Ng WH, Lam PY (2010) FasL and FADD delivery by a glioma-specific and cell cycle-dependent HSV-1 amplicon virus enhanced apoptosis in primary human brain tumors . Mol

Cancer 9(1) : 270

48. Tan DS, Gerlinger M, Teh BT, Swanton C (2010) Anti-cancer drug resistance: understandingthe mechanisms through the use of integrative genomics and functional RNA interference. Eur J Cancer 46(12) : 2166-2177

49. Xie M, Sabapathy K (2010) Tyrosine 170 is dispensable for c-Jun turnover . Cell Signal 22(2): 330-337

50. Thike AA, Iqbal J, Cheok PY, Chong AP, Tse GM, Tan B, Tan P, Wong NS, Tan PH (2010) TripleNegative Breast Cancer: Outcome Correlation With Immunohistochemical Detection ofBasal Markers . Am J Surg Pathol 34(7) : 956-964

51. Sun YJ, Luo JT, Wong SY, Lee AS (2010) Analysis of rpsL and rrs mutations in Beijing andnon-Beijing streptomycin-resistant Mycobacterium tuberculosis isolates from Singapore .Clin Microbiol Infect 16(3) : 287-289

52. Lee AW, Tung SY, Chan AT, Chappell R, Fu YT, Lu TX, Tan T, Chua DT, O'Sullivan B, Tung R, Ng

WT, Leung TW, Leung SF, Yau S, Zhao C, Tan EH, Au GK, Siu L, Fung KK, Lau WH (2010) Arandomized trial on addition of concurrent-adjuvant chemotherapy and/or acceleratedfractionation for locally-advanced nasopharyngeal carcinoma . Radiother Oncol 2010 Oct22 : Epub ahead of print

53. Lal S, Mahajan A, Chen WN, Chowbay B (2010) Pharmacogenetics of Target Genes AcrossDoxorubicin Disposition Pathway: A Review . Curr Drug Metab 11(1) : 115-128

54. Ngeow JY, Toh CK (2010) The Role of Pemetrexed Combined with Gemcitabine for Non-Small-Cell Lung Cancer . Curr Drug Targets 11(1) : 61-66


> 133

55. Li F, Fernandez PP, Rajendran P, Hui KM, Sethi G (2010) Diosgenin, a steroidal saponin, inhibitsSTAT3 signaling pathway leading to suppression of proliferation and chemosensitization ofhuman hepatocellular carcinoma cells . Cancer Lett 292(2) : 197-207

56. Subramaniam K, Ooi LL, Hui KM (2010) Transcriptional down-regulation of IGFBP-3 in humanhepatocellular carcinoma cells is mediated by the binding of TIA-1 to its AT-rich element inthe 3'-untranslated region . Cancer Lett 297(2) : 259-268

57. Koh TS, Thng CH, Hartono S, Kwek JW, Khoo JB, Miyazaki K, Collins DJ, Orton MR, Leach MO,

Lewington V, Koh DM (2010) Dynamic contrast-enhanced MRI of neuroendocrine hepaticmetastases: A feasibility study using a dual-input two-compartment model . Magn Reson

Med 2010 Sep 21 : Epub ahead of print

58. Toh HC, Chia WK, Sun L, Thng CH, Soe Y, Phoon YP, Yap SP, Lim WT, Tai WM, Hee SW, Tan SH,

Leong SS, Tan EH (2010) Graft-vs-tumor effect in patients with advanced nasopharyngealcancer treated with nonmyeloablative allogeneic PBSC transplantation . Bone Marrow

Transplant 2010 Jul 26 : Epub ahead of print

59. Bisdas S, Rumboldt Z, Surlan-Popovic K, Baghi M, Koh TS, Vogl TJ, Mack MG (2010) PerfusionCT in squamous cell carcinoma of the upper aerodigestive tract: long-term predictive valueof baseline perfusion CT measurements . Am J Neuroradiol 31(3) : 576-581

60. Surlan-Popovic K, Bisdas S, Rumboldt Z, Koh TS, Strojan P (2010) Changes in perfusion CTof advanced squamous cell carcinoma of the head and neck treated during the course ofconcomitant chemoradiotherapy . Am J Neuroradiol 31(3) : 570-575

61. Farber LJ, Kort EJ, Wang P, Chen J, Teh BT (2010) The tumor suppressor parafibromin isrequired for posttranscriptional processing of histone mRNA . Mol Carcinog 49(3) : 215-223

62. Chin WW, Praveen T, Heng PW, Olivo M (2010) Effect of polyvinylpyrrolidone on the interactionof chlorin e6 with plasma proteins and its subcellular localization . Eur J Pharm Biopharm 76(2): 245-252

63. Sia KC, Chong WK, Ho IA, Yulyana Y, Endaya B, Huynh H, Lam PY (2010) Hybrid herpes simplexvirus/Epstein-Barr virus amplicon viral vectors confer enhanced transgene expression inprimary human tumors and human bone marrow-derived mesenchymal stem cells . J Gene

Med 12(10) : 848-858

64. Leong SS, Fong KW, Lim WT, Toh CK, Yap SP, Hee SW, Tan EH (2010) A phase II trial ofinduction gemcitabine and vinorelbine followed by concurrent vinorelbine and radiotherapyin locally advanced non-small cell lung cancer . Lung Cancer 67(3) : 325-329

65. Ng QS, Goh V, Milner J, Sundin J, Wellsted D, Saunders MI, Hoskin PJ (2010) Quantitativehelical dynamic contrast enhanced computed tomography assessment of the spatial variationin whole tumour blood volume with radiotherapy in lung cancer . Lung Cancer 69(1) : 71-76

66. Ngeow J, Tan IB, Kanesvaran R, Tan HC, Tao M, Quek R, Lim ST (2010) Prognostic impact ofbleomycin-induced pneumonitis on the outcome of Hodgkin's lymphoma . Ann Hematol 2010Jul 31 : Epub ahead of print

67. Chua HW, Ng D, Choo S, Lum SS, Li H, Soh LY, Sabapathy K, Seow A (2010) Effect of MDM2SNP309 and p53 codon 72 polymorphisms on lung cancer risk and survival among non-smoking Chinese women in Singapore . BMC Cancer 10(1) : 88

> 134

68. Tan MH, Wong CF, Tan HL, Yang XJ, Ditlev J, Matsuda D, Khoo SK, Sugimura J, Fujioka T, Furge

KA, Kort E, Giraud S, Ferlicot S, Vielh P, Amsellem-Ouazana D, Debre B, Flam T, Thiounn N, Zerbib

M, Benoit G, Droupy S, Molinie V, Vieillefond A, Tan PH, Richard S, Teh BT (2010) Genomicexpression and single-nucleotide polymorphism profiling discriminates chromophobe renalcell carcinoma and oncocytoma . BMC Cancer 10(1) : 196

69. Ho IA, Hui KM, Lam PY (2010) Isolation of peptide ligands that interact specifically withhuman glioma cells . Peptides 31(4) : 644-650

70. Lim JS, Singh O, Ramasamy RD, Ramasamy S, Subramanian K, Lee EJ, Chowbay B (2010)

Pharmacogenetics of CYP1A2, novel polymorphisms and haplotypes in three distinct Asianpopulations . Drug Metab Pharmacokinet 2010 Oct 1 : Epub ahead of print

71. Olivo M, Lucky SS, Kent Mancer JF, Lau WK (2010) Altered expression of cell adhesionmolecules leads to differential uptake of hypericin in urothelial cancer . Urol Oncol 2010 Oct6 : Epub ahead of print

72. Bhuvaneswari R, Thong PS, Gan YY, Soo KC, Olivo M (2010) Evaluation of hypericin-mediatedphotodynamic therapy in combination with angiogenesis inhibitor bevacizumab using invivo fluorescence confocal endomicroscopy . J Biomed Opt 15(1) : 011114

73. Vasudevan S, Chen GC, Andika M, Agarwal S, Chen P, Olivo M (2010) Dynamic quantitativephotothermal monitoring of cell death of individual human red blood cells upon glucosedepletion . J Biomed Opt 15(5) : 057001

74. Ang MK, Tan SB, Lim WT (2010) Phase II clinical trials in oncology: are we hitting the target. Expert Rev Anticancer Ther 10(3) : 427-438

75. Idirisinghe PK, Thike AA, Cheok PY, Tse GM, Lui PC, Fook-Chong S, Wong NS, Tan PH (2010)

Hormone Receptor and c-ERBB2 Status in Distant Metastatic and Locally Recurrent BreastCancer: Pathologic Correlations and Clinical Significance . Am J Clin Pathol 133(3) : 416-429

76. Yap KY, Kuo EY, Lee JJ, Chui WK, Chan A (2010) An onco-informatics database for anticancerdrug interactions with complementary and alternative medicines used in cancer treatmentand supportive care: an overview of the OncoRx project . Support Care Cancer 18(7) : 883-891

77. Chan A, Fu WH, Shih V, Coyuco JC, Tan SH, Ng R (2010) Impact of colony-stimulating factorsto reduce febrile neutropenic events in breast cancer patients receiving docetaxel pluscyclophosphamide chemotherapy . Support Care Cancer 2010 Mar 17 : Epub ahead of print

78. Chan A, Tan EH (2010) How well does the MESTT correlate with CTCAE scale for the gradingof dermatological toxicities associated with oral tyrosine kinase inhibitors? . Support Care

Cancer 2010 Sep 5 : Epub ahead of print

79. Huynh H (2010) Tyrosine kinase inhibitors to treat liver cancer . Expert Opin Emerg Drugs 15(1): 13-26

80. Glenn ST, Head KL, Teh BT, Gross KW, Kim HL (2010) Maximizing RNA yield from archivalrenal tumors and optimizing gene expression analysis . J Biomol Screen 15(1) : 80-85


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81. Tan MH, Kanesvaran R, Li H, Tan LH, Tan PH, Wong FC, Chia SK, Teh BT, Yuen J, Chong TW

(2010) Comparison of the UCLA Integrated Staging System and the Leibovich score insurvival prediction for patients with nonmetastatic clear cell renal cell carcinoma . Urology 75(6): 1365-1370; 1370.e1-e3

82. Narasimhalu K, Effendy S, Sim CH, Lee JM, Chen I, Hia SB, Xue HL, Corrales MP, Chang HM,

Wong MC, Chen CP, Tan EK (2010) A randomized controlled trial of rivastigmine in patientswith cognitive impairment no dementia because of cerebrovascular disease . Acta Neurol

Scand 121(4) : 217-224

83. Iyer NG, Clark JR, Singham S, Zhu J (2010) Role of pretreatment 18FDG-PET/CT in surgicaldecision-making for head and neck cancers . Head Neck 32(9) : 1202-1208

84. Tan HK, Giger R, Auperin A, Bourhis J, Janot F, Temam S (2010) Salvage surgery afterconcomitant chemoradiation in head and neck squamous cell carcinomas-Stratification forpostsalvage survival . Head Neck 32(2) : 139-147

85. Leong C, Ngeow JY, Tan IB, Quek R, Tao M, Loh Y, Tan HC, Lim ST (2010) Second hematologicmalignancies after ABVD: Two case reports and a retrospective study of 183 Hodgkinlymphoma patients . Acta Oncol 49(2) : 257-259

86. Chay WY, Chew L, Yeoh TT, Tan MH (2010) An association between transient hypokalemiaand severe acute oxaliplatin-related toxicity predominantly in women . Acta Oncol 49(4) :515-517

87. Yap KY, Ho YX, Chui WK, Chan A (2010) Harnessing the internet cloud for managing druginteractions with chemotherapy regimens in patients with cancer suffering from depression. Acta Oncol 49(8) : 1235-1245

88. Lai GG, Koo YX, Tao M, Tan TT, Lim ST (2010) Use of rituximab in combination with high-dose methotrexate in the treatment of primary central nervous system lymphoma in amycophenolate mofetil treated patient with lupus nephritis . Acta Oncol 2010 Jul 29 : Epubahead of print

89. Yap KY, Chan A, Chui WK, Chen YZ (2010) Cancer informatics for the clinician: An interactiondatabase for chemotherapy regimens and antiepileptic drugs . Seizure 19(1) : 59-67

90. Tham IW, Lin S, Pan J, Han L, Lu JJ, Wee J (2010) Intensity-Modulated Radiation TherapyWithout Concurrent Chemotherapy for Stage IIB Nasopharyngeal Cancer . Am J Clin

Oncol 33(3) : 294-299

91. Chua TC, Liauw W, Koong HN, Esquivel J (2010) Surgical Therapies in Metastatic ColorectalCancer With a Potential for Cure . Am J Clin Oncol 2010 May 21 : Epub ahead of print

92. Teh J, Yap SP, Tham IW, Sethi VK, Chua EJ, Yeo R, Ho TH, Tay EH, Chia YN, Soh LT, Khoo-Tan

HS (2010) Concurrent chemoradiotherapy incorporating high-dose rate brachytherapy forlocally advanced cervical carcinoma: survival outcomes, patterns of failure, and prognosticfactors . Int J Gynecol Cancer 20(3) : 428-433

93. Kumar VJ, Nin CY, Kuei LY, Tan KH, Yeo R, Lam PY (2010) Survival and disease relapse insurgical stage I endometrioid adenocarcinoma of the uterus after adjuvant vaginal vaultbrachytherapy . Int J Gynecol Cancer 20(4) : 564-569

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94. Cheung YB, Xu Y, Tan SH, Cutts F, Milligan P (2010) Estimation of intervention effects usingfirst or multiple episodes in clinical trials: The Andersen-Gill model re-examined . Stat

Med 29(3) : 328-336

95. Chan A, Yap KY (2010) Detection and management of oncology drug interactions: Can wedo better? . Maturitas 65(3) : 181-182

96. Thng CH, Koh TS, Collins DJ, Koh DM (2010) Perfusion magnetic resonance imaging of theliver . World J Gastroenterol 16(13) : 1598-1609

97. Tham CK, Choo SP, Poon D, Toh HC, Ong SY, Tan SH, Wang ML, Foo KF (2010) Capecitabinewith radiation is an effective adjuvant therapy in gastric cancers . World J Gastroenterol 16(29): 3709-3715

98. Cheung YB, Wee HL, Thumboo J, Goh C, Pietrobon R, Toh HC, Yong YF, Tan SB (2010) Riskcommunication in clinical trials: A cognitive experiment and a survey . BMC Med Inform

Decis Mak 10 : 55

99. Ang D, Teo EK, Ang TL, Lim KH, Madhukumar P, Chung AY, Wang Y, Fock KM (2010) UnexplainedSmall-Bowel Obstruction in a Patient with Presumptive Achalasia: Need for Early Recognitionof Chronic Intestinal Pseudo-obstruction (CIPO) . Dig Dis Sci 55(9) : 2691-2692

100. Linn YC, Hui KM (2010) Cytokine-induced NK-like T cells: from bench to bedside . J Biomed

Biotechnol 2010 : 435745

101. Hao Q, Chang HM, Wong MC, Wong KS, Chen C (2010) Frequency of Microemboli Signal inStroke Patients Treated with Low Molecular Weight Heparin or Aspirin . J Neuroimaging 20(2): 118-121

102. Yap KY, Raaj S, Chan A (2010) OncoRx-IQ: a tool for quality assessment of online anticancerdrug interactions . Int J Qual Health Care 22(2) : 93-106

103. Cheung YT, Yap KY, Chui WK, Chan A (2010) Drug-Drug Interactions between Oral Antiepilepticsand Oral Anticancer Drugs: Implications to Clinicians . Eur Neurol 64(2) : 88-94

104. Chua TC, Koong HN (2010) Curative pulmonary metastasectomy for non-seminomatousgerm cell tumor of the testis . ANZ J Surg 80(5) : 380-381

105. Mohd Omar MF, Huang N, Ou K, Yu K, Putti TC, Jikuya H, Ichikawa T, Nishimura O, Tan P, Salto-

Tellez M (2010) Molecular-assisted immunohistochemical optimization . Acta Histochem 112(6): 519-528

106. Chiang J, Chan A, Shih V, Hee SW, Tao M, Lim ST (2010) A prospective study to evaluate thefeasibility and economic benefits of rapid infusion rituximab at an Asian cancer center . Int

J Hematol 91(5) : 826-830

107. Iyer NG, Shaha AR, Silver CE, Devaney KO, Rinaldo A, Pellitteri PK, Ferlito A (2010) Thyroidincidentalomas: to treat or not to treat . Eur Arch Otorhinolaryngol 267(7) : 1019-26

108. Tan MH, Yang J, Tan HL, Wong CF, Tan PH, Sim HG, Ang P, Toh CK, Tay MH, Poon E, Ooi AS, Teh

BT (2010) A Unique Pair of Monozygotic Twins with Concordant Clear Cell Renal CellCarcinoma: A Case Report . Ann Acad Med Singapore 39(1) : 61-63


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109. Teo MC (2010) Peritoneal-based malignancies and their treatment . Ann Acad Med

Singapore 39(1) : 54-57

110. Chan JJ, Loh AH, Sim HG, Tan MH, Toh CK (2010) Coexistence of unicentric Castleman'sDisease and locally advanced papillary renal cell carcinoma: More than a coincidentalassociation? . Ann Acad Med Singapore 39(7) : 584-592

111. Kanesvaran R, Phipps C, Cheng CW, Chan MM, Khoo D, Tan MH (2010) Management ofthrombotic thrombocytopenic purpura in metastatic prostate cancer with only endocrinetherapy . Ann Acad Med Singapore 39(7) : 580-582

112. Tan MH, Chay WY, Ng JH, Teh BT, Chew L (2010) Transient bilateral abducens neuropathywith post-tetanic facilitation and acute hypokalemia associated with oxaliplatin: a casereport . J Med Case Reports 4 : 36

113. Quek R, George S (2010) Update on the treatment of gastrointestinal stromal tumors (GISTs):role of imatinib . Biologics 4 : 19-31

114. Chen LH, Ho H, Lazaro R, Thng CH, Yuen J, Ng WS, Cheng C (2010) Optimum slicing of radicalprostatectomy specimens for correlation between histopathology and medical images . Int

J Comput Assist Radiol Surg 5(5) : 471-487

115. Yang Y, Kort EJ, Ebrahimi N, Zhang Z, Teh BT (2010) Dual KS: Defining Gene Sets with TissueSet Enrichment Analysis . Cancer Inform 9 : 1-9

116. Wee J, Ha TC, Loong SL, Qian CN (2010) Is Nasopharyngeal Cancer really a "CantoneseCancer"? . Chinese J Cancer 29(5) : 517-526

117. Iyer NG, Shaha AR (2010) Complications of thyroid surgery: prevention and management .Minerva Chir 65(1) : 71-82

118. Lee HP, Chew CT, Consigliere DT, Heng D, Huang DT, Khoo J, Khoo KS, Low J, Lui S, Ooi LL,

Puvanendran R, Siow A, Tan A, Yeoh KG (2010) Ministry of health clinical practice guidelines:cancer screening . Singapore Med J 51(2) : 170-175

119. Thng CH, Hartono S, Koh TS, Koh DM (2010) An Introduction to MR Perfusion Imaging of theLiver . Proceedings of Singapore Healthcare 19(1) : 26-35

120. Eng AKH, Kon OL (2010) Molecular Genetics of Gastric Adenocarcinoma . Proceedings of

Singapore Healthcare 19(1) : 57-63

121. Tan SB (2010) Three Myths about Biostatisticians . Proceedings of Singapore Healthcare 19(1): 83

122. Agasthian T, Lin SJ (2010) Clinical outcome of video-assisted thymectomy for myastheniagravis . Asian Cardiovasc Thorac Ann 18(3) : 234-239

123. Li Y, Zhang ZF, Chen J, Huang D, Ding Y, Tan MH, Qian CN, Resau JH, Kim H, Teh BT (2010)

VX680/MK-0457, a potent and selective Aurora kinase inhibitor, targets both tumor andendothelial cells in clear cell renal cell carcinoma . Am J Transl Res 2(3) : 296-308

124. Chan Q, Chan A (2010) Impact of erythropoiesis-stimulating agent prescribing at an Asiancancer center, after release of safety advisories . J Oncol Pharm Pract 2010 Jul 21. [ : Epubahead of print

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125. Agasthian T (2010) Revisiting the prone position in video-assisted thoracoscopic surgery .Asian Cardiovasc Thorac Ann 18(4) : 364-367

126. Tai D, Poon D (2010) Molecular and other novel advances in treatment of metastatic epithelialand medullary thyroid cancers . J Oncol 2010 (2010) : 398564

127. Tan PW, Wong CH, Koong HN, Tan BK (2010) Chest wall reconstruction using a combinedmusculocutaneous anterolateral-anteromedial thigh flap . Indian J Plast Surg 43(1) : 88-91

128. Reilly PT, Afzal S, Wakeham A, Haight J, You-Ten A, Zaugg K, Dembowy J, Young A, Mak TW

(2010) Generation and characterization of the anp32e-deficient mouse. . PLoS ONE 5(10): e13597

129. Tan G, Teo M, Choo SP (2010) Hypoglycaemia in a 63-Year-Old Female with a Large, Recurrent,Metastatic Gastrointestinal Stromal Tumour (GIST) . J Gastrointest Cancer 2010 Nov 6 : Epubahead of print


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Humphrey OeiDistinguishedLecture Series

DISTINGUISHED LECTURE SERIES

The NCCS Humphrey Oei Distinguished Lecture Series aspires to be one ofSingapore’s leading forums for intellectual inquiry and discussion in cancer andbiological research. With eminent scientists as guest speakers, the series hopesto create an environment for exploration of ideas and advances in cancer biologyand medicine.

Distinguished SpeakerSir John Skehel

Honorary Professor,Department of Virology,

University College London

Board Member, NationalBiological Standards Board,

UK

The Origins of Pandemic Influenza

19 April 2007

As one of the world’s leading virologists, Sir John Skehel has made a very special

contribution to medical science. His work elucidates the pathogenicity and

immunogenicity of influenza viruses through studies on the molecular and structural

interactions of the haemagglutinin membrane glycoproteins and its host cell

receptors. Because of his research, the medical community has a better

understanding of the pandemic influenza virus outbreak in 1918 that claimed

more than 20 million lives, and it has provided new insights into the pandemic

potential of the H5N1 influenza viruses. Sir John earned his PhD from the University

of Manchester in 1966, and served as Director of the National Institute for Medical

Research in 1969. He was conferred Fellow of the Royal Society in 1984. Two

years later he was awarded the Wilhelm Feldberg Prize, and in June 1996 he was

knighted. Sir John won the Royal Society’s Royal Medal in 2003. He is an Honorary

Professor at the University College London, Department of Virology. Sir John was

also appointed a board member of National Biological Standards Board (NBSB),

which has a key role in advising the British government on public health threats

like the bird flu.

Distinguished SpeakerProf Arnold Levine

Professor, The Simons Centerfor Systems Biology, Institutefor Advanced Study, Princeton

Joint Professor, Pediatrics andBiochemistry Departments,

Cancer Institute of NewJersey

SINGLE NUCLEOTIDE POLYMORPHISMS IN THE P53PATHWAY: CANCER, GENDER AND FECUNDITY

12 November 2007

Prof Arnold Levine has made significant contributions in the field of oncology in

his research on the causes of cancer in both humans and animals. He was the

first to discover the p53 tumour suppressor gene, which acts to protect individuals

from developing cancer. Following his discovery, thousands of researchers have

followed in Prof Levine’s footsteps, seeking to focus on the p53 gene, which is

the most commonly mutated gene in cancer. Prof Levine is currently a Professor

at The Simons Center for Systems Biology at the Institute for Advanced Study

in Princeton and a joint professor in the Paediatrics and Biochemistry Departments

at the Cancer Institute of New Jersey. He received his PhD in microbiology from

the University of Pennsylvania School of Medicine. Later he was a post-doctoral

fellow of the Public Health Service at the California Institute of Technology. He

has received many honours, the most recent include the Medal for Outstanding

Contributions to Biomedical Research from Memorial Sloan-Kettering Cancer

Center (2000), the Albany Medical Center Prize in Medicine and Biomedical

Research (2001), Award for Basic Research from the Surgical Society of Oncologists

(2003) and the Bristol Myers Squibb Freedom to Discover Award (2005).

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Distinguished SpeakerProf Tak Wah Mak

Director, Campbell FamilyInstitute for Breast CancerResearch, Prince Margaret

Hospital

University Professor,University of Toronto

DID THE ONCOGENE REVOLUTION SETBACK CLINICALONCOLOGY?

17 July 2008

Prof Tak W. Mak is the Director of the Campbell Family Institute for Breast Cancer

Research in the Princess Margaret Hospital and a University Professor at University

of Toronto. He was trained at the University of Wisconsin in Madison, University

of Alberta and Ontario Cancer Institute. Prof Mak’s research interests centre on

immune recognition and regulation, cell survival and cell death in normal and

malignant cells. He is best known as the leading scientist of the group that first

cloned the genes of the human T-cell antigen receptor. His recent works include

the creation of a series of genetically altered mice that have proved critical to

unravelling intracellular programmes governing the development and function of

the immune system, and the dissection of signal transduction cascades in various

cell survival and apoptotic pathways. Prof Mak is an Officer of the Order of Canada

and has been elected Foreign Associate of the National Academy of Sciences

(USA), Foreign Associate of the American Academy of Arts and Sciences, as well

as Fellow of the Royal Society of London (UK). He has won international recognition

in the forms of the Emil von Behring Prize, King Faisal Prize for Medicine, Gairdner

Foundation International Award, Sloan Prize of the General Motors Cancer

Foundation, Novartis Prize in Immunology and Paul Ehrlich Prize of Germany.

Distinguished SpeakerDr Richard Payne

Professor of Medicine andDivinity and Esther ColliflowerDirector, Institute on Care at

the End of Life, DukeUniversity Divinity School

PALLIATIVE CARE AS A HUMAN RIGHT

14 October 2008

Dr Richard Payne is a leading expert on pain relief and caring for those with

advanced disease in the fields of oncology and neurology. He is Professor of

Medicine and Divinity and the Esther Colliflower Director of the Institute on Care

at the End of Life in the Duke University’s Divinity School. A graduate of Yale

University and Harvard University, Dr Payne completed his post-graduate fellowship

in neuro-oncology and pain medicine at Memorial Sloan-Kettering Cancer Center

(MSKCC), New York. Dr Payne has served on numerous panels and advisory

committees, including the editorial boards of the journal, Pain, the Journal of Pain

and Symptom Management, the official journals of the American Pain Society

and the National Hospice and Palliative Care Organization (NHPCO), respectively.

Currently Dr Payne is Chair of the Board of Directors of the Foundation for

Hospices in Sub-Saharan Africa (FHSSA), an affiliate of the NHPCO; and sits on

the boards of directors of the National Coalition of Cancer Survivors and the

Hastings Bioethics Center. For his work and dedication, Dr Payne received a

Distinguished Service Award from the American Pain Society; Urban Resources

Institute’s Humanitarian Award, and the Janssen Excellence in Pain Award.


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Distinguished SpeakerDr John Dick

Professor of MolecularGenetics, University of

Toronto

Program Director, CancerStem Cells-GENESIS OntarioInstitute for Cancer Research

Canada Research Chair, StemCell Biology

CANCER STEM CELLS: FACT OR FICTION

31 July 2009

Dr John Dick is currently Professor of Molecular Genetics at the University of

Toronto, Program Director in Cancer Stem Cells-GENESIS Ontario Institute for

Cancer Research, and Canada Research Chair in Stem Cell Biology. He was

appointed Senior Scientist of the University Health Network in the Research

Institutes of the Toronto General and Princess Margaret Hospital as well as the

McEwen Centre for Regenerative Medicine in October 2002. Dr Dick’s research

focus on normal human blood and leukaemic stem cells has greatly advanced

the understanding of leukaemia’s origins. Elected as a Fellow of the Royal Society

of Canada Canadian Academy of Science in 2004, Dr Dick’s research has been

recognised by several major awards including: the 1997 Michael Smith Award of

Excellence (MRC), 2000 Robert Nobel Prize (NCI Canada), 2002 Herman Boerhaave

Medal (Leiden University), 2005 William Dameshek Prize (American Society of

Hematology), 2007 Metcalf Lecture (International Society for Experimental

Hematology), 2007 Premier’s Summit Award in Medical Research and 2008

Clowes Award (American Association for Cancer Research).

Distinguished SpeakerProf Harald zur Hausen

Professor Emeritus

INFECTIOUS CAUSES OF HUMAN CANCERS:PERSPECTIVES

2 April 2009

Prof Harald zur Hausen, best known for his work in virus-induced malignancies,

was awarded the Nobel Prize in Physiology or Medicine in 2008 for his discovery

of human papilloma viruses causing cervical cancer. He studied Medicine at the

Universities of Bonn, Hamburg and Düsseldorf and did his Postdoctoral Fellowship

at the Institute of Microbiology in Dü'fcsseldorf, before becoming an Assistant

Professor in the Virus Laboratories of the Children’s Hospital in Philadelphia. Prof

zur Hausen was a Senior Scientist at the University of Würzburg’s Institute of

Virology and Chairman and Professor of Virology at the University of Erlangen-

Nürnberg. He received numerous national and international awards, including the

Robert-Koch-Prize, the Charles S. Mott Prize of the General Motors Cancer

Research Foundation, and the Federation of the European Cancer Societies

Clinical Research Award. He is an elected member of various academies, such

as LEOPOLDINA, Academia Europaea, Heidelberg Academy of Sciences, Polish

Academy of Sciences, Institute of Medicine of the National Academy of Sciences

(USA), and of research organisations including EMBO and HUGO. Prof zur Hausen

also has memberships in Editorial Boards of several journals and is currently the

Editor-in-Chief of the International Journal of Cancer.

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Distinguished SpeakerDr Jerry Slater

Professor and Chairman,Department of Radiation

Medicine, Loma LindaUniversity

PROTON THERAPY: THE FUTURE OF RADIATION THERAPYOR A PASSING FAD?

6 August 2009

Dr Jerry Slater, Professor and Chairman of the Department of Radiation Medicine

at Loma Linda University (LLU), is one of the pioneers of hospital-based proton

radiation therapy. He designed the treatment protocols under which proton

radiation treatment was initiated at Loma Linda University Medical Center (LLUMC)

in 1990, and has since led the clinical applications and research at the center. A

graduate of LLU School of Medicine, Dr Slater took residency training in M.D.

Anderson Hospital and Tumor Institute, Houston, followed by a fellowship in

radiation oncology at Massachusetts General Hospital and Harvard Cyclotron

Laboratory, Boston. He has authored or co-authored numerous articles in peer-

reviewed journals, several book chapters and presentations. Dr Slater also holds

appointments at several other medical institutions in southern California, and is

active in many national and regional cancer and radiation-therapy committees

as well as institutional committees at LLU. Dr Slater’s professional pursuit has

been in the use and optimisation of radiation therapy, of which proton-beam

irradiation is one component. He has led clinical studies of proton therapy for

many cancers, investigations of proton and combined-modality treatment of

cancers and other diseases in a myriad of anatomic sites.

Distinguished SpeakerProf Yoshiaki Fujii-

Kuriyama

Professor Emeritus, TohokuUniversity

Adjunct Professor, MedicalResearch Institute, Tokyo

Medical and Dental University

Visiting Scientist, Institute ofMolecular and Cellular

Biosciences, University ofTokyo

PHYSIOLOGICAL FUNCTIONS OF DIOXIN (ARYLHYDROCARBON) RECEPTOR, A MULTI-FUNCTIONALREGULATOR THAT SENSES AND RESPONDS TOENVIRONMENTAL STIMULI

3 December 2009

Prof Yoshiaki Fujii-Kuriyama is best known for his work on the aryl-hydrocarbon

receptor, a human gene which may also act as a tumour suppressor, and

cytochrome P450 for xenobiotic metabolism. He graduated from the University

of Tokyo, where he did his Bachelor’s and Master’s degree in Science before

pursuing his doctoral degree at Osaka University. After his PhD, he took up the

job as a Research Associate at the Rockefeller University in New York City where

he focused on Cell Biology. He returned to Japan in 1975 and assumed the post

of an Instructor at the Kansai Medical University, a Member of Cancer Institute,

Japanese Foundation of Cancer Research and a Professor of Tohoku University.

Currently, Prof Fujii-Kuriyama is a Professor Emeritus of Tohoku University, an

Adjunct Professor at the Medical Research Institute of the Tokyo Medical and

Dental University as well as a Visiting Scientist of the Institute of Molecular and

Cellular Biosciences at the University of Tokyo. He has about 250 papers published

in leading medical journals. He is a recipient of the Princess Takamatsu Cancer

Research Award, which is given to scientists who have made significant

contributions to fundamental and clinical research on cancer.


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Distinguished SpeakerDr Manfred Dietel

Professor, Anatomic andSurgical Pathology

Director, Institute of Pathology,Charité University Hospital

Berlin, Humboldt-University

TISSUE-BASED MOLECULAR PATHOLOGY – THE KEY TOTARGETED THERAPY OF CANCER

2 March 2010

Dr Manfred Dietel is currently the Professor of Anatomic and Surgical Pathology

and Director of the Institute of Pathology, Charité University Hospital Berlin,

Humboldt-University. He is an expert in Diagnostic Pathology and works on more

than 60,000 biopsies and surgical specimens each year. This includes the

application of immunohistochemistry, electron microscopy, Polymerase Chain

Reaction (PCR) based molecular diagnostic (clonality testing, detection of micro-

organisms) and comparative genomic hybridisation during his stints at the

University Hospital Charité and affiliated hospitals. Dr Dietel’s focus is in pathology

of gynaecology, breast, lung, gastro-intestinum, kidney, urogenital tract, infectious

diseases and soft tissues. He has authored more than 200 peer review articles

and published chapters for two editions of HARRISONS Internal Medicine, German

Editions. Dr Dietel is on the editorial board of many scientific journals including

Virchow’s Archiv, Folia Histochemica et Cytobiologica, Pathology Research and

Practice and Veröffentlichungen aus der Pathologie. His research methods of

interest include cell culture, immunocytochemistry, electron microscopy, DNA-

cytophotometry, in-situ hybridisation, PCR, molecular pathology, LOH analyses,

DNA-arrays, methylation arrays, telepathology, and virtual microscopy.

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ResearchSupport Groups

Research Division AdministrationAudrey-Anne Oei

Operations and Core FacilitiesJustine Tan Siew Wee

Gerald Chua Wei Peng

Esabelle Yam Lo Yan

Christine Teo Chwee Teng

Purchasing and StoreJustine Tan Siew Wee

Kathy Koo Mei Cheng

Jordan Tan Yih Haur

Safety OfficeWan Mustaffa bin Wan Chik

Media Prep / GlasswareWan Mustaffa bin Wan Chik

Wendy Tan Ah Yang

Specific Pathogen-Free Unit / AnimalHolding FacilityJennifer Devera Germono

Magdalene Lim Hiong Lan

Jamaludin Bin Jantan

Rajeswarie Jeyaram

Arifin Bin Basir

Grants ManagementConnie Cheng Siew Khim

Research FinanceCassy Yeo Yoke Mei

Jessie Koh Puay Heng

Yvonne Kweh Bee Lian

Rebecca Tan Li Leng

Gwee Hui Eng

Tan Siew Kim

LibraryHo Shih Yao

Mary Tan Nga Khoon

DevelopmentPatrick Yuen Tat Yan

Teo Eng Seng

The following units provide administrative and operational support to the HumphreyOei Institute of Cancer Research of the National Cancer Centre Singapore.

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National Cancer Centre Singapore11 Hospital Drive

Singapore 169610

Tel: (65) 6436 8000

Fax: (65) 6225 6283

www.nccs.com.sg

Reg No 199801562Z

NCCS Humphrey Oei Institute of Cancer Research Brochure

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