TheOncologist®The International Peer-Reviewed Journalfor the Practicing Oncologist /Hematologist

TheOncologist®The International Peer-Reviewed Journalfor the Practicing Oncologist /Hematologist

The International Peer-Reviewed Journal for the Practicing Oncologist/Hematologist

TheOncologist.com Volume 19, Supplement 1, 2014

Page

Day One

S1 New Insights into Metabolic Regulation of Cancer Growth (abstracts 1-3)

S2 Immunotherapy (abstracts 4-5)

S3 Hematological Malignancies (abstracts 6-8)

S4 Massachusetts General Hospital Cancer Center Junior Faculty Forum (abstracts 9-12)

Day TwO

S5 Metabolic Lesions in Cancer (abstracts 13-14)

S6 Genetic Profiling for Treatable Mutations (abstract 15)

Collaboration in Cancer Drug Trials2014 Chabner Colloquium

November 10-11, 2014Liberty BallroomThe Liberty Hotel

Boston, Massachusetts

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MISSION AND BELIEFS

In a constantly changing field, oncology and hematology professionals must stay at the cutting edge of newdiagnostic and therapeutic advances for the benefit of their patients. To that end, The Oncologist® is dedicatedto translating the latest research developments into the best multidimensional care for cancer patients. Thus,The Oncologist is committed to helping physicians excel in this ever-expanding environment through thepublication of timely reviews, original studies, and commentaries on important developments. We believe thatthe practice of oncology requires both an understanding of a range of disciplines encompassing basic sciencerelated to cancer, translational research, and clinical practice, but also the socioeconomic and psychosocial factorsthat determine access to care and quality of life and function following cancer treatment.

TheOncologist’s Senior Editors are committed to the taskof sharing the same information base, in one journal,with cancer specialists from a broad array of disciplines, including clinical oncologists, outcomes researchers,epidemiologists, and experts in psychosocial aspects of cancer management. We have a particular interest inpresenting the interests and work of those involved in global oncology.

The Oncologist challenges its readers to understand what is new and better, to glimpse the future, not only interms of research, but also in terms of new team approaches to disease management. In short, we want ourreaders to explore how cancer medicine could be and will be practiced now and throughout the next decade.

Editor-in-Chief

Bruce A. Chabner

Deputy Editor

Lecia V. Sequist

Executive Editor

Martin J. Murphy, Jr.

Managing Editor

Ann Murphy

Senior Editors

Richard M. Goldberg Gabriel N. Hortobagyi Patrick G. Johnston H.M. Pinedo

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Editor-in-ChiefBruce A. ChabnerMassachusetts General HospitalHarvard Medical SchoolBoston, MAbruce.chabner@TheOncologist.com

Deputy EditorLecia V. SequistMassachusetts General HospitalHarvard Medical SchoolBoston, MA

Senior EditorsRichard M. GoldbergColumbus, OH

Gabriel N. HortobágyiHouston, TX

Patrick G. JohnstonBelfast, Northern Ireland

H.M. Pinedo Amsterdam, NL

Editors EmeritiFrank M. Balis Philadelphia, PAGregory A. Curt Garrett Park, MDEli Glatstein Philadelphia, PAJohn E. Niederhuber Falls Church, VA

Executive EditorMartin J. Murphy, Jr.Martin.Murphy@TheOncologist.com

Managing EditorAnn MurphyAnn.Murphy@TheOncologist.com

European Edition Co-EditorsPatrick G. Johnston Belfast, N IrelandH.M. Pinedo Amsterdam, NL

Chinese Edition Co-Editors秦叔逵 南京，中国 QIN Shukui Nanjing, China吴一龙 广东，中国 WU Yi-Long Guangzhou, China

CME ProgramFrank M. Balis EditorJayne Gurtler Associate EditorCharles R. Sherman Statistical Editor

Academia–Pharma IntersectH.M. Pinedo Amsterdam, NL

Breast CancerGabriel N. Hortobágyi Houston, TXKathleen I. Pritchard Toronto, Canada

Cancer Diagnostics and Molecular PathologyFred R. Hirsch Aurora, COJeffrey Ross Albany, NY

Cancer ImagingO.S. Hoekstra Amsterdam, NLLiselotte HØjgaard Copenhagen, Denmark

Challenging CasesDavid P. Ryan Boston, MA

Clinical and Molecular Genetics of CancerPatrick J. Morrison Belfast, N IrelandPaula D. Ryan Houston, TX

Clinical Trial ResultsSusan E. Bates Bethesda, MDAntonio Tito Fojo Bethesda, MD

Economics of Oncology PracticeThomas G. Roberts Jr. San Francisco, CA

EndocrinologyHerbert Chen Madison, WIStan B. Sidhu St. Leonards, Australia

Gastrointestinal CancerRichard M. Goldberg Columbus, OhioPatrick G. Johnston Belfast, N IrelandPeter J. O’Dwyer Philadelphia, PA

Genitourinary CancerMarc Dror Michaelson Boston, MA

Geriatric OncologyMatti S. Aapro Genolier, SwitzerlandArti Hurria Duarte, CAHyman Muss Chapel Hill, NC

Global Health and CancerFelicia M. Knaul Boston, MARifat Atun London, UKEduardo Cazap Buenos Aires, Argentina

Gynecologic OncologyDennis S. Chi New York, NYPeter G. Harper London, UK

Head and Neck CancersRobert Haddad Boston, MAMarshall Posner New York, NYJan B. Vermorken Edegem, Belguim

HepatobiliaryRené Adam Villejuif, FranceKenneth K. Tanabe Boston, MA

LeukemiasJoseph G. Jurcic New York, NY

Lung CancerNatasha Leighl Toronto, CanadaNathan A. Pennell Cleveland, OHLecia V. Sequist Boston, MA

LymphomaGeorge P. Canellos Boston, MA

Medical EthicsJoseph J. Fins New York, NYRebecca D. Pentz Atlanta, GA

Melanoma and Cutaneous MalignanciesKeith Flaherty Boston, MAWalter Urba Portland, OR

MyelomasBart Barlogie Little Rock, ARHeinz Ludwig Vienna, Austria

Narratives in OncologyDon S. Dizon Boston, MA

Neuro-OncologyTracy Batchelor Boston, MAJean-Yves Delattre Paris, France

New Drug Development and Clinical PharmacologyWilliam Douglas Figg Bethesda, MDJan H.M. Schellens Amsterdam, NLLillian Siu Toronto, Canada

Outcomes ResearchCarlo La Vecchia Milan, ItalyScott Ramsey Seattle, WABong-Min Yang Seoul, Korea

Pediatric OncologyRochelle Bagatell Philadelphia, PAJohn Cunningham Chicago, IL

Radiation OncologySuresh Senan Amsterdam, NLTheodore Hong Boston, MA

Regulatory IssuesFDA: Max Ning Silver Spring, MDEMA: Francesco Pignatti London, UK

SarcomasEdwin Choy Boston, MAHans Gelderblom Leiden, NL

Symptom Management and Supportive CareEduardo Bruera Houston, TXRussell K. Portenoy New York, NY

European Perspectives PierFranco Conte Padova, ItalyThierry Le Chevalier Villejuif, FrancePeter Selby Leeds, UK

Chinese Perspectives LU Shun Shanghai, China

Section Editors

The official journal of the Society for Translational Oncology

Editorial Board

中文版编委会 Chinese Edition Editorial Board

Rodrigo Arriagada Stockholm, SwedenAl Benson Chicago, ILJoseph R. Bertino New Brunswick, NJAmi S. Bhatt Boston, MAWilliam Blackstock Winston-Salem, NCSusan M. Blaney Houston, TXDouglas W. Blayney Stanford, CAJohann de Bono Surrey, UKHoward A. Burris III Nashville, TNHarold J. Burstein Boston, MALisa Anne Carey Chapel Hill, NCPaul Catalano Boston, MAStephen Chia Vancouver, CanadaMark Clemons Ottawa, ON, CanadaHernán Cortés-Funes Madrid, SpainVolker Diehl Köln, GermanyJason Efstathiou Boston, MAAlexander M.M. Eggermont Rotterdam, NLKaren Gelmon Vancouver, BC, CanadaGiuseppe Giaccone* Bethesda, MDTimothy Gilligan Cleveland, OHMichael L. Grossbard New York, NYFranklin Wei Huang Boston, MA

John Hainsworth Nashville, TNRobert C. Kane* Silver Spring, MDDwight Kaufman Jackson, TNEdward Kim Charlotte, NCJan G.M. Klijn Rotterdam, NLAndrew Ko San Francisco, CAPeter Kozuch New York, NYBeverly J. Lange Philadelphia, PAJay Loeffler Boston, MAThomas J. Lynch, Jr. New Haven, CTRobert Maki New York, NYNeal J. Meropol Cleveland, OHRandall Millikan Houston, TXFranco M. Muggia New York, NYFiemu Nwariaku Dallas, TXSteven J. O’Day Santa Monica, CAEileen O’Reilly New York, NYJoyce O’Shaughnessy Dallas, TXJoe O’Sullivan Belfast, N IrelandRoger J. Packer Washington, DCAnn Partridge Boston, MASergio Pecorelli Brescia, ItalyRichard T. Penson Boston, MA

Jeffrey Peppercorn Durham, NCDerek Raghavan Charlotte, NCGregory H. Reaman Silver Spring, MDPaul Richardson Boston, MALeslie L. Robison Memphis, TNRafael Rosell Badalona, SpainNagahiro Saijo Osaka, JapanDaniel Sargent Rochester, MNOliver Sartor New Orleans, LALidia Schapira Boston, MACharles Schiffer Detroit, MIMichael Seiden Philadelphia, PAChris H. Takimoto Radnor, PAJosep Tabernero Barcelona, SpainAyalew Tefferi Rochester, MNSabine Tejpar Leuven, BelgiumJoel E. Tepper Chapel Hill, NCEverett E. Vokes Chicago, ILJeffrey Weber Tampa, FL Brigitte Widemann* Bethesda, MDSam Yoon New York, NY

*The Oncologist does not represent the opinions of the NIH or the U.S. Federal Government.

编 委 Editors

蔡三军 CAI San-Jun曹梦苒 CAO Meng-Ran陈 功 CHEN Gong程 颖 CHENG Ying樊 旼 FAN Min范 云 FAN Yun傅剑华 FU Jian-Hua顾 晋 GU Jin管晓翔 GUAN Xiao-Xiang郭 军 GUO Jun郭 晔 GUO Ye赫 杰 HE Jie胡夕春 HU Xi-Chun季加孚 JI Jia-Fu姜文奇 JIANG Wen-Qi江泽飞 JIANG Ze-Fei蒋国樑 JIANG Guo-Liang李晔雄 LI Ye-Xiong李宇红 LI Yu-Hong梁 军 LIANG Jun

梁后杰 LIANG Hou-Jie林桐榆 LIN Tong-Yu刘基巍 LIU Ji-wei刘天舒 LIU Tian-Shu刘秀峰 LIU Xiu-Feng陆劲松 LU Jin-Song罗荣城 LUO Rong-Cheng莫树锦（香港） Tony Mok (Hong Kong)牛晓辉 NIU Xiao-Hui潘宏铭 PAN Hong-Ming邱 林 QIU Lin邵志敏 SHAO Zhi-Min沈 锋 SHEN Feng沈 琳 SHEN Lin孙新臣 SUN Xin-Chen唐平章 TANG Ping-Zhang王长利 WANG Chang-Li王 洁 WANG Jie王健民 WANG Jian-Min王杰军 WANG Jie-Jun

王绿化 WANG Lu-Hua吴令英 WU Ling-Ying吴 穷 WU Qiong徐兵河 XU Bing-He徐建明 XU Jian-Ming徐瑞华 XU Rui-Hua殷咏梅 YIN Yong-Mei于 丁 YU Ding于金明 YU Jin-Ming于世英 YU Shi-Ying袁响林 YUAN Xiang-Lin张 俊 ZHANG Jun张 力 ZHANG Li张 阳 ZHANG Yang张小田 ZHANG Xiao-Tian章 真 ZHANG Zhen郑安理（台湾）CHENG Ann-Lii (Taiwan)周爱萍 ZHOU Ai-Ping周清华 ZHOU Qing-Hua朱 军 ZHU Jun

学术顾问 Academic Consultants

副主编 Associate Editors

吴孟超 WU Meng-Chao 孙 燕 SUN Yan 管忠震 GUAN Zhong-Zhen 廖美琳 LIAO Mei-Lin

马军 哈尔滨，中国 MA Jun Harbin, China

李进 上海，中国 LI Jin Shanghai, China

陆舜 上海，中国 LU Shun Shanghai, China

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TheOncologist®

The International Peer-Reviewed Journalfor the Practicing Oncologist /Hematologist

The International Peer-Reviewed Journal for the Practicing Oncologist/Hematologist

Collaboration in Cancer Drug Trials

Volume 19, Supplement 1, 2014

Page

Day One

S1 New Insights into Metabolic Regulation of Cancer Growth (abstracts 1-3)

S2 Immunotherapy (abstracts 4-5)

S3 Hematological Malignancies (abstracts 6-8)

S4 Massachusetts General Hospital Cancer Center Junior Faculty Forum (abstracts 9-12)

Day Two

S5 Metabolic Lesions in Cancer (abstracts 13-14)

S6 Genetic Profiling for Treatable Mutations (abstract 15)

Abstract 1 – Insights Into Pancreatic Cancer Metabolism

NABEEL BARDEESY,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA

Cancercellsdependonwidespreadchanges incellmetabolismtomaintain rapidgrowth.Themetabolic requirementsofpancreaticcancers may be particularly stringent because of their fibrotic and poorly vascularized tumor microenvironment and resultinghypoxia and limited nutrient availability. Accordingly, these tumors exhibit multiple alterations in nutrient acquisition andutilization that are required for malignant growth, including activation of autophagy, a process by which organelles and proteinaggregates are recycled by engulfment in modified membranes and degraded in lysosomes. In this presentation, we discuss themechanisms leading to autophagy activation and the output from this process that maintains energy homeostasis in pancreaticcancer.We also discuss howmutations in pancreatic cancer driver genes rewire tumor cell metabolism as part of their oncogenicprogram. The identification of these metabolic dependencies in pancreatic cancer suggests novel therapeutic strategies.

Abstract 2 – TheHistoneDeacetylase SIRT6: Linking Epigenetics to CancerMetabolism

RAUL MOSTOSLAVSKY,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA

Efficient glucose metabolism is critical for maintaining cellular viability. Under normal nutrient and oxygen conditions, glucose isconverted to pyruvate, entering the mitochondria for oxidative phosphorylation and ATP production. Under hypoxia or nutrientstress,metabolismis switchedtoglycolysis, increasing lactateproductionandreducingmitochondrial respiration—aswitchknownto play an important role in cancer cells, as defined by OttoWarburg decades ago. Little is known about whether chromatin playsa role in carbohydrate flux. Recently,wediscovered that themammalian histone deacetylase sirtuin 6 (SIRT6) is a chromatin factorthat influences glucose metabolism and DNA repair. At the cellular level, SIRT6 inactivation leads to increased cellular glucoseuptake, higher lactate production, and decreased mitochondrial activity. Our results indicate that SIRT6 directly regulatesexpression of several key glycolytic and ribosomal genes. SIRT6 corepresses hypoxia-inducible factor-1a, acting as a histone H3lysine 9andH3 lysine 56deacetylase to inhibit expressionof their target genes and functioningas a tumor suppressor to inhibit theWarburg effect. Strikingly, our new studies indicate that SIRT6, in contrast to other histone deacetylases (HDACs), appears toregulate transcriptional elongation, a novel function for HDACs. Our work identified SIRT6 as a critical chromatin deacetylase ata nodal point between epigenetics and metabolism, functioning as an important tumor suppressor.

Abstract 3 – Improving the Treatment of Prostate Cancer

JOHANN DE BONO, INSTITUTE OF CANCER RESEARCH, THE ROYAL MARSDEN, SUTTON, UNITED KINGDOM

This presentation will focus on the improved understanding of castration-resistant prostate cancer and the delivery of precisionmedicine for this disease. Recent developments with abiraterone, enzalutamide, cabazitaxel, and radium-223 will be discussed.Dataonnovelagents includingAKT,p110b,andpoly(ADP-ribose)polymerase inhibitorsandcabozantinibwill alsobediscussed.Thestudy of exome and transcriptome data in early clinical trials for advanced prostate cancer to drive the pharmacological audittrail will also be presented.

TheOncologist 2014;19(Supplement 1):S1–S6 www.TheOncologist.com ©AlphaMed Press 2014

Abstract 4 – Curative Potential of Cell Transfer Immunotherapy for Cancer

STEVEN A. ROSENBERG, NATIONAL CANCER INSTITUTE, BETHESDA, MARYLAND, USA

Adoptive cell transfer (ACT) immunotherapy for patients with metastatic melanoma using autologous tumor-infiltratinglymphocytes (TILs) mediated a 56% objective response rate, including 20% of patients with durable complete regression ongoingfrom6.7 to 10.3 years. Administration of autologous TILs to nine patients with human papillomavirus-inducedmetastatic cervicalcancer mediated objective responses in three patients, including two complete regressions that are ongoing beyond a year.

The ideal targets for ACT are the uniquemutations that occur in cancers (Table 1). Using deep exomic sequencing, a techniquehas been developed to identify any cancer mutation—presented on any of the patient’s major histocompatibility complexmolecules—that gives rise to reactive T cells.We recently reported the successful application of this approach to treat a patientwith ametastatic bile duct cancer. Because virtually all cancers containmutations, this approach is nowbeing vigorously studied toexpand the current reach of cancer immunotherapy to common epithelial cancers.

Genes encoding conventional a-b T-cell receptors or chimeric antigen receptors (CARs) can be efficiently transduced intoautologous lymphocytes, although choosing suitable targets expressed on the cancer is critical to avoid toxicities to essential normaltissues. ACT using CARs to target the CD19 molecule present on normal B cells and on the great majority of B-cell lymphomasand leukemiaswas first reportedtosuccessfully treatapatientwith refractory lymphoma in2010; thatpatient remainsprogressionfree at 5 years. Durable complete and partial responses have been seen in patients with chemotherapy-refractory indolent andaggressive large B-cell lymphomas. Of 9 patients heavily pretreated with large cell lymphomas receiving ACT, 4 patients have hadcomplete regressions (2 ongoing from 9 to 22 months), and 2 additional patients have had partial response.

Cancer-testis antigens such as NY-ESO-1 and MAGE-A3 are expressed during fetal development and in 10%–80% of cancersfrommultiple tissuesbutoftenarenotexpressed inadult normal tissues.ACT targetingNY-ESO-1 resulted ina67%response rate in15 treated patients with refractory synovial cell sarcoma and a 53% response rate in 19 patientswithmelanoma including durablecomplete regressions. Shared mutations that are unique to an individual cancer type also represent excellent targets for celltransfer immunotherapy, andweare conducting a trial usinga CAR targeting the EGFRvIIImutation, expressed in∼40%ofpatientswith high-grade glioblastoma.

Table 1. Surgery Branch, National Cancer Institute program for the application of cell transfer therapy to awide variety of human

cancers

Receptor Type Cancers Status

Mutations TCR All cancers Accruing

MART-1 TCR Melanoma Closed

gp100 TCR Melanoma Closed

NY-ESO-1 TCR Epithelial and sarcomas Accruing

CEA TCR Colorectal Closed

CD19 CAR Lymphomas Accruing

VEGFR2 CAR All cancers Accruing

2G-1 TCR Kidney Accruing

IL-12 Cytokine Adjuvant for all receptors Accruing

MAGE-A3 TCR Epithelial Accruing

EGFRvIII CAR Glioblastoma Accruing

SSX-2 TCR Epithelial In development

Mesothelin CAR Pancreas and mesothelioma Accruing

CSP4 (HMWAg) CAR Melanoma, TN breast, Pancreas In development

HPV-16 and -17 TCR Cervix, anal, oropharyngeal In development

Abbreviations: CAR, chimeric antigen receptor; HPV, human papillomavirus; TCR, T-cell receptor; TN breast, triple-negative breast.

©AlphaMed Press 2014TheOncologist®

S2

Abstract 5 – Immune Checkpoint Therapy

F. STEPHEN HODI, DANA-FARBER CANCER INSTITUTE, BOSTON, MASSACHUSETTS, USA

The past several years have witnessed a paradigm shift in the success of immune therapies for the treatment of cancer. CytotoxicT-lymphocyte antigen-4 blockade with ipilimumab as a single agent or in combination with dacarbazine chemotherapy was firstdemonstrated to improve survival in patients with metastatic melanoma. More recently, blockade of programmed death 1 orprogrammed death-ligand 1 revealed tremendous promise for the treatment of several types of cancer. Immune checkpointtherapies are currently being evaluated in a number of solid tumors and liquid tumors. Additional antagonist antibodies that takethe brakes off the immune system and agonist antibodies that accelerate immune responses are in current or planned clinicaltesting. Increasing understanding of the regulatory components of the immune system continues to shed insight into clinicalapplications for patients.

Abstract 6 –Molecular Profile of Acute Myeloid Leukemia

TIMOTHY A. GRAUBERT,MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MASSACHUSETTS, USA

Comprehensive studies of the acute myeloid leukemia (AML) genome have revealed new insights into the genetic basis of thisdisease.Recurrentlymutatedgenes fall intopathwayspreviously implicated inAMLpathogenesis (e.g., cytokine signaling, lineage-specific transcription factors) and novel pathways (e.g., RNA splicing, epigenetic regulation, cohesin biology). This increasedknowledge provides opportunities to refine prognostic algorithms and has identified new potential targets for therapy. Notableexamples of the latter are the mutant isocitrate dehydrogenase enzymes, for which preliminary results from ongoing phase Istudies are extremely promising. Routine use of comprehensivemutational profiling in AML raisesmany challenges, including thegenetic heterogeneity of the disease, intrapatient clonal heterogeneity, and mutations of uncertain clinical and biologicalsignificance. Nevertheless, improved understanding of the genetic “rules” of AML and deployment of tools that allow cliniciansaccess to this information provide a foundation for future clinical investigation.

Abstract 7 – Understanding Myelodysplastic Syndromes

BENJAMIN L. EBERT, BRIGHAM AND WOMEN’S HOSPITAL, BOSTON, MASSACHUSETTS, USA

Recent discoveries have yielded profound insights into the genetic basis of myelodysplastic syndromes and other myeloidmalignancies. A central challenge is to translate these discoveries into clinical practice. Genetic lesions are powerfully associatedwith specific aspects of clinical phenotype, including hematologic parameters, particularmorphologic abnormalities, response totherapy, and overall survival. Current research studies aim to integrate existing clinical prognostic scoring systemswithmoleculardatatorefinethetaxonomyofmyeloidmalignancies,to improvethepredictionofprognosisandresponsetospecific therapies,andto develop novel therapeutic strategies based on insights into disease biology.

www.TheOncologist.com ©AlphaMed Press 2014

S3

Abstract 8 – Pathogenesis and Therapy of IDH/TET-Mutant Myeloid Malignancies

ROSS LEVINE,MEMORIAL SLOAN KETTERING CANCER CENTER, NEW YORK, NEW YORK, USA

Clinical, cytogenetic, and gene-based studies have been used to inform biology and improve prognostication for patients withacute myeloid leukemia (AML). Most recently, a series of candidate-gene and whole-genome studies has identified recurrentsomaticmutations inAMLpatients, including TET2,ASXL1,DNMT3A, andEZH2mutations.Ofbiological importance, theTET familyofproteinshasbeenshowntoplaceahydroxylmarkonmethylatedDNAand leadtoDNAdemethylation.Weandothershave foundthat TET2mutations and IDH1 and IDH2mutations lead to loss of DNA hydroxymethylation and hypermethylation phenotypes inleukemia patients. In addition, in vitro and in vivo studies show that TET2 loss or IDH1 and IDH2 neomorphic mutations lead toimpaired hematopoietic differentiation, increased stem cell self-renewal, and myeloid transformation in vivo.

Abstract 9 –Molecular Interrogation of Circulating Tumor Cells for Drug Developmentin Breast Cancer

ADITYA BARDIA,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA

Circulatingtumorcells (CTCs) canserveaspotential “liquidbiopsies,”offeringapotential, relativelynoninvasive tool formonitoringof breast cancer. However, the relatively low number of CTCs isolated using traditional technologymakes adaptation tomolecularor multimarker analyses difficult and has limited the types of clinical applications beyond cell enumeration and prognosticmeasurements. In partnership with the laboratory of Dr. Mehmet Toner of theMassachusetts General Hospital (MGH) Center forEngineering in Medicine, Dr. Daniel Haber and colleagues recently developed a nanotechnology micropost-based microfluidicdevice, the CTC-iChip, specifically designed to accurately capture rare and delicate CTCs from whole blood following processingthrougha low-shear-flowchamber.The isolatedcells areunfixedandcapturedunderconditions thatallowsophisticatedmolecularanalyses and imaging, including RNA sequencing, unlike other currently available technologies. The MGH CTC team recentlyapplied the CTC assay to identify dynamic changes in epithelial and mesenchymal composition of CTCs over time in response tovarious therapies for metastatic breast cancer and observed a potential association between mesenchymal CTCs and diseaseprogression. Furthermore, we established CTC cultures from patients with hormone receptor-positive breast cancer; identifiednewly acquiredmutations in ESR1, PIK3CA, and FGFR2; and conducted drug testing on the CTC cultures to identify drug sensitivityand new therapeutic targets. Consequently, CTCs have the potential not only to be used for cell enumeration and prognosticmeasurements but also to monitor response to targeted therapies, to better understand tumor biology, and to identify novelactionable targets in breast cancer.

Abstract 10 – Evolution of Acquired Resistance to Targeted Therapies in Lung Cancer

AARON N. HATA,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA

The development of acquired drug resistance limits the effectiveness of targeted therapies for lung cancer. Much effort has beenfocused on identifying potential resistance mechanisms in laboratory models of acquired resistance and in tumors from patientswho have developed clinical resistance to targeted therapies. However, little is known about the dynamic processes occurringwithin a tumor that lead to the acquisition of resistance and whether this results from natural selection of pre-existing resistantsubclones or adaptive cellular changes induced by drug treatment. Using models of EGFR-mutant lung cancer, we have observedthat clinically relevant resistance mechanisms may arise through both processes. Furthermore, our results suggest that this mayinfluence responsiveness to subsequent targeted therapies.

©AlphaMed Press 2014TheOncologist®

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Abstract 11 –Models for IDH Mutant Cholangiocarcinoma

SUPRIYA SAHA,MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MASSACHUSETTS, USA

Withmedian survival of,1year, there is anurgent need for translational research focusedon intrahepatic cholangiocarcinoma (ICC).Recent studies have identifiedmutations in the isocitrate dehydrogenase (IDH) enzymes as themost common genetic alterations inICC. Mutant IDH (IDH*) has been proposed to act through an intriguing mechanism whereby the IDH* enzyme produces anoncometabolite, 2-hydroxglutarate (2HG), that inhibits a family of enzymes requiring a-ketoglutarate as a cofactor; however, thespecificpathwaysandcellularalterationsunderlying IDH*-mediatedoncogenic transformationremainpoorlyunderstood.Moreover,there is a paucity of relevantmodel systems to approach these questions and to devise and test potential new therapeutic strategiesagainstthisdisease.Bydevelopingnovel invitrocell systemsandgeneticallyengineeredmousemodels,wehavedefinedamechanismby which IDH* subverts hepatocyte differentiation of liver progenitor cells through the production of 2HG and suppression of thehepatocytenuclear factor4a transcription factor.Moreover, onacquisitionofmutations inKRAS, these IDH* liverprogenitorsexpandto form premalignant biliary lesions and eventually progress to metastatic ICC. Consequently, we have identified mutant IDH asa prominent regulator of hepatic cell fate and present a novel genetically engineered mouse model of IDH-driven malignancy.Simultaneously, we have implemented a clinical protocol to obtain fresh patient samples from liver resections, core biopsies, andmalignant ascites fluid to generate an extensive panel of human ICC cell lines and xenografts, including several with IDH mutations.These model systems have been subjected to high-throughput drug screens to identify novel genotype-specific sensitivities.

Abstract 12 – Targeting EZH2 in SWI/SNF Altered Sarcomas

GREGORY M. COTE,MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER, BOSTON, MASSACHUSETTS, USA

The ATP-dependent chromatin remodeling complex SWI/SNF is a powerful epigenetic tumor suppressor that directly antagonizesthe polycomb group histone methyltransferase EZH2. Alterations in SWI/SNF members, such as INI1/SNF5/SMARCB1, and EZH2are increasingly being recognized in malignancies, including sarcoma. Examples include malignant rhabdoid tumor, epitheloidsarcoma, myoepithelial carcinoma, and synovial sarcoma. In preliminary work we have identified 17 SWI/SNF aberrations in 91sarcomapatient samples.Additionally, emergingevidencesuggests that the fusiongeneproductSS18-SSX insynovial sarcomamayinduce tumorgenesis via displacementofwild-type INI1/SNF5, inducingaberrant targetingofpolycombcomplexes andblockingofcell differentiation programming.We and others hypothesize that this dysfunction may underlie the epigenetic tumorgenesis ina subset of connective tissuemalignancies and that pharmacologic EZH2 inhibition will reverse this phenomenon.To this end, wehave initiated a series of in vitro and in vivo studies exploring the antitumor activity of the EZH2 inhibitors in sarcoma cell lines andmousemodels.Wehopethesedatawill ultimately serveasthe framework forclinical trialsofEZH2 inhibition in sarcomasandotherSWI/SWF-altered connective tissue malignancies.

Abstract 13 – Serine Metabolism and Cancer

MATTHEW VANDER HEIDEN,MASSACHUSETTS INSTITUTE OF TECHNOLOGY, CAMBRIDGE, MASSACHUSETTS, USA

Eukaryotic cells compartmentalize biochemical processes in different organelles, often relying on metabolic cycles to shuttlereducing equivalents across intracellular membranes. NADPH serves as the electron carrier for the maintenance of redoxhomeostasis and reductive biosynthesis, with separate cytosolic and mitochondrial pools providing reducing power in eachrespective location. This cellular organization is critical for numerous functions but complicates analysis of metabolic pathwaysusing available methods. Serine metabolism is a compartmentalized pathway of cells that is critical to support folate and one-carbon metabolism needed for cell proliferation. Increased serine biosynthesis is important for many cancer cells, but thisrequirement for serine production is present evenwhen serine is abundant.Wehavedeveloped an approach to resolve serine andone-carbonmetabolism inacompartment-specificmannerandtodetermine thedirectionofserine-glycine interconversionwithinthe mitochondria and cytosol. These studies provide novel insight into how cells derive one-carbon units to support nucleotidesynthesis and may suggest new targets for cancer therapy.

www.TheOncologist.com ©AlphaMed Press 2014

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Abstract 14 – Exploiting Methylthioadenosine Phosphorylase Deficiency in Cancer

JOSEPH R. BERTINO, RUTGERS CANCER INSTITUTE OF NEW JERSEY, NEW BRUNSWICK, NEW JERSEY, USA

Sixty years ago, 6-thioguanine (6-TG) was introduced into the clinic. Although not yet tested in humans, 6-TG has recently beenproposed to treat a wide variety of cancers with a high frequency of homozygous deletion of the gene for methylthioadenosinephosphorylase (MTAP), often codeleted with the adjacent tumor suppressor CDKN2A (p16). Among the cancers with a highfrequency of MTAP deficiency are leukemias; lymphomas; mesothelioma; melanoma; biliary tract cancer; glioblastoma;osteosarcoma; soft tissue sarcoma; neuroendocrine tumors; and lung, pancreatic, and squamous cell carcinomas. A method toprotect normal host tissues but notMTAP-deficient cancers from6-TG toxicity involves pretreatmentwith the naturally occurringnucleosidemethylthioadenosine (MTA), the substrate for the enzymeMTAP.MTA pretreatment permits administration of dosesof 6-TG that are much higher than can now be safely administered. The combination of MTA and 6-TG has produced substantialshrinkage or slowing of growth in two different xenograft human tumormodels: lymphoblastic leukemia andmetastatic prostatecarcinoma with neuroendocrine features. Further development and a clinical trial of the proposed MTA/6-TG treatment ofMTAP-deficient cancers seem warranted.

Abstract 15 – Lessons From the Study of Extraordinary Responders

DAVID B. SOLIT,MEMORIAL SLOAN KETTERING CANCER CENTER, NEW YORK, NEW YORK, USA

One long-standing problem in clinical oncology is the variability of treatment response observed in early stage clinical trials.Weperformed a genetic and functional analysis of an outlier curative response of a patient with metastatic small cell cancer tocombined checkpoint kinase 1 (Chk1) inhibition and DNA-damaging chemotherapy.Whole-genome sequencing revealed a clonalhemizygousmutation in theMre11 complex gene RAD50 that attenuated ATM signaling, which, in the context of Chk1 inhibition,contributed, via synthetic lethality, to extreme sensitivity to irinotecan. Because Mre11 mutations occur in a diversity of humantumors, the results suggesta tumor-specific combination therapystrategywherebycheckpoint inhibition incombinationwithDNAdamaging chemotherapy is synthetically lethal in tumor cells (but not normal cells) with somatic mutations that impair Mre11complex function.This paradigmofn-of-1 analysis has nowbeenextended toother cancer types, and representative resultswill bereviewed.Novel clinical trial designsoptimized toconfirmphenotype-to-genotype correlations identified inn-of-1 studieswill alsobe reviewed.

©AlphaMed Press 2014TheOncologist®

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