Cancer Biology Course Tuesdays, 12 noon, Southwest Tower 7 th Floor Conference Room All...
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Transcript of Cancer Biology Course Tuesdays, 12 noon, Southwest Tower 7 th Floor Conference Room All...
Cancer Biology CourseTuesdays, 12 noon, Southwest Tower 7th Floor Conference Room All students,Postdocs, faculty, staff welcome
Schedule for 2012 CourseJan 17 – Ratner Intro (Paper: Hanahan & Weinberg, Cell 2011;144:646, Hallmarks of cancer: the next generation)Jan 24 – Curiel - Strategies to Adapt Adenoviruses for Cancer Therapy ApplicationsJan 31 – Denardo – Immune regulation of cancer preventionFeb 7 – Govindan – Lung cancerFeb 14-Ornitz – FGF Signaling in Non-Small Cell Lung CancerFeb 21 Oltz – Epigenomics in lymphomaFeb 28 Tran - GliomasMar 6 Dehdashti - PETMar 13 Tomasson –Biology & Treatment of Myeloma and Plasma Cell DyscrasiasMar 20 Schroeder – The Graft versus Tumor EffectMar 27 Yaseen - Molecular Pathogenesis of Acute Myeloid LeukemiaApr 3 Zighelboim – Ovarian CaApr 10 Kriesel – Genetics of DLBCL Apr 17 or 24 for Student Invited SpeakerAttendance of all sessions & active discussion esp during presentation classic paper
WebSite:http://www.siteman.wustl.edu/physician/prof_education/courses_online.shtmlFormat: 45 min didactic/30 min discussion
Introduction
• History• Epidemiology• Biology• Diagnosis• Treatment• Prevention• Social Issues
See Perspectives in Nature Reviews in Cancer
JCO Jan 1, 2012, Clinical Cancer Advances
Cancer – Historical Perspective1600 BC Egyptian physician record 1st description of breast cancer
460 BC Hippocrates uses “carcinos” to describe tumors (Greek – crab)
129 AD Galen attributes cancer to black bile
1660 Mastectomy for breast cancer
1713 Ramazzini notes absence of cervical but increased breast ca in nuns
1775 Pott describes scrotal cancer in chimney sweeps
1838 Muller describes cancer as abnormalities of cells
1896 Grubbe administers xrays to cancer patient
Cell-cycle checkpoints (Hemmungseinrichtung: inhibitory mechanism) that would allow cell division only when a specific external stimulus is experienced by the cell.
The clonal origin of tumours.
Genetic mosaicism.
Tumour-suppressor genes (Teilungshemmende Chromosomen), the effects of which can be overcome by external signals, and which are physically lost in progressively growing tumours.
Oncogenes (Teilungsfoerdernde Chromosomen) that become amplified (im permanenten Übergewicht) during tumour development.
Tumour progression from benign to malignant, involving sequential changes of increased growth-stimulatory chromosomes and loss of growth-inhibitory chromosomes.
Cancer predisposition through inheritance of chromosomes (genes) that are less able to suppress malignancy.
Cancer predisposition through inheritance of genes that cause aberrant mitoses.
Inheritance of the same 'weak chromosome' from both parents leads to homozygosity for the defective chromosome and, consequently, to high-penetrance cancer syndromes — for example, xeroderma pigmentosum.
The role of wounding and inflammation in tumour promotion.
Loss of cell adhesion in metastasis.
Sensitivity of malignant cells to radiation therapy.
Boveri’s Predictions (1902)
Cancer – 20th Century1903 Radium isolated by Curies used for tumor treatment
1913 American Cancer Society founded
1928 Papanicolau provides basis for PAP smears
1937 Roosevelt creates NCI
1941 Huggins used hormones to treat prostate Ca
1948 Hitchings uses 6MP for childhood leukemia
1955 MTX used for solid tumor
1957 IFN and FU introduced
1966 NCI testing for cancer-causing chemicals
1970 DeVita develops MOPP for Hodgkin
Therapeutic Targeting of the Hallmarks of Cancer
Estimated proportion of cancer in US that could have been avoided by changes in
each category of non-genetic cancer causes – Risk
– Structured-data summaries
– Meta-analysis
– Pooled analysis
– Prospective studies
– Retrospective studies
– Bias
– Confounding
– Randomized controlled trials
– Statistical power
ChromosomalTranslocations in CML and Solid
Tumors1961-Nowell & Hungerford – Ph chromosome
1972 Rowley t9;22 CML
t8;14 Burkitt, t15;17 APL,
t11;22 Ewings
1984 – BCR-ABL fusion
1988 – Huang – ATRA
1998 – Druker – Imatinib, Gleevec
2009 – EML4-ALK in Lung Cancer
Multiple Steps to Cancer
Reversibility?
Cancer Genome Atlas - Glioblastoma
Tran
Intracellular Signaling Networks Regulate the Operations of the Cancer Cell
NFKBIA Deletion in Glioblastoma (NEJM 2011; 364: 627)
Tran
BRAF Inhibitor for Melanoma
Targeting Mutations in Lung Cancer
Govindan 90% stable or shrinkage with crizotinib
Phase 1screening
Zigelboim 8 vs 5 mos PFS
Signal Transduc-
tion by HER
family
Trastuzumab improves survival for patients with HER2+ gastric cancer
Fig. 1. Her-2 IHC (A) and HE (B) in intestinal-type gastric cancer (magnification ×100). FISH analysis shows homogenous amplification of HER-2 (C) and TOP2A (D) in gastric carcinoma (clusters of red signals). Green signals represent centromere 17. Cell nuclei are counterstained with blue dye.
International, phase III trial found 26% reduction in deaths with addition of trastuzumab to standard chemo
Dual HER2 inhibition improves survival in advanced breast cancer
Pertuzumab and trastuzumab
Science 8 May 2009: Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer
Sawyers and colleagues
Cabozantinib active in protstate cancer, esp bone mets
86% response65% dec pain46% off narcsAlso active in melanoma
Ruxolitinib effective at blocking Jak1 & 2 in Myelofibrosis
Yaseen,AML
50% mut
Old, 1996
Brentuximab approved for refractory Hodgkin’s lymphoma and ALCL
Kriesel, DLBCL
86% response in HLD and ALCL
Ipilimumab doubles survival in melanoma
47% vs 36% OS
Signaling Interactions in the Tumor Microenvironment during Malignant Progression
Angiogenesis and other inhibitors
Pazopanib has activity in several soft tissue sarcomas
Brivanib has activity in soft tissue sarcomas (blocks VEGF and FGF)
Axitinib sup to sorafenib in renal cell ca Bevacizumab for ovarian cancer
52% dec disease progression; 80% response; 36% dec in deaths in advanced ovarian Ca Denosumab for bone metastases
Developments in Screening US panel recommended against routine use of
PSA for prostate screening Low dose CT scanning reduces lung cancer
deaths (20% vs CXR screen) Cervical cancer screening extended to 3 yrs,
HPV testing superior to Pap testing alone
Dehdashti
Exemestane reduces risk of invasive breast cancer in high-risk, post menopausal women
65% reduction in invasive ca
Racial disparities in the use of hospice services according to geographic residence and socioeconomic status in an elderly cohort with nonsmall cell lung cancer
Cancer117: 1506-1515, 8 NOV 2010Review also indicates racial disparities in myeloma survival, ovarian cancer care, and cancer death rates, which may be due to differences in education level
ASCO Recommendations Continued progress depends on access to clinical
trials and quality care Faster and smarter clinical trials utilizing information
technology Revitalize federal funding of clinical trials
Examine potential impact of health care reform on cancer disparities
Assist FDA in addressing cancer drug shortages Improve advanced cancer care planning
Highlight potential solutions for oncology workforce shortages
Assist UN in addressing cancer crisis in developing counties