Cancer Biology Course

1. Tuesdays, 12 noon, Farrell Teacher Center, Holden Auditorium, All students, Postdocs, faculty, staff welcome Schedule for 2010 Course Jan 19 - Lee Ratner – Intro Jan 26 – Len Maggi - Translational Regulation of Cancer Feb 2 - Laura Beirut - Genetics of Lung Cancer Prevention Feb 9 - Dennis Hallahan – Radiosensitizers Feb 16 – Tom Ellenberger - Molecular Logic of DNA Repair Feb 23 – David Linehan - Immune Dysregulation of Pancreatic Ca Mar2 – Will Gilanders - Breast Ca Vaccine Mar 9 –Elaine Mardis – Genomics of Breast Ca Mar 16 – To be scheduled Mar 23 - You - ATM, DNA Damage Signaling and Cancer *Mar 30 - Lihong Wang - Photoacoustic Imaging *Apr 6 – Fehniger - microRNAs and hematologic malignancies Apr 13 - Mills - Metaplasia and the Mists of change: the molecular basis of gastric cancer Apr 20 - ? Visiting Speaker Apr 27 - ? Visiting Speaker Attendance of all sessions & active discussion esp during presentation classic paper Cancer Biology Course WebSite:http://www.siteman.wustl.edu/physician/prof_education/courses_online.shtml Format: 45 min didactic/30 min discussion

2. Introduction • History • Epidemiology • Biology • Diagnosis • Treatment • Prevention • Social Issues See Perspectives in Nature Reviews in Cancer JCO Dec 10 2009, Advances in Cancer

3. Cancer – Historical Perspective • 1600 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 • Mastectomy for breast cancer • 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

4. Cancer – 20th Century 1903 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

5. Boveri’s Predictions (1902) 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.

6. Acquired Capabilities of Cancer Genetic and epigenetic instability

9. 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

10. Multiple Steps to Cancer Reversibility?

11. Cancer Genome Atlas - Glioblastoma Mardis

12. ChromosomalTranslocations in CML and Solid Tumors 1961-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

13. Cancer Stem Cells Stem cells in adult somatic tissues, Scenarios involving cancer stem cells

14. Metastasis Paget, 1889 “seed and soil”

15. Bevacizmab slows disease progression of metastatic renal cell carcinoma

16. Signal Transduc-tion by HER family

17. 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 trail found 26% reduction in deaths with addition of trastuzumab to standard chemo Mills

18. Platinum-Based Chemotherapy plus Cetuximab in Head and Neck CancerNEJM Sep 08 Improved survival with cetuximab

19. The molecular circuitry of cancer. * * *

21. Maggi

22. Hallahan, Ellenberger, You

23. Fostamatinib, Syk inhibitor, shrinks CLL Fehniger

24. Old, 1996 Linehan, Gillanders

25. Lancet. 2009 Jun.Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial.

26. Molecular Imaging New Linkages in Imaging XRT Surgery Molecular Biology Radiology Wong Nanotechnology; BLI

27. Phase I, II, III CR, PR, stable, progressive QoL, DFS, OS, surrogate markers – cancer Ag, PET NCI, FDA, IRB

29. Oncotype Dx for stage II colon cancer 4 studies (total n=1,851; 761 candidate genes) identified 48 genes associated with recurrence risk and 66 genes predictive of 5FU/LV benefit Multivariate analysis, in the context of stage, grade, nodes examined, and MSI status, yielded 18 genes (7 prognostic genes, 6 predictive genes, 5 reference genes) and separate prognostic recurrence score (RS) and predictive treatment score (TS) algorithms. In validation study, tumor blocks of 1,490 pts with blocks had stage II colon cancer and RT-PCR was successful in 1,436 eligible pts (711 Sx, 725 Sx+5FU/LV) Median FU=6.6 yrs. In the primary analysis pts following Sx, the RS predicted recurrence risk (HR/25 units=1.58, 95% CI 1.15-2.15; p=0.004). The RS also predicted DFS (p=0.01) and OS (p=0.04). Recurrence risk increased monotonically with increasing RS. In multivariate analyses, RS retained prognostic significance (p=0.008) independent of mismatch repair (MMR), T stage, nodes examined, grade, and lymphovascular invasion. MMR deficiency (HR=0.31, 95% CI 0.15-0.63; p<0.001) and T4 stage (HR=1.94, 95% CI 1.35-2.79; p=0.005), together ~25% of pts, also were independently prognostic. 5FU/LV benefit was significant (p<0.001). However, TS was not validated as a predictor of 5FU/LV benefit (interaction p=0.19).

30. J Natl Cancer Inst. 2009 January; Meta-analysis of Risk Reduction Estimates Associated With Risk-Reducing Salpingo-oophorectomy in BRCA1 or BRCA2 Mutation Carriers RRSO was also associated with a statistically significant reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer (HR = 0.21; 95% CI = 0.12 to 0.39).

31. Animal models & safety

32. Quality of Life & Prevention Advances US cancer screening rates are low or declining PSA screening has limited benefit Survivors of childhood cancer are not receiving recommended cancer screening tests Androgen receptor inhibitor reduces prostate cancer risk Supplements (vit E, minerals) ineffective False positive screening tests increase number of f/u tests Studies identify determinants of and effects of end-of-life care

34. ASCO Recommendations Strengthen nation’s clinical research funding, support, insurers, regulatory barriers High quality cancer care for all

35. Acquired Capabilities of Cancer Genetic & epigenetic instability Hanahan & Weinberg Cell 100:57-70, 2000 Discussion Paper