Advanced Cancer Biology II with Computer-Aided Discovery Methods

1. Cancer Biology II Computer-Aided Discovery Methods Adrian V. Lee, Ph.D. Associate Professor Breast Center Departments of Medicine and Molecular and Cellular Biology

2. Cancer Statistics • Cancer affects 1 in 3 people • Worldwide incidence of 10M cases/year • 555,500 Americans died from cancer in 2002

3. US Mortality, 2004 No. of deaths % of all deaths Rank Cause of Death 1. Heart Diseases 652,486 27.2 2. Cancer553,888 23.1 3. Cerebrovascular diseases 150,074 6.3 4. Chronic lower respiratory diseases 121,987 5.1 5. Accidents (Unintentional injuries) 112,012 4.7 6. Diabetes mellitus 73,138 3.1 7. Alzheimer disease 65,965 2.8 8. Influenza & pneumonia 59,664 2.5 9. Nephritis 42,480 1.8 10. Septicemia 33,373 1.4 Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

4. 2007 Estimated US Cancer Deaths* Men289,550 Women270,100 Lung & bronchus 31% Prostate 9% Colon & rectum 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4%bile duct Esophagus 4% Urinary bladder 3% Non-Hodgkin 3% lymphoma Kidney 3% All other sites 24% 26% Lung & bronchus 15% Breast 10% Colon & rectum 6% Pancreas 6% Ovary 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Brain/ONS 2% Liver & intrahepatic bile duct 23% All other sites ONS=Other nervous system. Source: American Cancer Society, 2007.

6. Change in the US Death Rates* by Cause, 1950 & 2004 Rate Per 100,000 586.8 600 1950 2004 500 400 300 217.0 193.9 185.8 180.7 200 100 50.0 48.1 19.8 0 HeartDiseases CerebrovascularDiseases Pneumonia/Influenza Cancer * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2004 Mortality Data: US Mortality Public Use Data Tape, 2004, NCHS, Centers for Disease Control and Prevention, 2006

7. Trends in the Number of Cancer Deaths Among Men and Women, US, 1930-2004 Men Men Women Number of Cancer Deaths Women Source: US Mortality Public Use Data Tape, 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

8. Cancer Death Rates*, All Sites Combined, All Races, US, 1975-2003 Rate Per 100,000 300 Men 250 Both Sexes 200 Women 150 100 50 0 1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 *Age-adjusted to the 2000 US standard population. Source: Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality - All COD, Public-Use With State, Total U.S. (1969-2003), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2006. Underlying mortality data provided by NCHS (www.cdc.gov/nchs).

9. Age-Adjusted Female Cancer Death Rates 33% 28% EBCTG. Lancet. 2005 May 14-20;365(9472):1687-717.

10. Decline in Breast Cancer Incidence Rates in 2003 Ravdin PM, N Engl J Med. 2007 Apr 19;356(16):1670-4.

11. Why are we interested in the molecular biology of cancer? • Cancer is a genetic disease • Agents that cause cancer cause genetic change • Agents that cause genetic change cause cancer e.g. chemical carcinogens, ionizing radiation, viruses

12. Why are we interested in the molecular biology of cancer? If we can understand the molecular biology of cancer we may be able to • Prevent cancer • Better treat cancer

14. Targets in Cancer • Proliferation • Apoptosis/survival • Differentiation

19. Numerous Oncogenes Control Cell Growth Growth factors (I) Growth factor receptors (II) Intracellular Transducers (III) Transcription factors (IV) Intracellular receptors (II)

20. Selected Oncogenes and the Proteins of Their Proto-Oncogenes Animal Retrovirus Nonviral Tumor Subcellular Location of Protein Protein Encoded by Proto-Oncogene Oncogene Class I: Growth Factors Sis Simian sarcoma Secreted Platelet-derived growth factor Class II: Receptors A. Cell-surface receptors with protein-tyrosine kinase activity fms McDonough feline sarcoma Plasma membrane CSF-1 receptor erbB Avian erythroblastosis Plasma membrane Epidermal growth factor receptor Neu (or erb-2) Breast Cancer Plasma membrane Related to epidermal growth factor receptor ros UR II avian sarcoma B. Intracellular receptors erbA Avian erythroblastosis Nuclear Thyroid hormone receptor

21. Subcellular Location of Protein Protein Encoded by Proto-Oncogene Animal Retrovirus Nonviral Tumor Oncogene Class III: Intracellular Transducers A: Protein-tyrosine kinase src Rous avian sarcoma Cytoplasm yes Yamaguchi avian sarcoma Cytoplasm Fps (fes) Fujinami avian sarcoma (and feline sarcoma) Cytoplasm Protein kinases that phosphorylate tyrosine residues abl Abelson murine leukemia Chronic myelogenous leukemia Cytoplasm and nucleus met Murine osteosarcoma

22. Subcellular Location of Protein Protein Encoded by Proto-Oncogene Animal Retrovirus Nonviral Tumor Oncogene B. Protein-serine/threonine kinases mos Moloney murine sarcoma Cytoplasm Protein kinases specific for serine or threonine Raf (mil) 3611 murine sarcoma Cytoplasm C. Ras proteins Ha-ras Harvey murine sarcoma Bladder, mammary, and skin carcinomas Plasma membrane Guanine nucleotide-binding proteins with GTPase activity Ki-ras Kirsten murine sarcoma Lung and colon carcinomas Plasma membrane N-ras Neuroblastoma and leukemias Plasma membrane D. Adaptors crk Avian sarcoma virus Cytoplasm Contains protein with SH2 and SH3 domains but not catalytic domain

23. Subcellular Location of Protein Protein Encoded by Proto-Oncogene Animal Retrovirus Nonviral Tumor Oncogene Class IV: Nuclear Transcription Factors jun Avian sacroma virus 17 Nucleus Transcription factor AP1 fos FBJ osteo-sarcoma Nucleus myc Avian MC29 Myelocytomatosis Nucleus N-myc Neuroblastoama Nucleus Protein that regulate transcription myb Avian myelo-blastosis Leukemia Nucleus ski Avian SKV770 Nucleus rel Avian reticuloendotheliosis Nucleus and cytoplasm

27. Targeted Biologic Therapies – HER2 • 20-30% of primary invasive cancers overexpress HER-2 (90% of these are via gene amplification) • Overexpression of HER-2 correlates with high mitotic rate and poor prognosis (node-positive patients) • HER-2 overexpression is associated with a better patient resposne to doxorubicin, but a poor response to other drugs (methotrexate, 5-fluorouracil, cyclophosphamide and tamoxifen) • Auto-antibodies to HER-2 are found in patient serum and may be a marker for tumor burden • HER-2 is a therapeutic target using a humanized antibody (trastuzumab – Herceptin)

28. New Targeted Biologic Therapies Baselga and Norton. Focus on Breast Cancer. Cancer Cell; 1; 319-322

29. Bange et al. Molecular targets for breast cancer therapy and prevention. Nat Med 2001;7:548 Signaling is more complex than you can possibly imagine

30. Estrogen and Estrogen Receptor as a Therapy for Breast Cancer

35. Benefit of Adjuvant Tamoxifen

36. Clustering of breast tumors associated with ER and coregulated genes West et al. Stanford/Norway Van’t Veer et al. data from Sorlie et al. PNAS, 100: 8418, 2003

37. cyclins, GFs IGFs, Bcl2 Rb, PP2A ER ER MMPs, Cadherins telomerase VEGF, Ets-1 Hanahan and Weinberg: The hallmarks of cancer. Cell. 2000

38. ECM Kinases Growth factors Estrogen Receptor as a ‘Signaling Node’ Estradiol ER RNA AP-1 SP-1 Co-regulators ERE STATs D1/CDKs

41. Loss of regulation of the cell cycle

45. DSB DNA repair complex

50. APOPTOSIS