Targeted Medicine and Molecular Therapeutics. Angus McIntyre, M.D. Medical Oncologist, Addison Gilbert Hospital and Beverly Hospital October 6, 2009

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1 Targeted Medicine and Molecular Therapeutics Angus McIntyre, M.D. Medical Oncologist, Addison Gilbert Hospital and Beverly Hospital October 6, 2009

2 Approaches to Cancer Prevention Screening and early diagnosis Treatment Early stage: surgery, radiation Advanced stage: Drug treatment (usually chemotherapy) Surgery and radiation only to relieve symptoms Supportive care

3 Chemotherapy Originally mustard gas as chemical warfare agent Most chemotherapy injures cells that are growing and dividing by targeting DNA, RNA, and protein synthesis Injures normal proliferating cells (WBC s) and some other tissues

4 Limitations of Chemotherapy Cures some cancers : testicular, lymphoma Does not cure the common cancers: lung, breast, colon (but responsive) Minimally responsive cancers: kidney, melanoma, pancreas Toxic side effects Advances, but no breakthroughs

5 Targeted Therapy New approach focused on molecular biology of cancer cells Selective toxicity for cancer cells Reduced toxicity to normal cells Molecular markers define patient population for a particular treatment

6 Cell Structure

7 DNA Messenger RNA Protein Structural components Enzymes (chemical rxns) Surface receptors and intracellular signaling

8 Signal Transduction by Protein Tyrosine Kinases Surface Receptors & Intracellular Signaling Proteins Control Gene Expression

9 Types of Treatments Monoclonal antibodies Large molecules given IV Act at the surface of tumor cells Target surface receptors or induce an immune response against the tumor Also target circulating growth factors

10 Types of Treatments Tyrosine kinase inhibitors (TKI s) Small molecules given orally Act inside cells Target signal transduction

11 Current Drugs and Type of Target Monoclonal antibodies targeting the receptor. cetuximab (Erbitux) - Colon cancer, trastuzumab (Herceptin) breast cancer, Symposium on Molecular Biology ASCO 2004

12 Current Drugs and Type of Target: Monoclonal antibodies targeting circulating growth factor: bevacizumab (Avastin) against VEGF colon and other cancers

13 Current Drugs and Type of Target TKI s targeting the internal signaling proteins: Sunitinib (Sutent) kidney cancer Erlotinib (Tarceva) lung cancer Symposium on Molecular Biology ASCO 2004

14 1962 synthesized Tamoxifen in breast cancer: the first targeted therapy? 1971 activity in advanced breast cancer 1980 active as adjuvant treatment in early breast cancer

15 Tamoxifen: rationale for effect Blocks the effects of estrogen Shrinks breast cancers that are estrogen dependent Spares normal tissues that are much less estrogen sensitive

16 Normal Breast DCIS Invasive Ductal Cancer

17 ER + Breast Cancer

18 Tamoxifen binds the estrogen receptor and changes its shape so that it is no longer active. J. Clin. Invest. 116(3): (2006).

19 Imatinib (Gleevec) the leukemia pill

20 Case Report: 51 year old man: Night sweats 15 lbs. weight loss Fatigue WBC 400,000 (normal is 6000)

21 Chronic Myelogenous Leukemia (CML) Uncontrolled proliferation of white blood cells Clonal disorder arising from a single cell with well defined mutation that turns on signal for growth Acute leukemia culminated after several years, resulting in death

22 Philadelphia chromosome - First consistent chromosomal abnormality found in cancer cells

23 New Bcr-Abl gene Transcribed and translated into a novel protein: Active tyrosine kinase, which turns on cell growth. We know the detailed structure and how imatinib binds it and inactivates it. Cell 2003; 112:859

24 Response of CML to Gleevec Felt better in 2 weeks ongleevec WBC down to normal in 6 weeks

25 It works! After 5 years, the survival rate improved from 30% to 89% with imatinib Usually mild side effects Other cancers proving more complex and more difficult to target 19 years from target discovery to drug approval

26 Signaling Pathways are Complex Cancer cells may bypass a blocked pathway. Molecular profiling to select the right treatment Symposium on Molecular Biology ASCO 2004

27 Targeted Therapy the scorecard Highly successful treatments in a few rare tumors Modest successes in the more common tumors Toxicity generally less, but not trivial Combination with chemotherapy Possibly new goals for treatment: stabilization rather than cure

28 Molecular Medicine the Future Enormous amount of new knowledge about how cells work Increasingly sophisticated tools for molecular profiling to guide therapy Development of new and more effective treatments that are less toxic Should result in faster progress and possibly less costly drug development

29 WE CAN NOT lose sight of the underlying importance of the basic research