molecular targeting drugs for cancer therapy.ppt

Targeted Cancer Therapy Drugs: Hype, Hope, Myths and Reality Jianjiang Fu Ph.D. Pharmacy School What is CANCER? Theories of carcinogenesis Stem cell Initiation-Promotion-Progression (Multi-hit hypothesis) Immune surveillance Oncogene and tumor suppressor gene Chemotherapy Cytotoxic drugs: taxol, camptothecin, etc. Targeted therapy agents WHAT IS A “TARGETED” THERAPY? Some Success Stories EGFR inhibitors: -- Iressa(gefitinib, ZD1839), Tarceva (Erlotinib), Erbitux (Cetuximab, EGFR Monoclonal antibody) HER-2/Neu monoclonal antibody: -- Herceptin (transtuzumab) ABR-BCL inhibitor: -- Glivec (imatinib myslate, STI571), Dasatinib, Nilotinib VEGF Monoclonal antibodies: -- Avastin (Bevacizumab), PTK787, EGFR expression in human tumors High EGFR expression is generally associated with Invasion Metastasis Late-stage disease Chemotherapy resistance Hormonal therapy resistance Poor outcome How to hit the target ? If you know the target, and there is only one target you can be very specific. If you don’t really know or it’s a really big target, a larger weapon may be needed. IRESSA? is a small molecular RTK inhibitor Iressa received accelerated FDA approval in May 2003 as a 3rd line therapy in NSCLC based on the IDEAL-2 study. IRESSA Unprecedented activity in target population Symptom control Excellent tolerability IRESSA? Non-Clinical Summary IC50 (μM) Selective enzyme inhibition EGFR (ErbB-1): 0.033 Other cellular kinases 3 EGFR autophosphorylation 1 inhibition in tumor cell lines Tumor cell growth inhibition EGF stimulated 0.054 Basal 8.8 IRESSA? ISEL: Iressa Survival Evaluation in Lung Cancer IRESSA? – Phase II trials Skin Rash Chronic Myelogenous Leukemia Genetic abnormality Chronic Myelogenous