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Targeted Therapy: A Giant Step Forward Ian Krop, MD-PhD Dana-Farber Cancer Institute Brigham and Women’s Hospital Harvard Medical School May 2009 “Targeted” therapy • Drug which inhibits a protein or molecule that is only expressed in cancer or which only the cancer is dependent • Offer the promise of reduced side effects compared to less targeted drugs Breast cancer is family of different cancers HER2+ GENES Triple Negative TUMORS Estrogen receptor + Kaplan Meier plots allow comparison of clinical outcome over time Percentage of women WITHOUT recurrence 100- Time Breast cancer is family of different cancers Estrogen receptor + Percentage of women WITHOUT recurrence HER2+ GENES Triple Negative TUMORS Breast Cancer in the U.S. All Breast Cancer 180,000 + cases 20% = 36,000 cases HER 2 + Disease Amplification of the HER2 gene observed in a subset of breast cancers FISH - FISH + % without recurrence HER2 amplification impacts prognosis Time (months) HER2 is a cell surface signaling protein HER2 is a cell surface signaling protein <10,000 HER2 proteins on normal breast cell HER2 gene amplification results in marked overexpression of HER2 proteins 2,000,000 HER2 proteins on cancer cell Herceptin (trastuzumab) is a recombinant antibody that specifically binds to the HER2 protein HER2 binding domain By attaching to HER2, Herceptin prevents HER2 proteins from binding to each other, leading to inhibition of signaling Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer Slamon, et al. NEJM 2001 (data originally presented 1998) U.S. Adjuvant Herceptin Trials (May, 2005) Chemo+herceptin 85% AC T % Chemo alone Romond, Perez et al, Years NEJMFrom 2005Randomization 67% B31/N9831 Herceptin given with chemotherapy improves outcome for patients with HER2+ advanced breast cancer Slamon, et al. NEJM 2001 (data originally presented 1998) Overcoming Herceptin resistance Her2 Her2 From Hanahan and Weinberg, 2000 HER2 is a kinase, a protein that adds phosphate to other proteins Lapatinib is an oral inhibitor of the HER2 kinase Clinical trial of lapatinib for women with HER2+ metastatic breast cancer that had progressed on Herceptin R A N D O M I Z E Lapatinib + Capecitabine Capecitabine alone Lapatinib improves outcome in patients with metastatic HER2+ breast cancer Geyer CE et al. N Engl J Med 2006;355:2733-2743 HER2 Kinase inhibitors – Results of first study confirm role for HER2 targeted therapy after progression on Herceptin – Is it better than Herceptin? – Can it add to benefit of Herceptin – Are there particular types of tumors that are better treated with one or the other – Lapatinib being tested in adjuvant setting • Additional inhibitors in development – HKI272 – BIBW227 Clinical trial of Herceptin and xeloda for women with HER2+ metastatic breast cancer that had progressed on Herceptin R A N D O M I Z E Herceptin + Capecitabine Capecitabine alone Trastuzumab Treatment Beyond Progression in Locally Advanced or MBC Von Minckwitz, G et al, SABCS 2007 and ASCO 2008 The HER Family HER2 can dimerize with itself or other HER family members Courtesy of Kenneth Bloom. Intracellular Herceptin and pertuzumab bind to distinct epitopes on HER2 extracellular domain Pertuzumab Herceptin Hubbard 2005 HSP90 is a chaperone for proteins like HER2 Trastuzumab-DM1, a novel antibody drug conjugate Drug Drug Herceptin DM1 Her2 • Delivers high concentrations of drug to tumor • Spares normal tissue from toxicity Trastuzumab-DM1, a novel antibody drug conjugate Drug Drug Herceptin DM1 Her2 • Delivers high concentrations of drug to tumor • Spares normal tissue from toxicity Trastuzumab-DM1, a novel antibody drug conjugate Drug Drug Herceptin DM1 Her2 • Delivers high concentrations of drug to tumor • Spares normal tissue from toxicity HER2 A Good ADC Target • Tumor expression >>> Normal-tissue expression • Absolute Expression levels very high • Internalized without down regulation Austin et al. (2004) Mol Biol Cell 15, 5268-82. Trastuzumab-DM1, a novel antibody drug conjugate • Results of early studies of TDM1 encouraging – Response rate ≈40% in patients whose tumors had progressed on Herceptin – Side effects minimal (validates strategy of antibody–drug conjugate) • Larger trials are underway PI3-kinase may be an important target in breast cancer Targeting HER2+ Tumors Inhibit Dimerization Inhibit Kinase activity Antibody conjugates Moderate receptor expression Inhibit downstream effects Burstein, H. J. N Engl J Med 2005;353:1652-1654 Breast cancer is family of different cancers Estrogen receptor + Percentage of women WITHOUT recurrence HER2+ GENES Triple Negative TUMORS The link between BRCA1 associated breast cancer and basal like cancers • Inherited mutations in the BRCA1 gene account for a small percentage of breast cancers • 80% of BRCA1 associated breast cancers are basal like (triple negative) The link between BRCA1 associated breast cancer and basal like cancers • BRCA1 associated breast cancers have a fundamental defect in DNA repair – Evolving data suggest that spontaneous TN breast cancers share this defect Basal-like Tumors Show DNA Damage Sensitivity NATURE REVIEWS | GENETICS VOLUME 2 | JUNE 2001 | 447 Platinum Damages DNA 04-183 Preoperative CisPlatinum in Triple Negative Breast Cancer Women with newly diagnosed ER-/PR/HER2- breast cancer CisPlatinum x 4 doses Research Biopsy, Blood S U R G E R Y Tissue for Research Standard Treatment Redundant Mechanisms of DNA Repair X Homologous Recombination Base excision repair Base excision repair requires PARP Huber et al. DNA Repair 3 (2004) 1103–1108 Redundant Mechanisms of DNA Repair X Homologous Recombination Base excision repair AZD2281 – PARP inhibitor Hereditary ovarian cancer summary Total number of patients 13 No. of Platinum Ongoing GCIG CA125 evaluable resistant response and/or patients RECIST radiological response 11 7/11 5/11 6/11 Next Step Women with newly diagnosed ER-/PR/HER2- breast cancer CisPlatinum/ PARP INHIBITOR x 4 doses Research Biopsy, Blood S U R G E R Y Tissue for Research Standard Treatment Cancers are dependent on new blood vessel growth (angiogenesis) Blocking VEGF with Avastin leads to loss of tumor vasculature and tumor regression Blocking VEGF may also lead to “normalization” of blood vessels ECOG 2100: Trial Design • Patients enrolled Dec. 2001- March 2004 • First interim analysis with data cut-off Feb. 2005 with 355 events Miller KD ASCO 2005 Progression Free Survival *Benefit the same in ER+ and ER- patients Miller KD ASCO 2005 Cancer stem cell model of therapeutic resistance Drugs that kill cancer stem cells Tumor looses its ability to generate new cells CSC Drugs that kill cancer cells but not CSCs Tumor regresses CSC Tumor degenerates, patient is cured CSCs regenarate tumor Tumor recurs CSC Novel strategies for estrogen receptor expressing cancers • Hormonal therapy + therapies targeting growth factor receptors • Avastin and other anti-angiogenic drugs seem to work well in ER+ breast cancer • Currently, major advance is observation that for many women, prolonged adjuvant therapy (>5yr) can offer additional benefit How long does it take? Conclusion • The number of new drugs in development is increasing quickly • Targeted therapy’s promise of improved effectiveness and decreased side effects is being fulfilled • If a good target is identified, the drugs will come • Participation in clinical trials in needed to accelerate the pace of drug development