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New Developments in Biology and Targets of Epithelial Ovarian Cancer Michael Birrer Ian McNeish Ovarian Cancer Historic Perspective All serous tumors thought to arise from surface epithelium/inclusion cysts. 75% patients present with advanced stage disease. 80% respond to chemotherapy. Vast majority of patients relapse and eventually develop drug resistant disease. Minimal increase in overall survival over last 30 years. All patients treated with surgery and chemotherapy. New Development in Biology Origins Integrating the models of serous carcinogenesis – a binary model Levanon, Crum, and Drapkin, JCO, 2008 How does it affect screening? Is the target lesion a 1mm lesion in the fallopian tube? How rapidly do these progress? What about tumors arising from the surface of the ovary? How does it affect treatment? Two types of Serous Tumors? Surface Epithelium versus Fallopian tube Are they biologically the same? Is Ovarian Cancer a Homogenous Disease? Histology ENDOMETRIUM OVARY OVARIAN AND ENDOMETRIAL CANCER SUBTYPES SEROUS ENDOMETRIOID CLEAR CELL OVARIAN & ENDOMETRIAL CANCER QuickTime™ and a Cinepak decompressor are needed to see this picture. OVARIAN ENDO & SEROUS ENDOMETRIAL ENDO & SEROUS OVARIAN CLEAR CELL ENDOMETRIAL CLEAR CELL Zorn et. al. Clinical Cancer Research 2005 CLEAR CELL CANCER QuickTime™ and a Cinepak decompressor are needed to see this picture. OVARIAN ENDOMETRIAL RENAL Zorn et. al. Clinical Cancer Research 2005 Clinical Impact of Genomic Characterization of Clear Cell Cancers Remove clear cell tumors from ovarian cancer phase III trials. Create clear cell specific phase II trials. Utilize understanding of molecular pathways of clear cell cancers from other organs to better treat ovarian cancer. Expression Profiling of Clear Cell Tumors of the Ovary 15 clear cell cancers of the ovary Whole genome profiling Supervised clustering Pathway identification Clear Cell Ovarian Cancer HIF1 alpha Pathway Angiogenesis Cell Migration Glycolysis HIF1alpha degradation Cell Cycle Progression Is ovarian cancer a homogenous disease? Grade Unsupervised Hierarchical Clustering of Serous Ovarian Cancers Ovarian Cancer Papillary Serous Ovarian Tumors High Grade P53Normal Cells P53+ LMP/Low Grade B-raf, ras Bonome et al Cancer Research 2005 Low Grade Phase II Trials GOG 239 AZ MEK Inhibitor What About Papillary Serous Ovarian Cancer? 90% of ovarian cancers are papillary serous tumors. All tumors high grade tumors treated with surgery and chemotherapy. Activated pathways remain unknown. Figure 5"> Tothill, R. W. et al. Clin Cancer Res 2008;14:5198-5208 Copyright ©2008 American Association for Cancer Research Gene signatures predicts survival only for suboptimally debulked tumors Optimally Debulked Suboptimally Debulked Co-regulated Signaling Events In Sub-optimal Patient Subgroups TCGA 200 high grade serous ovarian cancers 6000 genes sequenced Expression profiling Copy number differences Methylation status Future Directions Histo/grade specific trials and regimens. Identification of sub-groups of patients based upon genomic patterns and activated pathways. Future Challenges Validation of prognostic and predictive biomarkers. Identification and validation of small molecule inhibitors targeting pathways Larger numbers of carefully annotated specimens FFPE technologies Integrated biomarkers will be mandated. Molecular basis for resistance Recurrent tumor biopsies should be a requirement. Michael J. Birrer M.D. Ph.D. Professor of Medicine Harvard Medical School Director Gynecologic Medical Oncology Massachusetts General Hospital