Transcriptomic Profiling and Functional Characterization of Fusion Genes in Recurrent Ovarian Cancer
Abstract
High-grade serous ovarian cancer (HGSOC) has a high rate of mortality due to late detection and a lack of targeted therapies. The standard therapy for late-stage disease is tumor debulking with multiple cycles of platinum and taxane-based chemotherapy. Intriguingly, HGSOC is exquisitely sensitive to primary intervention with most patients achieving complete clinical remission. However, disease recurs in the majority of patients, and clinicians then resort to a "maintenance" therapy to try to stop the cancer progressing. Clinical trials assessing different maintenance regimens of chemotherapy and/or targeted therapies have thus far yielded limited increases in overall survival. There is thus an urgent need to identify biological mediators of HGSOC relapse and the associated mechanisms of drug resistance. Indeed, the Ovarian Cancer Research Program made the understanding of chemoresistance a Fiscal Year 2015 Area of Encouragement. HGSOC, like all other cancers, is a disease resulting from changes (mutations) in DNA. In HGSOC the majority of these mutations are changes in the amount of DNA (increase or loss) or changes to the structure (e.g., DNA being moved around the genome). In this proposal, we will study a particular genetic alteration that causes two genes, often located a long distance apart in the genome, to become crushed together ¿ so-called fusion genes. These fusion genes are essentially new genes to the cell and often lack normal regulation and can be tumor-promoting. Importantly, HGSOC harbors the highest numbers of fusions of any solid cancer type, yet there has been relatively little study of fusion genes in relapsed chemoresistant HGSOC. Fusions have been identified in other cancers, are mostly tumor-specific, and have been successful therapeutic targets. The best example is the BCR-Abl fusion (Philadelphia chromosome) in chronic myelogenous leukemia, which has recently been clinically targeted with Gleevec® (imatinib mesylate, Novartis), a drug that has revolutionized patient outcomes in this disease. We will use state-of-the-art sequencing technologies in a unique cohort of frozen banked HGSOC to identify RNA fusions in relapsed ovarian cancer with the goal of identifying new therapeutic targets that may represent new prognostic markers and ultimately therapeutic targets for reversing HGSOC chemoresistance, reducing recurrence, and extending patient survival.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610403
Entities
People
- Adrian V Lee
Organizations
- United States Army
- University of Pittsburgh