Elucidation of the impact of commonly co-altered genes on chemosensitivity using a novel model of high-grade serous ovarian cancer

Harvard Medical School, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): High-grade serous ovarian cancer (HGSC) is the most prevalent gynecological malignancy diagnosed in females and accounts for most ovarian-cancer mortality. Current standard care for these tumors is platinum-based therapies along with taxane agents. While most tumors respond to chemotherapy initially, this is typically followed by relapse and progression to resistance in the clinic. Resistance has been shown to involve many diverse mechanisms. Recent multiplatform genomic analyses have revealed that HGSCs display a high level of chromosomal instability, which leads to extensive copy number variations due to regional amplifications and deletions. The occurrence of different combinations of genetic aberrations among patients as well as genetic diversity within individual tumors provides extraordinary challenges for treatment of this disease. The objective of this project is to investigate molecular mechanisms by which HGSC develops resistance to chemotherapy with a particular focus on analysis of the effects of different combinations of genetic alterations within distinct subpopulations of tumor cells. This investigation will be conducted in cell cultures and i animal models, and we will evaluate the clinical relevance using multiple HGSC patient-derived xenograft models. These approaches provide an integrative framework to discover and evaluate the extent to which the genetic complexity and heterogeneity of HGSC confer differential chemo-sensitivity. The sets of co-altered genes identified in this study could also serve as biomarkers to individualize treatment in ovarian cancer patients. My passion for translational medicine has been leading me into the journey of cancer research with a particular focus on drug resistance since I was an undergraduate student. I recently pursued a postdoctoral position in the laboratory of Dr. Joan Brugge at Harvard Medical School to gain a better understanding of complexity of drug resistance in cancers and to interact with an interdisciplinary group of many intelligent engineers, biologists, and clinician-scientists. My career goal is to become an independent investigator, and my mission will be to make important advances in cancer treatment. These long-term goals will become feasible through the skills that I will develop through pursuit of this project and other aspects of my training, as outlined i my research and training plan. The training will help me enrich my clinical oncology background and deepen my understanding of the mechanisms underlying cancer progression and therapy resistance in the context of clinically important questions. It also gives me the opportunity to be mentored by Dr. Joan Brugge, a renowned basic cancer scientist with an excellent track record in training next generation cancer scientists. The collaborations with gynecological cancer pathologists (Dr. Drapkin) and basic cancer scientists (Dr. Mills) through this project, as well as the courses, seminars and meetings I will attend, will provide me with a strong foundation in basic and clinical ovarian cancer research. This experience will pave my path towards becoming an independent scientist and striving to achieve better outcomes for patients afflicted by ovarian cancer.