Exploiting metabolism to alter the epigenome of Cyclin E-altered ovarian cancer

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Project Summary The goals of this F31 NRSA are to request support for training to develop expertise in the progression of high- grad serous epithelial ovarian cancer while addressing a fundamental gap in knowledge that has the potential to significantly impact healthcare options for ovarian cancer patients. F31 Ruth L. Kirschstein NRSA support will highly impact this integral phase of my current scientific career and my future aspirations of becoming an independent academic researcher. The training plan described will utilize all relevant resources available at Penn State College of Medicine; as well as resources provided by my dynamic mentoring committee at Drexel University and University of Pennsylvania. The scientific portion of this proposal focuses on experimentally and mechanistically determining the role of metabolism and epigenetic modulation in cyclin E-altered high-grade serous carcinoma (HGSC) and whether this pathway can be targeted as a pro-senescent therapy in the clinic. The proposed studies are based on my robust preliminary data suggesting that TCA cycle enzyme, IDH1, is upregulated in epithelial ovarian cancer when compared to the fallopian tube, the potential site of HGSC origin. Additional preliminary data suggests that IDH1 is upregulated in order to increase transcription of DNA damage response gene, ataxia telangiectasia mutated (ATM) through histone methylation status, a topic of which I have previously published a review. Interestingly, my strong preliminary data also indicates that knockdown of IDH1 induces senescence. Therefore, in continuation of these robust preliminary data I will explore three scientific aims: 1) to determine the mechanism by which cyclin E upregulates IDH1 expression; 2) to investigate the role of IDH1 in the DNA damage response; and 3) to develop inhibition of IDH1 as a novel therapeutic strategy in cyclin E-altered HGSC. The completion of the proposed scientific aims will develop my research skills utilizing HGSC as a model in addition to increasing my independence as a scientific researcher. Conclusions drawn from the proposed studies may develop rationale for targeting IDH1 in cyclin E-altered HGSC clinically.