PROJECT SUMMARY/ABSTRACT Death rates have decreased across many cancer types owing to improved early detection and treatment methods, but remained largely stagnant for ovarian cancer over the last four decades. High grade serous ovarian carcinoma (HGSOC) is the most common and deadly subtype, accounting for almost 70% of all ovarian cancer cases and 70-80% of deaths. HGSOC likely develops from secretory cells of the fallopian tube epithelium (FTE) and neoplastic transformation typically produces highly metastatic tumor cells that are p53 mutant and homologous recombination defective. Apoptosis (programmed cell death) is a fundamentally important process for removing damaged and malignant cells and evasion of apoptosis is a hallmark of cancer. The intrinsic apoptosis pathway is controlled by the BCL-2 family of proteins, which are often dysregulated in cancer cells to confer a survival advantage. We have recently detected an upregulation of the BCL2L1 gene, which encodes pro-survival protein BCL-XL, in HGSOC compared to normal fallopian tube epithelium. This upregulation produces a dependency on this pro-survival protein that may be targeted therapeutically. For my F31 research proposal, I hypothesize that HGSOC cells have increased pro-survival protein expression, particularly BCL-XL, to buffer against the increased pro-apoptotic signaling that is associated with neoplastic transformation, which can be therapeutically targeted to increase tumor cell death. I propose to test this in three aims: 1) ascertain apoptotic regulation and pro-survival protein dependence in pre-malignant and malignant stages of transformation; 2) use HGSOC patient derived xenograft (PDX) mouse models to assess the efficacy of combining pro-survival protein targeting drugs with first-line chemotherapeutics to enhance tumor cell death; and 3) elucidate how hormone and follicular fluid exposure affects apoptotic regulation in fallopian tube epithelial cells in an air-liquid interface culture. The training plan for this proposal is designed to give me the mentorship, experience and skillset needed to obtain a postdoctoral position and ultimately transition into an independent research career working in the field of gynecological cancer biology. Being mentored by my sponsors, Drs. Kristopher Sarosiek and David Christiani, and working with close collaborators that specialize in ovarian cancer research will allow me to learn the necessary laboratory techniques and gain subject matter expertise in apoptosis, ovarian carcinogenesis, cancer therapeutics and environmental health as it relates to cancer risk. The Science Advisory and Career Mentoring committees that I have established will provide further guidance in my growth as a successful, independent scientist. I will publish manuscripts and attend conferences to present my findings and hone my written and verbal scientific communication. Ultimately, this F31 will provide me with the training and expertise necessary for a career...