PROJECT SUMMARY/ABSTRACT – OVERALL Ovarian cancer (OvCa) has the third highest mortality to incidence ratio and is the fifth leading cause of cancer death in American women. The typical disease course of a patient with OvCa spans four and a half years from the time of diagnosis to death. During the course of patient care, acquired and innate resistance to our most effective and promising therapies, such as chemotherapy, PARP inhibitor therapy, and immunotherapy, drives disease progression. The overall goal of the UPMC Hillman Cancer Center (HCC) OvCa SPORE is to prevent and/or overcome therapeutic resistance to improve patient survival. Each of the SPORE’s three Projects evolved from the innovative concepts and findings of SPORE investigators. Each project involves a clinical trial with a new agent. In addition, each project, through complementary investigator expertise, incorporates critical translational aims to identify patients most likely to respond to therapy. Project 1 will assess the ability of inhibitors of the epigenetic regulator EZH2 to prevent/overcome OvCa stromal progenitor cell-driven resistance to platinum-based chemotherapy. Project 2 will determine whether BET inhibitors, which downregulate critical DNA repair and cell cycle checkpoint proteins, can reverse resistance to PARP inhibitors. Project 3 will test whether inhibitors of the hedgehog signaling pathway, which drives tumor immune exclusion, can improve OvCa patient response to immune checkpoint inhibitor therapy. The HCC OvCa SPORE will include a Career Enhancement Program (CEP) and Developmental Research Program (DRP) in order to both encourage early career investigators to enter the field of translational OvCa research and engage more established investigators in OvCa research. The CEP and the DRP, which are cost-shared and proactive at providing research funding to investigators from under-represented minority groups, will provide a pipeline of potential future SPORE Projects. All SPORE, CEP, and DRP Projects will be receive fiscal and scientific oversight from an Administrative Core and support from two shared resource cores. The Translational Pathology Core will collect, annotate, archive, and distribute biospecimens and clinical data derived from the more than 300 HCC OvCa patients seen each year. It will also develop new preclinical experimental models that behave more like human OvCa. The Biostatistics and Bioinformatics Core will aid in design and analysis of all studies, including ‘omic’ technologies that can provide molecular and spatial characterization of individual cells within a tumor. The SPORE Projects will also be supported by established and new collaborators who are internal and external to HCC. Combined, the SPORE projects, CEP, DRP, and cores are positioned, together with our vertical collaborators, to improve the outcomes of patients with ovarian cancer. The findings generated by the SPORE will be advanced through further collaboration and future non-SPORE funding.

NARRATIVE – OVERALL The goal of the UPMC HCC Ovarian Cancer SPORE is to improve the outcomes of patients with ovarian cancer. We propose (i) three clinical trials, each with critical translational aims to identify patients most likely to benefit from therapy; and (ii) a Career Enhancement Program (CEP) and Developmental Research Program (DRP) to ensure a pipeline of ovarian cancer researchers as well as novel diagnostic and therapeutic strategies. The three projects, CEP, and DRP will be supported by three cores to increase success.