BCCMA: Overcoming chemoresistance in ovarian cancer: Targeting Unique Vulnerabilities in Neuroendocrine-like Ovarian Cancer Cells

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This Collaborative Merit Award application (CMA), consisting of three projects (CMA1-3), addresses a critical challenge in the clinical management of ovarian cancer (OC). The most common and lethal subtype of OC is high-grade serous ovarian carcinoma (HGSOC). Standard treatment for HGSOC combines surgical cytoreduction with platinum-based chemotherapy. Patients diagnosed with HGSOC often suffer from disease relapse associated with the emergence of chemotherapy resistance. The clinically needed key to increasing survival in HGSOC is to prevent the development of platinum resistance or identify alternative means of targeting platinum resistant (PtR) tumors. The main goal of this interdisciplinary and collaborative project is to identify novel targets and biomarkers of therapeutic efficacy for HGSOC. This requires a better understanding of the mechanisms that results in transformation of HGSOC cells to an aggressive, therapy-resistant phenotype. Increasing evidence support the hypothesis that a key contributor to platinum resistance is the reprogramming of cancer cells into a less differentiated and metabolically adaptable state. This collaborative proposal by three established OC researchers will leverage their interdisciplinary expertise and resources to define new mechanisms of resistance in OC. CMA1 will use spatial profiling and systems biology to provide a holistic understanding of PtR as well as prioritize cell-intrinsic and microenvironmental clinically relevant underlying molecular pathways. Preclinical immunocompetent mouse models and co-culture models will be used to study the role of the tumor microenvironment in PtR. CMA2 will study metabolic adaptation associated with the emergence of PtR focusing on a shift to fatty acid oxidation in PtR HGSOC tumors CMA2 will use resources shared with CMA1&3 and cellular biology and single cell metabolic imaging to define unique metabolic dependencies of PtR HGSOC. As PtR tumors are susceptible to death induced by oxidized lipid membranes, mechanisms of ferroptosis will be examined in PtR models treated with novel metabolism targeting agents, which will be tested with CMA1. CMA3 will explore the reprogramming of recurrent HGSOC cells into more tumor subpopulations with neuroendocrine (NE)-like features. Mounting evidence in other tumors suggest progression to a NE-like state results in therapy resistance- a concept yet to be explored in OC. To identify NE-like cells in OC, the transcriptome, proteome, gene vulnerability, and drug sensitivity landscape of matched patient tumors and model systems will be evaluated for emergence of NE-like cells under chemotherapeutic pressures. Data emerging from the analysis of patient tumor samples in this proposal in addition to existing drug dependency databases will be mined for identification of druggable targets in NE-like cells. Drugs effective against these cells will be tested alone or in combination with carboplatin in targeting PtR OCs. Hallmarks of NE-like cells including metabolic adaptations and histologic characteristics will be explored with CMA2 & CMA1 respectively. Rationale: Recent work demonstrates that many epithelial cancers converge to more aggressive state with genetic hallmarks and characteristics of NE-like cells. Histologic analysis, the original standard for defining neuroendocrine phenotypes, of recurrent ovarian tumors supports emergence of NE-like cells. Our preliminary bulk RNA sequencing data from longitudinally collected ovarian tumor samples, further supports chemo-induced progression to an NE-like state based on our previously published NE gene expression signatures. Pan cancer data has revealed that NE-like cells are more aggressive and resistant to chemotherapy. This is why understanding the molecular underpinnings of NE-like cells in ovarian cancers is critical. We hypothesize that eradication of PtR disease, requires additional therapeutic approaches that are directed to target NE-like cells in ovarian tumors. CMA3 plans to mechanistically define vital pathways for survival of PtR NE-like tumor cells and test drugs that can eliminate this tumor subpopulation. We envision our work will result in immediate clinical trial designs that can test new approaches for treating OC patients.