Understanding Metabolic Reprogramming in Platinum Resistant Ovarian Cancer

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PROJECT SUMMARY This Collaborative Merit Award application (CMA), consisting of three projects (CMA1-3), addresses a critical challenge in the clinical management of ovarian cancer. The most common and most lethal subtype of ovarian cancer is high-grade serous ovarian carcinoma (HGSOC). Standard treatment for HGSOC combines surgical cytoreduction with platinum-based chemotherapy. The treatment is initially successful in achieving remission. However, cancer recurs in most women. Patients with recurrent disease may continue to respond to additional rounds of platinum but will ultimately develop platinum resistance (PtR). At that point, the tumor is typically resistant to other treatment strategies. The key to increasing survival in HGSOC is to prevent the development of PtR or identify alternative means of targeting resistant 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 either select for, or promote transformation of, HGSOC cells to an aggressive, therapy-resistant phenotype. While previous studies on PtR have focused on DNA repair pathways or altered membrane transporters, new concepts support the hypothesis that a key contributor to PtR is the reprogramming of cancer cells into a less differentiated and metabolically adaptable state. This collaborative proposal by three established ovarian cancer researchers will leverage their interdisciplinary expertise and rich resources to define new molecular mechanisms of PtR in ovarian cancer. CMA1 will utilize deep imaging to define clinically-relevant biomarkers of PtR while digital spatial profiling and systems biology will be used to identify molecular pathways underlying PtR. Preclinical immunocompetent mouse models will be used to test potential targeted therapies discovered in CMA1,2&3. CMA2 will study metabolic adaptation associated with the emergence of PtR focusing on a shift to fatty acid oxidation in resistant HGSOC cells and tumors. CMA2 will use resources shared with CMA1&3 and cellular biology and novel single cell metabolic imaging to define unique metabolic dependencies of PtR HGSOC. As resistant tumors are highly 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 together with CMA1. CMA3 will define the emergent de-differentiated phenotype in recurrent HGSOC through transcriptomic analysis of patient tumors collected at various stages of disease progression. By defining molecular pathways that lead to cellular de-differentiation, we will reveal new vulnerabilities that can be therapeutically exploited using small molecules, kinase inhibitors, and cell-based immune therapy approaches Multi-omics data, patient derived organoids, and PDX models will provide valuable shared resource for collaborative projects in CMA1&2. The overarching hypothesis of CMA2 is that metabolic reprogramming is a key and necessary step in the development of PtR. We speculate that this shift is initiated through altered oxidative status in cancer cells, due to DNA injuries inflicted by platinum. To test the hypothesis, we will determine whether Pt-R cancer cells and tumors undergo a metabolic shift to fatty acid oxidation caused by increased generation of reactive oxygen species (ROS). We will measure intracellular ROS, glucose and lipid consumption and quantify expression and function of key lipid transporters and rate limiting enzymes regulating lipogenesis. Molecular findings will be validated by using high content stimulated Raman scattering (SRS) metabolic imaging and multimodal SRS / two-photon excitation fluorescence (TPEF). We will test whether by blockade of key enzymes or transporters involved in metabolic reprogramming can overcome the state of resistance and whether these inhibitors induce cell death in PtR cells through ferroptosis. Mechanistic understanding of this process will lead to new treatment opportunities for fatal PtR HGSOC and other cancers.