Abstract 5029: Targeting fatty acid oxidation to promote anoikis and inhibit ovarian cancer progression

Purpose: Epithelial-derived high-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy and in the US accounts for over 14,000 deaths per year. Roughly 80% of patients are diagnosed with late-stage disease, which is defined by wide-spread cancer dissemination throughout the pelvic and peritoneal cavities. HGSOC dissemination is dependent on tumor cells acquiring the ability to resist anoikis (apoptosis triggered by the loss of attachment). Epithelial cell detachment from the underlying basement membrane or extracellular matrix leads to cellular stress, including nutrient-deprivation. Reports describe metabolic reprogramming that promotes fatty acid oxidation (FAO) potentially supports anoikis resistance. Experimental Design: Examination of a panel of HGSOC cell lines cultured in adherent and suspension conditions. Evaluated anoikis by caspase 3/7 activity, cleaved caspase 3 immunofluorescence, and flow cytometry. Using the Seahorse Bioanalyzer examined mitochondria activity in suspension. Tested the role of exogenous free fatty acids in anoikis resistance and metabolism. In a patient-derived xenograft model, administered an FAO inhibitor and/or platinum-based chemotherapy. Results: HGSOC cultured in suspension upregulated the FAO rate-limiting enzyme, Carnitine Palmitoyltransferase 1A (CPT1A). CPT1A is overexpressed in HGSOC and correlates with poor overall survival. The knockdown of CPT1A promoted anoikis. HGSOC cells in suspension culture have decreased oxygen consumption that is rescued by exogenous fatty acids. In a patient-derived xenograft of HGSOC, a CPT1A inhibitor, etomoxir, significantly inhibited tumor growth and reduced tumor distribution. Conclusions: Targeting FAO in HGSOC to promote anoikis and attenuate dissemination is a potential approach to promote a more durable anti-tumor response and improve patient outcomes. Citation Format: Benjamin Guy Bitler, Brandon Sawyer, Lubna Qamar, Jennifer K. Richer, Kian Behbakht, Isabel R. Schlaepfer. Targeting fatty acid oxidation to promote anoikis and inhibit ovarian cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5029.