Abstract A81: Targeting of free fatty acid signaling in ovarian cancer may serve as a potential therapeutic approach.

Recent studies have revealed an association between adipocyte driven free fatty acids (FFA) and the aggressiveness of epithelial ovarian cancer (EOC). Adipocyte derived free fatty acids (FFA) seem to promote epithelial ovarian cancer (EOC) growth and progression by acting as mitochondrial fuel source to support the energy requirements of EOC cells. Apart from acting as a fuel source, FFA may also enhance tumor growth through other signaling pathways that can promote proliferation and regulate metabolism. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified, including: FFAR1/GPR40, FFAR2/GPR42, FFAR3/GPR41, FFAR4/GPR120 and GPR84. Using RT-PCR, we have found that exposing EOC cells to adipocytes results in overexpression of FFAR1/GPR40 in multiple ovarian cancer cell lines (ID8, A2780, C200, OVCAR3 and SKOV3). In mRNA extracted from formalin-fixed paraffin embedded tumor specimens, approximately 80% of high-grade serous ovarian carcinomas exhibited increased FFAR1 expression. Additionally, analysis of TCGA database revealed that patients with tumors exhibiting increased mRNA expression of FFAR1/GPR40 had poor overall survival and progression free survival. We have also found that targeting FFAR1 using its specific antagonist GW1100 inhibited the proliferation of A2780, ID8, C200, OVCAR3 and SKOV3 cell lines and resulted in downstream inhibition of insulin secretion and the Akt signaling pathway. On the other hand, treatment of the same cells with the FFAR1 agonist ,CAY10587, had no effect on proliferation. Thus, we conclude that FFAR1 may play an important role in the regulation of FFA mediated EOC cell proliferation. Targeting of FFAR1/GPR40 may be an attractive strategy in EOC, particularly for EOC patients presenting with high adiposity. Citation Format: Adnan Munkarah, Suhail Hamid, Jasdeep Chhina, Ismail Mert, LaToya Jackson, Sharon Hensley-Alford, Dhananjay Chitale, Shailendra Giri, Ramandeep Rattan. Targeting of free fatty acid signaling in ovarian cancer may serve as a potential therapeutic approach. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A81.