Abstract A74: Preclinical evaluation of a fatty acid synthase inhibitor in pancreatic cancer

Abstract

Abstract Fatty Acid Synthase (FASN) is a key enzyme in lipid biosynthesis and is overexpressed in many cancers, including pancreatic ductal adenocarcinoma (PDA). Upregulation of FASN in pancreatic cancer is correlated to poor prognosis, poor differentiation, and advanced tumor grade. In contrast, most normal cells have very low rates of de novo fatty acid synthesis and negligible FASN expression, making FASN inhibition an attractive therapeutic option. Current strategies for treating pancreatic cancer have severe side effects and low response rates. An alternative strategy is to target the changes in metabolic state that arise during tumor development, including an increase in anabolic processes such as de novo fatty acid synthesis. Both the de novo fatty acid synthesis pathway and FASN have been targeted previously. However past agents suffered from issues of poor bioavailability, metabolic stability, and potency. In addition several of the drugs induced significant side effects in mice, including weight loss and decreased appetite. IPI-9119 is an irreversible inhibitor of FASN with excellent pharmacological properties. This agent is highly potent and has been shown to inhibit FASN and have anti-proliferative effects in pancreatic cancer cell lines and in vivo. We utilize a clinically relevant genetically engineered mouse model of PDA and an advanced preclinical infrastructure to evaluate IPI-9119 as a therapeutic for PDA. Preliminary in vivo studies demonstrated effective delivery of IPI-9119 to pancreatic tumor tissues, resulting in near-complete inhibition of FASN function. Short-term studies found elevated levels of apoptosis and reduced proliferation in IPI-9119 treated tumors. Combination with the genotoxic agent gemcitabine did not alter drug delivery or biochemical efficacy. These results will serve as a foundation for a comprehensive preclinical evaluation of IPI-9119 in which we will explore pharmacology, tolerability, and mechanisms of IPI-9119 action. Citation Format: Roshan A. Ahmed. Preclinical evaluation of a fatty acid synthase inhibitor in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A74.