Abstract 1815: Efficacy of FASN-selective small molecule inhibitors in preclinical tumor models

Abstract

Abstract Fatty acid synthase (FASN) expression increases with tumor progression and is associated with impaired response to chemotherapy and diminished patient survival in many solid and hematopoietic tumor types. Palmitate, the product of FASN enzymatic activity, functions in vital cellular processes including energy metabolism and cell growth, cellular membrane biosynthesis and architecture, and protein localization and function. 3-V Biosciences has discovered and developed a series of potent, selective, orally available, and reversible FASN inhibitors with excellent pharmaceutical properties. Single agent FASN inhibition has been shown to cause anti-tumor activities in preclinical models of human cancer, including inhibition of AKT and mTOR signal transduction, induction of tumor cell apoptosis, and tumor growth inhibition and regression in pancreatic, ovarian, and lung cancer xenograft tumor models of human cancer. Current studies are supporting the active clinical development of TVB-2640, 3-V Biosciences' first-in-class FASN inhibitor, as an oncology therapeutic. These studies have multiple objectives: (1) characterizing a wide range of tumor types for responsiveness to FASN inhibition using tumor cell line and Champions TumorGraftTM efficacy models; (2) investigating the benefit of FASN combination therapy with chemotherapeutic or targeted anti-cancer agents; (3) developing biomarkers that characterize efficacy response; and (4) further elucidating the mechanisms of action that emanate from the inhibition of palmitate synthesis and lead to tumor cell apoptosis and in vivo anti-tumor efficacy. The results of these investigations show that FASN inhibition causes tumor growth inhibition or regression in diverse tumor types; and moreover, that tumor growth inhibition additivity or synergy is observed when FASN inhibition is combined with chemotherapy agents. Genomics and directed analysis of mRNA, proteins, and lipids following FASN inhibition have identified biomarker candidates and provided insights into the tumor growth inhibition mechanisms of action. For example, genome-wide gene expression analysis shows FASN inhibition to significantly increase the expression of many genes in biosynthetic (sterol, lipid, etc.) and apoptosis pathways while significantly reducing the expression of many genes in cell growth and proliferation pathways (DNA replication, cell cycle progression, mitosis, etc.). These data strongly support the clinical development of TVB-2640 as a first-in-class single and combination oncology therapeutic and are advancing the discovery and validation of biomarkers to inform clinical utility and response. Citation Format: Timothy S. Heuer, Richard Ventura, Joanna Waszczuk, Kasia Mordec, Julie Lai, Russell Johnson, Lilly Hu, Haiying Cai, Allan Wagman, Douglas Buckley, Stanley T. Parish, Elizabeth Bruckheimer, George Kemble. Efficacy of FASN-selective small molecule inhibitors in preclinical tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1815. doi:10.1158/1538-7445.AM2014-1815