Abstract 4446: Discovery of tumor types highly susceptible to FASN inhibition and biomarker candidates for clinical analysis

Abstract

Abstract Inhibition of de novo palmitate synthesis by fatty acid synthase (FASN) is a novel cancer therapeutic approach with strong biological rationale. Tumor cells have an increased dependence on FASN-synthesized palmitate compared to non-tumor cells, which obtain many of their required lipids from the extracellular milieu. FASN expression increases with tumor progression in human tumors and associates with chemoresistance, metastasis, and diminished patient survival in many tumor types. Palmitate and palmitate-derived lipids comprise diverse cellular components and function in processes required for tumor cell proliferation and survival. TVB-2640 and TVB-3166 belong to a series of orally available, reversible, potent, and selective FASN inhibitors discovered and developed by 3-V Biosciences that exhibit anti-tumor activity in diverse preclinical tumor models. FASN inhibition induces tumor cell apoptosis by remodeling tumor cell membranes, blocking signal transduction, and reprogramming gene expression. These effects lead to inhibition of anchorage-independent tumor cell growth under lipid-rich conditions and inhibition of in vivo xenograft tumor growth in mice and rats. Studies to understand the mechanisms of action and biological consequences of FASN inhibition are guiding the discovery of tumors highly dependent on FASN activity and biomarkers for assessment of pharmacodynamic activity and patient selection. Using quantitative genomics and a variety of directed analytical approaches, we identified lipid, mRNA, and protein profiles in tumor cells that change in response to FASN inhibition. Subsets of the changes show correlation with FASN inhibitor sensitivity. Marker candidates, such as gene expression signatures that classify in vitro sensitivity to FASN inhibition, are being investigated for detection in clinical human tumor data sets. Our studies also identified FASN inhibitor-mediated mechanisms of action that function in specific tumor types and biomarkers with potential utility for selecting responsive patients and measuring tumor response. Inhibition of the Wnt/b-catenin pathway and expression of TCF-promoter-regulated genes such as c-Myc are examples. Tumors dependent on Wnt/b-catenin activity or with lower intracellular palmitate stores prior to drug treatment may be susceptible to FASN inhibitor treatment. Pairing MYC expression with additional markers improves the performance of MYC as a marker to select tumor cell lines highly sensitive to FASN inhibition. Biomarker candidates from in vitro studies have been examined in vivo using xenograft tumor studies. These preclinical data support 3-V Biosciences’ ongoing Phase I clinical study of a first-in-class FASN inhibitor TVB-2640, and help guide the next steps in its development. Citation Format: Timothy S. Heuer, Richard Ventura, Kasia Mordec, Julie Lai, Joanna Waszczuk, Glenn Hammonds, Marina Fridlib, Russell Johnson, Lily Hu, Allan Wagman, Marie O' Farrell, Douglas Buckley, George Kemble. Discovery of tumor types highly susceptible to FASN inhibition and biomarker candidates for clinical analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4446. doi:10.1158/1538-7445.AM2015-4446