Abstract C175: FASN inhibition studies in preclinical tumor models identify biomarkers that align with in vitro and in vivo sensitivity to TVB-2640

Abstract

Abstract 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. Palmitate and palmitate-derived lipids comprise diverse cellular components and function in processes required for tumor cell proliferation and survival. Previously we showed that FASN inhibition results in tumor cell apoptosis in vitro and xenograft tumor growth inhibition in vivo. Our studies demonstrated that diverse tumor types exhibit sensitivity to FASN inhibition and characterized mechanisms of action that associate with the antitumor activity of highly selective small molecule FASN inhibitors. In vitro studies with diverse tumor cell types elucidated a mechanism of action that includes plasma membrane remodeling, signal transduction pathway inhibition, and gene expression reprogramming. 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. Tumor xenograft studies were conducted in rats and mice to examine the in vitro and in vivo relationship of tumor cell sensitivity to FASN inhibition. Pharmacodynamic analyses of tumor and serum samples from these studies characterized the mechanism of action and biomarkers of sensitivity to in vivo FASN inhibition. Once daily oral dosing of TVB-2640 or TVB-3166 caused inhibition of xenograft tumor growth for varied tumor models that included COLO-205 and HCT-116 colon adenocarcinoma cell lines. In vivo sensitivity to FASN inhibition was in agreement with in vitro data. Analysis of lipid, metabolite, protein, and RNA expression in tumor, blood or serum samples showed drug-induced modulation that was consistent with independent in vitro or in vivo studies. Lipid and metabolite changes included decreased palmitate and palmitate-associated lipids as well as increased expression of acylcarnitine species. Decreased expression of pAkt (S473), β-catenin, pβ-catenin (S675), and Myc proteins were found to associate quantitatively with xenograft tumor growth inhibition. Additionally, mRNA expression was modulated in a manner that revealed coordinated changes in the mRNAs from fatty acid, metabolism, cell survival, and cell growth-associated pathways. Expression changes in lipids, metabolites, proteins, and RNA species are leading to the development of a biomarker panel that describes FASN inhibitor target engagement and tumor sensitivity in both in vitro and in vivo studies. These mechanism-based marker panels will be evaluated in current and upcoming clinical studies of TVB-2640. Citation Format: Timothy S. Heuer, Richard Ventura, Kasia Mordec, Julie Lai, Joanna Waszczuk, Claudia Rubio, Marie O' Farrell, Douglas Buckley, George Kemble. FASN inhibition studies in preclinical tumor models identify biomarkers that align with in vitro and in vivo sensitivity to TVB-2640. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C175.