Abstract A75: Translational studies of a first-in-class FASN Inhibitor, TVB-2640, linking preclinical studies to clinical laboratory observations in solid tumor patients

Abstract

Abstract Dysregulated expression of FASN is a central mediator of neoplastic lipogenesis. FASN catalyzes the production of palmitate, the building block of long chain fatty acids, providing a mechanism to convert glucose and other carbon sources into lipids needed for production of phospholipids, formation of lipid rafts and the subsequent assembly of receptor tyrosine kinases and other signaling molecules in microdomains juxtaposed to the membrane. Inhibition of FASN in tumor cells leads to disruption of PI3K/Akt/mTOR and other important pathways leading to apoptosis. Targeting this critical nexus between lipogenesis and cellular survival/proliferation signaling pathways makes inhibition of FASN a novel therapeutic approach with a strong biological rationale and 3-V Biosciences has initiated clinical studies with its first-in-class FASN inhibitor. 3-V Bio has developed a series of orally available, reversible, potent, and selective FASN inhibitors that remodel tumor cell membranes, disrupt pAkt and Wnt/beta-catenin pathways, and reprogram gene expression. These effects lead to apoptosis of tumor cells in culture, inhibition of anchorage-independent cell growth under lipid-rich conditions and inhibition of in vivo xenograft tumor growth in mice and rats. We are currently using transcriptomic and metabolomic analyses, including lipidmomic profiling, to explore the fundamental mechanisms resulting in sensitivity to the FASN inhibitor, TVB-3166. These same platforms are used to examine the changes in response to FASN inhibition in tumor and surrogate tissues of xenograft models as well as surrogate tissues of cancer patients. A panel of tumor and normal cell lines was assembled and lipids were assessed prior to and 72 hours after treatment with TVB-3166. A reduction of saturated fatty acids was observed in all cell lines indicative of FASN inhibition. A similar extent of reduction was observed in media in the presence of 1% or 10% serum; these results demonstrated that the tumor cells did not compensate for FASN inhibition by increasing uptake of saturated fatty acids from the extracellular milieu. An inverse correlation was observed between the pretreatment quantities of saturated fatty acids and the induction of apoptosis resulting from FASN inhibition with TVB-3166; low levels of saturated fatty acids in cell lines such as COLO-205, correlated with a high level of cell killing. Normal, untransformed cells had significantly higher levels of pretreatment saturated fatty acids and a commensurate insensitivity to TVB-3166. These in vitro observations were extended to a COLO-205 rat xenograft model. Significant tumor growth inhibition was measured in these animals in response to FASN inhibition by TVB-3166. Tumor tissues were isolated and a reduction in pAkt and c-Myc expression were observed, the latter consistent with a reduction of Wnt/beta-catenin driven transcription. Further metabolomic analyses of surrogate and tumor tissues from this model continue. The power of the metabolomic/lipidomic and transcriptomic analyses to evaluate drug responsiveness was applied to surrogate tissues of a small number of cancer patients treated with the FASN inhibitor, TVB-2640. Following 8 days of oral dosing, a preliminary evaluation of aqueous metabolites and lipids in patients' sera demonstrated changes consistent with the mechanism of FASN inhibition. Larger numbers of patients are being evaluated in order better characterize the extent of these changes. Preclinical evaluations of the molecular transformations caused by 3-V Bio's FASN inhibitors are being translated into clinical assessments that may ultimately lead to a more complete understanding of the impact of FASN inhibition in cancer patients and potentially the identification of tumor types that are likely to respond to treatment. Citation Format: Doug Buckley, Tim Heuer, Marie O'Farrell, Bill McCulloch, George Kemble. Translational studies of a first-in-class FASN Inhibitor, TVB-2640, linking preclinical studies to clinical laboratory observations in solid tumor patients. [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 A75.