Abstract 1048: Modulation of lipid metabolism through inhibition of acetyl-CoA carboxylase with ND-646 leads to potent inhibition of breast cancer cell growth in vitro and in vivo

Abstract

Abstract Metabolic attenuation is a promising approach to cancer therapy and rate-limiting steps in key biosynthetic pathways are particularly attractive targets. Many cancer types are dependent on fatty acid synthesis as a primary source of energy and for providing lipids for expansion of cell and nuclear membranes in rapidly proliferating cells. The rate-limiting enzyme in fatty acid synthesis, acetyl-CoA carboxylase (ACC), has been shown to be highly expressed in human breast cancer. ACC is thought to be critical for the growth and survival of cancer cells, especially within a tumor microenvironment where exogenous fatty acids might be limited. Effective therapeutic options for triple negative breast cancer are limited and identification of robust targeted agents without overt toxicity for this indication are especially needed. Dual inhibition of the ACC isozymes, ACC1 and ACC2, results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. We have identified ND-646, a potent, selective, allosteric inhibitor of ACC with broad tissue distribution that binds to the ACC biotin carboxylase domain and potently inhibits the dimerization and enzymatic activity of both ACC1 (IC50 = 3.5nM) and ACC2 (IC50 = 4.1nM). Profiling the potency of ND-646 in vitro in a panel of breast cancer cell lines including triple negative and BRCA1 mutant cell lines demonstrated potent inhibition of cell proliferation with IC50s<100nM. The anti-proliferative effects were more pronounced when cells were cultured in media containing delipidated serum. Daily oral dosing of ND-646 at 25 mg/kg BID, 50 mg/kg QD, and 50 mg/kg BID in mice bearing orthotopic triple negative MDA-MB-468 breast cancer xenografts led to tumor growth inhibition of 60-70% that correlated with compound exposure and target engagement in the tumor. Analysis of ND-646 treated tumors demonstrated disruption of tumor tissue architecture and induction of apoptosis and necrosis suggesting a direct effect on cell survival. These results provide further evidence that de novo lipogenesis is an important mediator of breast cancer cell growth and survival, and that selective inhibition of ACC is a viable therapeutic strategy for treatment of breast cancer. Citation Format: Jennifer L. Rocnik, Wenyan Miao, Geraldine Harriman, Jeremy Greenwood, Sathesh Bhat, H. James Harwood, Rosana Kapeller, William F. Westlin. Modulation of lipid metabolism through inhibition of acetyl-CoA carboxylase with ND-646 leads to potent inhibition of breast cancer cell growth in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1048.