Abstract 3781: Combination therapy with a liver selective acetyl-CoA carboxylase inhibitor ND-654 and sorafenib improves efficacy in the treatment of cirrhotic rats with hepatocellular carcinoma
Authors: Wei Lan , Harriman Geraldine , Ghoshal Sarani , Moaven Omeed , Greenwood Jeremy , Bhat Sathesh , Westlin William F. , Harwood H. James , Kapeller Rosana , Tanabe Kenneth K. , Fuchs Bryan C. 
Published: July 2016

Abstract
Background: Hepatocellular carcinoma (HCC) is increasing in incidence worldwide. Current treatment options for HCC are limited, and as such, prognosis is extremely poor with a 5-year survival less than 12%. Sorafenib is the only FDA-approved drug for the treatment of HCC but its effects are marginal as it only extends survival by a few months. Therefore, new treatment options are urgently needed. Metabolic attenuation is a promising approach to cancer therapy, and rate-limiting steps in key biosynthetic pathways are particularly attractive targets. We recently identified ND-654, a hepatoselective (∼3000:1 liver to muscle exposure), allosteric ACC inhibitor that binds to the ACC subunit dimerization site and inhibits the enzymatic activity of both ACC1 (IC50 = 3 nM) and ACC2 (IC50 = 8 nM). Daily oral administration of 10 mg/kg ND-654 reduced tumor incidence by 55% and significantly improved median survival time in a rat model of cirrhosis and HCC. Here, we examine the effects of ND-654 alone and in combination with sorafenib on HCC development in cirrhotic rats. Methods: Male Wistar rats were treated once weekly with 50 mg/kg diethylnitrosamine (DEN) for 18 weeks to induce sequential development of fibrosis, cirrhosis and HCC. After establishment of cirrhosis and when HCCs are first developing (13 weeks), rats were treated daily by oral gavage with either 1) vehicle control, 2) 10 mg/kg ND-654, 3) 10 mg/kg sorafenib, or 4) 10 mg/kg ND-654 and 10 mg/kg sorafenib. After 18 weeks, tumor nodules were counted and liver and tumor tissue was harvested for analysis. Results: Similar to our previous study, simultaneous inhibition of ACC1 and ACC2 significantly reduced HCC incidence by 41% (p &lt; 0.05) which was comparable to results with sorafenib (57% reduction, p &lt; 0.01). Remarkably, the combination of ND-654 and sorafenib significantly reduced HCC incidence by 81% (p &lt; 0.001). We are currently examining the effects of combining ND-654 and sorafenib on markers of tumor proliferation and apoptosis. Conclusions: These results provide further evidence that de novo lipogenesis is an important mediator of hepatic carcinogenesis and that selective inhibition of hepatic ACC is a viable cancer metabolism therapeutic strategy for treating HCC that could be combined with sorafenib.
Citation Format: Lan Wei, Geraldine Harriman, Sarani Ghoshal, Omeed Moaven, Jeremy Greenwood, Sathesh Bhat, William F. Westlin, H. James Harwood, Rosana Kapeller, Kenneth K. Tanabe, Bryan C. Fuchs. Combination therapy with a liver selective acetyl-CoA carboxylase inhibitor ND-654 and sorafenib improves efficacy in the treatment of cirrhotic rats with hepatocellular carcinoma. [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 3781.