Abstract 4452: Liver selective acetyl-CoA carboxylase inhibition by ND-654 improves survival in cirrhotic rats with hepatocellular carcinoma

Abstract

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%. Therefore, there is an urgent medical need for new therapeutic strategies. Metabolic attenuation is a promising approach to cancer therapy, and rate-limiting steps in key biosynthetic pathways are particularly attractive targets. Simultaneous inhibition of the acetyl-CoA carboxylase isozymes, ACC1 and ACC2, results in concomitant inhibition of fatty acid synthesis (FASyn) and stimulation of fatty acid oxidation (FAOxn) in cultured cells and in animals and impedes tumor cell growth in vitro. 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). We previously demonstrated that daily oral administration of 10 mg/kg ND-654 reduced tumor incidence by 55% in a rat model of HCC. Here, we test the hypothesis that ND-654 can decrease the number of tumor-related deaths and improve survival time in this model. Methods: Male Wistar rats were treated weekly with 50 mg/kg diethylnitrosamine (DEN) to induce sequential development of fibrosis, cirrhosis and HCC. After establishment of cirrhosis (13 wks), rats were treated daily by oral gavage with vehicle containing either 0, 10, or 30 mg/kg ND-654. At the time of death, tumor nodules were counted and liver and tumor tissue was analyzed to assess the effects of ND-654 on disease progression. Results: Simultaneous inhibition of ACC1 and ACC2 significantly improved median survival time in this lethal model of cirrhosis and HCC from 114 days in vehicle control animals to 126 (p = 0.02) and 129 days (p = 0.009) in animals treated with either 10 or 30 mg/kg ND-654. Analysis of tumor tissue revealed that ND-654 decreased tumor cell proliferation as assessed by PCNA staining. In addition, compared to vehicle control, ND-654 induced massive tumor necrosis, as assessed by H&E staining, but minimal apoptosis, as assessed by caspase-3 staining. Sirius red staining of the liver parenchyma revealed decreased accumulation of collagen fibers and therefore fibrosis in ND-654 treated animals as compared to vehicle control animals. Conclusions: These results provide further evidence that de novo lipogenesis is an important mediator of hepatic fibrosis and carcinogenesis and that selective inhibition of hepatic ACC is a viable cancer metabolism therapeutic strategy for treating HCC and liver fibrosis/cirrhosis. Citation Format: Omeed Moaven, Lan Wei, Geraldine Harriman, Jeremy Greenwood, Sathesh Bhat, William F. Westlin, H. James Harwood, Rosana Kapeller, Danielle K. DePeralta, Kenneth K. Tanabe, Bryan C. Fuchs. Liver selective acetyl-CoA carboxylase inhibition by ND-654 improves survival in cirrhotic rats with hepatocellular carcinoma. [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 4452. doi:10.1158/1538-7445.AM2015-4452