Abstract 1427: Liver selective Acetyl-CoA Carboxylase inhibition by ND-654 decreases hepatocellular carcinoma development in cirrhotic rats

Abstract

Abstract Background: Hepatocellular carcinoma (HCC) is increasing in incidence worldwide. This increase is in part due to the obesity epidemic which is an independent risk factor for both nonalcoholic fatty liver disease (NAFLD) and HCC. In fact, recent evidence suggests that enhanced de novo lipogenesis is a critical mediator for HCC development. 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. 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, reduces hepatic steatosis, and impedes tumor cell growth in vitro. Here, we test the hypothesis that simultaneous reduction of hepatic FASyn through inhibition of ACC1 and stimulation of hepatic FAOxn through inhibition ACC2 is a potential therapeutic target for HCC. Results: Using state-of-the-art structure-based drug design and crystal structures of the human ACC2 biotin carboxylase domain, we identified ND-654, a hepatoselective (2700:5:1 liver to plasma to muscle exposure), allosteric inhibitor that binds to the ACC subunit dimerization site, inhibits the enzymatic activity of both ACC1 (IC50 = 3 nM) and ACC2 (IC50 = 8 nM), and inhibits FASyn in HepG2 cells (IC50 = 14 nM) and in rats (ED50 = 0.3 mg/kg). 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 either vehicle or 10 mg/kg ND-654. At the end of the study (18 wks), rats were sacrificed and tumor nodules were counted. Liver tissue and plasma were also analyzed to assess the effects of ND-654 on disease progression. When measured four hours after the final dose, ND-654 showed preferential liver exposure, with steady state levels reaching 3.7±1.8 µM in cirrhotic tissue and 2.2±1.8 µM in tumor tissue. ND-654 did not alter body weight or food consumption, but reduced serum triglyceride levels by 35%. Importantly, ND-654 significantly (p < 0.01) inhibited HCC development in DEN-injured livers from an average of 15.8 tumor nodules in controls to an average of 7.1 tumor nodules in ND-654-treated rats. Consistently, ND-654 reduced the DEN-induced increase in liver weight by 48%, and decreased the number of tumor related deaths by 67% (6 of 8 controls vs 2 of 8 ND-654-treated rats). 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 potential therapeutic strategy for HCC. Citation Format: Danielle K. DePeralta, Lan Wei, Geraldine Harriman, Jeremy Greenwood, Sathesh Bhat, William Westlin, H. James Harwood, Rosana Kapeller, Kenneth K. Tanabe, Bryan C. Fuchs. Liver selective Acetyl-CoA Carboxylase inhibition by ND-654 decreases hepatocellular carcinoma development in cirrhotic rats. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1427. doi:10.1158/1538-7445.AM2014-1427