Abstract 1129: How to develop ACC1 inhibitors targeting lipid metabolism and oncogenic signaling pathways effectively and safely

Abstract

Abstract Although targeting lipogenesis for cancer treatment appears to have a strong rationale, drug discovery in this field has not been fully explored due to the lack of understanding the mode of action as well as the therapeutic window. We reported previously on a class of novel ACC inhibitors with potent and selective activity against human ACC1, an isoform overexpressed in many cancer types. These ACC inhibitors revealed strong anti-tumor activity, including induction of tumor cell apoptosis in vitro and tumor regression in vivo in a sub-set of tumor models. To further demonstrate the therapeutic potential of ACC inhibitors, we conducted a series of studies in xenograft mice and rat to evaluate the anti-tumor efficacy of ACC inhibitors and to characterize their safety profile. We report that breast, prostate, and pancreatic cancers are among the most sensitive tumors to ACC inhibition. Interestingly, the anti-tumor kinetics correlated with reduction in palmitate levels without substantial changes in structural lipid components. In addition, a sub-type of KRAS mutation and activation of the Wnt pathway correlates with the sensitivity of tumors to ACC inhibitors. Treatment with ACC inhibitors at high doses caused an immediate decrease in food intake and followed with body weight loss. A clear correlation between the reduction of food intake and exposure of ACC inhibitor was observed. Upon withdrawing drug, the effect on food intake is restored. Therefore, we investigated intermittent dosing schedules and food effects on the tolerability and anti-tumor efficacy of ACC inhibitors. We could demonstrate that the tolerability was improved without compromising the efficacy compared to continuous treatment. Furthermore, feeding animals a high fat diet prevented body weight loss and meanwhile maintained the antitumor activity. These results indicate that strong reduction of food intake seems the cause of intolerability, which can be prevented and reversed either by intermittent dosing, or by exogenously supplementing with a high fat diet. Furthermore, for the first time we provided in vivo evidence that exogenous lipids could complement de novo lipogenesis inhibition in normal cells, while tumor growth requires lipogenesis irrespective of existing circulating lipids. In summary, these assessments provide scientific insights and strategy on how to best target tumor lipid metabolism and lipid signaling effectively and safely for cancer therapy. Citation Format: Ningshu Liu, Wilhelm Bone, Sendhil S. Velan, Krishnarao Doddapuneni, Jadegoud Yaligar, Kai Thede Thede, Ursula Moenning, Xiaohe Shi, Xianfeng Tian, Elissaveta Petrova1, Franz von Nussbaum, Dominik Mumberg, Michael Brands, Karl Ziegelbauer. How to develop ACC1 inhibitors targeting lipid metabolism and oncogenic signaling pathways effectively and safely. [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 1129. doi:10.1158/1538-7445.AM2015-1129