Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment

改变的细胞代谢已被广泛认为是癌症的一个新的标志。虽然 癌症代谢研究的最新进展已经开始阐明代谢变化如何支持 癌细胞的生长和存活，癌细胞中脂肪酸（FA）代谢的改变受到较少的关注。 关注越来越多的证据表明，增加FA的生物合成不仅需要 通过为膜合成提供构件来适应高增殖速率，而且还 增强癌细胞防御氧化应激或化疗诱导的细胞死亡的能力， 改变膜脂质组成。我们的实验室和其他机构的研究表明，FA 脂肪酸合成酶（Festivalsynthase，Festivalase）是脂质从头合成的关键酶，在结直肠癌中显著上调 （CRC）。我们的体内研究表明，RNAi介导的抑制FXR显著降低了肺功能， 肝CRC转移和抑制肿瘤血管生成。总的来说，我们的研究表明， 作为新型治疗剂的潜在靶点。最近，几种口服的、可逆的、有效的和 我们的合作者3-V Biosciences已经开发了选择性Festival小分子抑制剂。这些 这些药物具有优异的药物特性，并且在广泛的耐受剂量下实现抗肿瘤作用。 一系列肿瘤，包括非小细胞肺癌、卵巢癌和三阴性乳腺癌。的 我们项目的翻译目标是定义结肠癌中发生的代谢适应， 进行一项临床试验，以评估FXR抑制剂TVB-2640对调节细胞代谢的作用 以及结肠癌患者的增殖。我们建议的中心假设是， FcB的表达和活性发生在结肠癌患者的一个子集中;因此，这些个体将 受益于包括从头脂肪生成的靶向抑制的治疗方法。以下 具体目标是：1）确定改变FcB表达对代谢重编程的影响 2）使用患者来源的异种移植物描述FcB抑制的抗增殖作用 (PDX)结肠癌模型;以及3）与3-V Biosciences合作进行试点临床试验， 评估新的芬太尼短期治疗后对代谢终点的药效学影响 抑制剂（TVB-2640）。我们高度合作的团队拥有必要的专业知识， 创新的模型系统，最先进的技术和新型抑制剂，以取得快速进展， 显着推进我们对FASN介导的结肠癌代谢改变的理解， 潜在地基于更集中和个性化的方法提供新的治疗策略。

Altered cellular metabolism has been widely recognized as an emerging hallmark of cancer. Although recent advances in cancer metabolism research have begun to elucidate how metabolic changes support cancer cell growth and survival, alterations in fatty acid (FA) metabolism in cancer cells have received less attention. Increasing evidence has suggested that increased FA biosynthesis is needed not only to accommodate high rates of proliferation by providing building blocks for membrane synthesis, but also to enhance the ability of cancer cells to defend against oxidative stress- or chemotherapy-induced cell death by changing membrane lipid composition. Studies from our laboratories and others have demonstrated that FA synthase (FASN), a key enzyme of de novo lipid biosynthesis, is significantly upregulated in colorectal cancer (CRC). Our in vivo studies demonstrate that RNAi-mediated inhibition of FASN markedly reduces lung and hepatic CRC metastases and inhibits tumor angiogenesis. Collectively, our studies indicate FASN may serve as a potential target for novel therapeutic agents. Recently, several orally-available, reversible, potent and selective FASN small molecule inhibitors have been developed by our collaborator 3-V Biosciences. These agents have excellent pharmaceutical profiles and achieve antitumor effects at tolerated doses in a broad range of tumors including non-small cell lung cancer, ovarian and triple negative breast cancers. The translational goal of our project is to define the metabolic adaptations that occur in colon cancer and to conduct a clinical trial to evaluate the effect of FASN inhibitor, TVB-2640, on modulating cellular metabolism and proliferation in colon cancer patients. The central hypothesis for our proposal is that upregulation of FASN expression and activity occurs in a subset of colon cancer patients; therefore, these individuals would benefit from a therapeutic approach that includes targeted inhibition of de novo lipogenesis. The following Specific Aims are proposed: 1) to determine the effect of altered FASN expression on metabolic reprograming in colon cancer; 2) to delineate the anti-proliferative effect of FASN inhibition using patient-derived xenograft (PDX) models of colon cancer; and 3) to perform a pilot clinical trial in collaboration with 3-V Biosciences to assess pharmacodynamic effects on metabolic endpoints following short-term treatment with a novel FASN inhibitor (TVB-2640) prior to colon resection. Our highly collaborative group has the requisite expertise, innovative model systems, state-of-the-art technology and novel inhibitors to make rapid progress that will significantly advance our understanding of the FASN-mediated metabolic alterations of colon cancers and potentially provide novel treatment strategies based on a more focused and personalized approach.