Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment

改变脂质代谢作为结肠癌治疗的新目标

• 批准号: 10227741
• 负责人: Bernard Mark Evers
• 金额: $ 42.53万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227741
• 关键词: Acute; Address; Apoptosis; Attention; Behavior; Benign; Biological; Biological Models; Biological Sciences; Cancer Cell Growth; Cancer Etiology; Carnitine; Cell Death; Cell Proliferation; Cell Survival; Cells; Cessation of life; Clinical Trials; Collaborations; Colon; Colon Carcinoma; Colorectal Cancer; DNA Sequence Alteration; Development; Dose; Enzymes; Epithelial Cells; Etiology; Excision; Fatty Acids; Fatty-acid synthase; Future; Glucose; Glycolysis; Goals; Growth; Hepatic; Individual; Laboratories; Lead; Lipids; Lung; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Membrane Lipids; Metabolic; Metabolism; Mitochondria; Mucous Membrane; Non-Small-Cell Lung Carcinoma; Oncogenic; Oral; Ovarian; Oxidative Stress; Palmitates; Pharmacodynamics; Pharmacologic Substance; Phospholipids; Production; RNA Interference; Research; Resected; Respiration; Signal Pathway; Slice; Techniques; Technology; Therapeutic; Therapeutic Agents; Tissues; Triglycerides; Tumor Angiogenesis; United States; Up-Regulation; Warburg Effect; antitumor effect; base; beta catenin; cancer cell; cell growth; cell transformation; chemotherapy; colon cancer patients; colon cancer treatment; colorectal cancer metastasis; colorectal cancer progression; experimental study; extracellular; fatty acid biosynthesis; fatty acid metabolism; in vivo; inhibitor/antagonist; innovation; lipid biosynthesis; lipid metabolism; membrane synthesis; metabolomics; multidisciplinary; neoplastic; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; overexpression; patient derived xenograft model; patient subsets; personalized approach; randomized placebo-controlled clinical trial; response; secondary endpoint; small molecule inhibitor; stable isotope; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor metabolism; tumorigenesis

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.

细胞代谢改变已被广泛认为是癌症的新兴标志。虽然 癌症代谢研究的最新进展已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）代谢的改变较少 注意力。越来越多的证据表明，不仅需要增加FA生物合成 通过为膜合成提供构建块来适应高增殖率，但也可以 通过 改变膜脂质成分。我们的实验室和其他人的研究表明，FA 合酶（FASN）是从头脂质生物合成的关键酶，在大肠癌中显着上调 （CRC）。我们的体内研究表明，RNAi介导的FASN抑制显着降低了肺和 肝CRC转移并抑制肿瘤血管生成。总的来说，我们的研究表明FASN可能服务 作为新型治疗剂的潜在靶标。最近，几种口服，可逆，有效的，并且 选择性FASN小分子抑制剂是由我们的3-V生物科学家开发的。这些 代理具有出色的药物特征，并在广泛的剂量下实现抗肿瘤作用 包括非小细胞肺癌，卵巢癌和三重阴性乳腺癌在内的肿瘤范围。这 我们项目的转化目标是定义结肠癌中发生的代谢适应 进行临床试验，以评估FASN抑制剂TVB-2640的影响，对调节细胞代谢 结肠癌患者的增殖。我们建议的中心假设是 FASN表达和活性发生在结肠癌患者的一部分中。因此，这些人会 受益于一种治疗方法，包括针对性抑制从头脂肪生成。下列 提出了具体目的：1）确定FASN表达改变对代谢重编程的影响 在结肠癌中； 2）描绘使用患者衍生异种移植物的FASN抑制作用的抗增殖作用 （PDX）结肠癌模型； 3）与3-V Biosciences合作进行试验临床试验 用新的FASN评估短期治疗后对代谢终点的药效动力作用 结肠切除之前的抑制剂（TVB-2640）。我们高度协作的小组具有必要的专业知识， 创新的模型系统，最先进的技术和新型抑制剂，以取得快速进步 显着提高我们对FASN介导的结肠癌的代谢改变的理解和 有可能基于一种更加集中和个性化的方法提供新颖的治疗策略。