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.

细胞代谢的改变已被广泛认为是癌症的一个新标志。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 癌细胞生长和存活、癌细胞脂肪酸（FA）代谢的改变受到的影响较少 注意力。越来越多的证据表明，增加 FA 生物合成不仅是为了 通过提供膜合成的构建模块来适应高增殖率，而且还可以 增强癌细胞抵御氧化应激或化疗诱导的细胞死亡的能力 改变膜脂成分。我们实验室和其他实验室的研究表明 FA 合成酶（FASN）是脂质从头生物合成的关键酶，在结直肠癌中显着上调 （CRC）。我们的体内研究表明，RNAi 介导的 FASN 抑制可显着降低肺和 肝结直肠癌转移并抑制肿瘤血管生成。总的来说，我们的研究表明 FASN 可以服务 作为新型治疗剂的潜在靶点。最近，一些口服的、可逆的、有效的和 选择性 FASN 小分子抑制剂由我们的合作者 3-V Biosciences 开发。这些 药物具有优异的药物特性，并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。这 我们项目的转化目标是定义结肠癌中发生的代谢适应，并 进行临床试验以评估 FASN 抑制剂 TVB-2640 对调节细胞代谢的作用 和结肠癌患者的增殖。我们提案的核心假设是上调 FASN 表达和活性存在于部分结肠癌患者中；因此，这些人将 受益于包括靶向抑制从头脂肪生成的治疗方法。下列 提出的具体目标是：1) 确定 FASN 表达改变对代谢重编程的影响 结肠癌； 2) 使用患者来源的异种移植物描述 FASN 抑制的抗增殖作用 (PDX) 结肠癌模型； 3) 与 3-V Biosciences 合作进行试点临床试验 评估新型 FASN 短期治疗后对代谢终点的药效学影响 结肠切除术前使用抑制剂（TVB-2640）。我们高度协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，这将 显着增进我们对 FASN 介导的结肠癌代谢改变的理解 可能提供基于更有针对性和个性化方法的新颖治疗策略。