Targeting Lipid Metabolism in Colorectal Cancer

靶向结直肠癌的脂质代谢

• 批准号: 10374051
• 负责人: YEKATERINA ZAYTSEVA
• 金额: $ 34.69万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374051
• 关键词: Biological; Biological Assay; Biological Sciences; CD36 gene; Cancer Etiology; Cancer Patient; Cause of Death; Cecum; Cell Survival; Cessation of life; Clinical; Collaborations; Colorectal Cancer; Data; Development; Disease; Drug Evaluation; Drug Targeting; Environment; Enzymes; Fatty Acids; Fatty-acid synthase; Goals; Growth; Human; In Vitro; Incidence; Injections; Knowledge; Lipids; Literature; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Metastatic to; Microarray Analysis; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Oncology; Organ; Organoids; Outcome; Palmitates; Pathway interactions; Patients; Pharmacology; Phase I/II Clinical Trial; Phase II Clinical Trials; Pre-Clinical Model; Prognosis; Public Health; Recurrence; Regulation; Research; Role; Sampling; Signal Pathway; Solid; Solid Neoplasm; Specimen; Sphingolipids; Sphingosine; Testing; Therapeutic; Tissue Microarray; Tumor Angiogenesis; United States; Up-Regulation; Validation; Woman; analog; antibody inhibitor; base; cancer cell; colorectal cancer metastasis; colorectal cancer progression; disorder risk; fatty acid metabolism; genetic approach; high risk; in vivo; in vivo Model; inhibitor; lipid biosynthesis; lipid metabolism; men; metabolomics; mortality; mouse model; neutralizing antibody; new therapeutic target; novel; novel therapeutic intervention; overexpression; patient derived xenograft model; preclinical study; prevent; resistance mechanism; response; sphingosine 1-phosphate; sphingosine kinase; stable isotope; targeted treatment; therapeutic target; transcriptome sequencing; translational impact; translocase; tumor; tumor metabolism; uptake

PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). Our long-term goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by understanding how changes in fatty acid metabolism contribute to metastatic disease. Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated and activated in CRC, and its activity is associated with poor prognosis, higher risk of disease recurrence, and death. We identified FASN as a potential target for advanced CRC and showed that upregulation of this enzyme is a key mechanism supporting metastasis in CRC. However, the underlying mechanisms of FASN regulation of metastasis and potential mechanism of resistance to FASN inhibition are not understood. The current application proposes a comprehensive research plan to study novel mechanisms of regulation of CRC metastasis by lipid metabolism. Our preliminary data suggest that the primary product of de novo fatty acid synthesis, palmitate, is selectively used for sphingolipid synthesis. Overexpression of FASN selectively regulates activity of SphK1 and SphK2 and increases the level of sphingosine-1-phosphate (S1P), a bioactive sphingolipid implicated in metastasis. Therefore, in Aim 1, we will test the hypothesis that FASN enhances metastasis by upregulating the SphK/S1P axis and we will determine the contributions of SphK1 and SphK2 to CRC metastasis. Furthermore, our preliminary studies show a correlation between expression of FASN and CD36, a fatty acid translocase responsible for exogenous FA uptake. Our data show that inhibition of FASN leads to upregulation of CD36 and it can be a potential mechanism of resistance to novel FASN inhibitors that are currently being tested in Phase II clinical trials. Therefore, in Aim 2, we will elucidate how FASN regulates CD36 and determine molecular mechanisms by which upregulation of CD36 contributes to CRC metastasis including the effect of CD36 upregulation on sphingolipid metabolism and S1P synthesis. In Aim 3, we will test whether inhibition of FA uptake via CD36 will increase efficacy of a novel FASN inhibitor TVB-3664 in CRC. We will utilize biological samples from patients, human primary CRC cells, tumor organoids established from genetically modified mice and CRC metastasis models, which are the most advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with state-of-the-art approaches, including targeted and stable isotope-resolved metabolomics (SIRM), to evaluate the effect of alteration in lipid synthesis and FA uptake on cancer cell metabolism. These studies have a high translational impact since CD36 and FASN inhibitors are currently tested in multiple pre-clinical studies and Phase I-II clinical trials and there is urgent need for more research and knowledge on their effects in CRC. Beside validation of FASN, SphKs and CD36 as therapeutic targets in CRC, the comprehensive analysis of metabolic and signaling pathways proposed in the current application also have the potential to identify new druggable targets and therapeutic strategies for CRC.

项目概要 转移是包括结直肠癌（CRC）在内的实体瘤死亡的主要原因。我们的长期目标是通过了解脂肪酸代谢的变化如何导致转移性疾病，开发更具选择性的治疗方案，以预防或减少结直肠癌转移的发生率。 脂肪酸合酶（FASN）是脂质从头合成的关键酶，在结直肠癌中显着上调和激活，其活性与不良预后、较高的疾病复发和死亡风险相关。我们将 FASN 确定为晚期 CRC 的潜在靶标，并表明该酶的上调是支持 CRC 转移的关键机制。然而，FASN 调节​​转移的潜在机制和抵抗 FASN 抑制的潜在机制尚不清楚。当前的申请提出了一项综合研究计划，以研究脂质代谢调节结直肠癌转移的新机制。我们的初步数据表明，脂肪酸从头合成的主要产物棕榈酸酯选择性地用于鞘脂合成。 FASN 的过度表达选择性调节 SphK1 和 SphK2 的活性，并增加 1-磷酸鞘氨醇 (S1P) 的水平，S1P 是一种与转移有关的生物活性鞘脂。因此，在目标 1 中，我们将检验 FASN 通过上调 SphK/S1P 轴增强转移的假设，并将确定 SphK1 和 SphK2 对 CRC 转移的贡献。此外，我们的初步研究表明 FASN 和 CD36 的表达之间存在相关性，CD36 是一种负责外源 FA 摄取的脂肪酸转位酶。我们的数据表明，抑制 FASN 会导致 CD36 上调，这可能是对目前正在 II 期临床试验中测试的新型 FASN 抑制剂产生耐药性的潜在机制。因此，在目标2中，我们将阐明FASN如何调节CD36，并确定CD36上调导致CRC转移的分子机制，包括CD36上调对鞘脂代谢和S1P合成的影响。在目标 3 中，我们将测试通过 CD36 抑制 FA 摄取是否会提高新型 FASN 抑制剂 TVB-3664 在 CRC 中的疗效。 我们将利用来自患者的生物样本、人类原代结直肠癌细胞、转基因小鼠建立的肿瘤类器官和结直肠癌转移模型，这些是临床前靶点和药物评估的最先进模型。这些模型将与最先进的方法结合使用，包括靶向稳定同位素解析代谢组学 (SIRM)，以评估脂质合成和 FA 摄取的改变对癌细胞代谢的影响。这些研究具有很高的转化影响，因为 CD36 和 FASN 抑制剂目前正在多项临床前研究和 I-II 期临床试验中进行测试，并且迫切需要对其在 CRC 中的作用进行更多研究和了解。除了验证 FASN、SphKs 和 CD36 作为 CRC 的治疗靶点外，本申请中提出的代谢和信号通路的综合分析也有可能确定 CRC 的新药物靶点和治疗策略。