Aspirin Metabolomics in Colorectal Cancer Chemoprevention

阿司匹林代谢组学在结直肠癌化学预防中的应用

• 批准号: 9316318
• 负责人: ELIZABETH L BARRY
• 金额: $ 44.13万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316318
• 关键词: Acetylation; Address; Adjuvant; Arachidonic Acids; Aspirin; Biocompatible Materials; Biological Markers; Biopsy; Blood; Caliber; Cardiovascular system; Colon; Colorectal Adenoma; Colorectal Cancer; Data; Data Analyses; Development; Dinoprostone; Discipline; Dissociation; Dose; Drug Design; Dysplasia; Effectiveness; Folic Acid; Fourier Transform; Goals; Human; Incidence; Intestines; Ions; Lesion; Liquid Chromatography; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Meta-Analysis; Metabolic; Metabolic Pathway; Metabolism; Methodology; Methods; Molecular; Mucous Membrane; National Cancer Institute; Neoplasm Metastasis; Nitric Oxide; Outcome; PTGS2 gene; Participant; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Placebos; Plasma; Play; Polyamines; Polyps; Positioning Attribute; Prevention; Probability; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Public Health; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Research; Research Proposals; Resolution; Resources; Risk; Role; Sampling; Signal Transduction; Spectrum Analysis; Time; Tissue Sample; Tissues; Villous; Work; adenoma; arm; base; burden of illness; cancer chemoprevention; cancer prevention; cancer therapy; cancer type; carcinogenesis; carcinogenicity; cyclooxygenase 1; design; double-blind placebo controlled trial; epidemiologic data; folic acid supplementation; high risk; innovation; metabolic profile; metabolomics; mortality; new therapeutic target; novel therapeutics; protective effect; public health relevance; treatment duration

 DESCRIPTION (provided by applicant): Substantial evidence supports the effectiveness of aspirin for cancer chemoprevention in addition to its well-established role in cardiovascular protection. In recent meta-analyses of randomized controlled trials in humans, daily aspirin use reduced incidence, metastasis and mortality from several common types of cancer, especially colorectal cancer. The mechanism(s) by which aspirin exerts an anticancer benefit is uncertain; numerous effects have been described involving both cyclooxygenase-dependent and -independent pathways. The goal of this research is to elucidate the key metabolic changes that are responsible for the anticancer effects of aspirin in humans using untargeted metabolomics analysis. Metabolomics, or global metabolite profiling, is an emerging discipline that has the potential to transform the study of pharmaceutical agents. Our innovative approach will use high-resolution mass spectroscopy to detect thousands of metabolites in blood plasma and normal colon mucosa biopsies that were collected from participants in the Aspirin/Folate Polyp Prevention Study, a randomized, double-blind, placebo-controlled trial of aspirin and/or folic acid supplementation for the prevention of colorectal adenomas. Participants in the trial were assigned with equal probability to three aspirin treatment arms (placebo, 81 mg, or 325 mg daily). Over the three-year treatment period, 81 mg/day of aspirin reduced the risk of adenomas, whereas the 325 mg/day dose had less effect. The aims of the current proposal are to identify metabolomic signatures, including specific metabolites and metabolic pathways, that are associated with aspirin treatment in blood and normal colon mucosal tissue of participants after three years of randomized aspirin treatment; and then to assess the associations of these metabolic signatures with adenoma risk and whether they mediate the reductions in risk due to 81 mg/day aspirin treatment. We will prioritize metabolites for study by evaluating metabolite levels in patients from the placebo and treatment arms while controlling the false discovery rate, use correlation analysis to enhance identification of relevant metabolic modules associated with these prioritized metabolites, and apply pathway mapping with post-hoc application of ion dissociation spectroscopy to representative metabolites to confirm pathway identification. Because aspirin is a multifunctional drug that is thought to modify numerous pathways with potential roles in carcinogenesis, a global discovery-based metabolomics approach is the best way to identify its key activities. The public health significance of this work is substantial because understanding the mechanism of aspirin's anticancer effects is key to optimizing its use and to the development of novel drugs targeting the metabolic pathways identified.

 描述（由适用提供）：大量证据还支持阿司匹林对癌症化学预防的有效性，除了其在心血管保护中的良好作用。在人类随机对照试验的最新荟萃分析中，每日阿司匹林使用几种常见类型的癌症（尤其是结直肠癌）的发病率，转移和死亡率降低。阿司匹林施加抗癌益处的机制尚不确定；已经描述了许多涉及环氧酶依赖性和非依赖性途径的影响。这项研究的目的是阐明使用未靶向的代谢组学分析，导致阿司匹林在人类中的抗癌作用的关键代谢变化。代谢组学或全球代谢产物分析是一门新兴学科，有可能改变药物研究的研究。我们的创新方法将使用高分辨率质谱法检测血浆和正常结肠粘膜活检中的数千种代谢产物，这些代谢物是从阿司匹林/叶酸息肉预防研究的参与者中收集的，这是一项随机，双盲，安慰剂对照试验的阿司匹林和/或叶酸的试验 补充预防有色腺瘤。试验的参与者分配了与三个阿司匹林治疗组（安慰剂，81 mg或每天325 mg）相同的可能性。在三年治疗期间，阿司匹林的81 mg/天降低了腺瘤的风险，而325 mg/天剂量的作用较小。当前建议的目的是确定与阿司匹林治疗在三年的随机阿司匹林治疗后，与参与者的血液和正常结肠粘膜组织有关的代谢组学特征，包括特定的代谢产物和代谢途径；然后评估这些代谢信号与腺瘤风险的关联，以及它们是否介导了由于81 mg/天阿司匹林治疗而导致的风险降低。我们将通过评估安慰剂和治疗臂的患者的代谢物水平来确定代谢物进行研究，同时控制错误的发现率，使用相关分析来增强与这些优先级代谢物相关的相关代谢模块的鉴定，并将途径映射到hoc-Hoc的途径映射中，以确认代表代理识别离子离子离子分离率的识别。由于阿司匹林是一种多功能药物，被认为可以修改具有潜在作用在癌变中的众多途径，因此一种基于全球发现的代谢组学方法是识别其关键活动的最佳方法。这项工作的公共卫生意义是很大的，因为了解阿司匹林抗癌作用的机制是优化其使用和针对瞄准代谢途径的新型药物的关键。