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: 9109579
• 负责人: ELIZABETH L BARRY
• 金额: $ 36.34万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109579
• 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; Health; Human; Incidence; Intestines; Ions; Lesion; Liquid Chromatography; Malignant Neoplasms; Maps; 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; 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; cyclooxygenase 1; design; double-blind placebo controlled trial; epidemiologic data; evidence base; folic acid supplementation; high risk; innovation; metabolic profile; metabolomics; mortality; new therapeutic target; novel therapeutics; protective effect; 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（由申请人提供）：大量证据支持阿司匹林除了在心血管保护方面的公认作用外，还可用于癌症化学预防。在最近对人类随机对照试验的荟萃分析中，每日使用阿司匹林可以降低几种常见癌症的发病率，转移和死亡率，特别是结直肠癌。阿司匹林发挥抗癌作用的机制尚不确定;已经描述了许多涉及环加氧酶依赖性和非依赖性途径的作用。这项研究的目的是阐明关键的代谢变化，负责阿司匹林在人类中使用非靶向代谢组学分析的抗癌作用。代谢组学，或全球代谢物分析，是一个新兴的学科，有可能改变药物的研究。我们的创新方法将使用高分辨率质谱检测血浆和正常结肠粘膜活检中的数千种代谢物，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，阿司匹林和/或叶酸的随机，双盲，安慰剂对照试验 补充用于预防结肠直肠腺瘤。试验参与者以相同的概率被分配到三个阿司匹林治疗组（安慰剂，81 mg或325 mg每日）。在三年的治疗期间，81毫克/天的阿司匹林降低了腺瘤的风险，而325毫克/天的剂量效果较小。当前提案的目的是确定代谢组学特征，包括特定的代谢物和代谢途径，这些代谢物和代谢途径与随机阿司匹林治疗三年后参与者血液和正常结肠粘膜组织中的阿司匹林治疗相关;然后评估这些代谢特征与腺瘤风险的相关性，以及它们是否介导了81 mg/天阿司匹林治疗导致的风险降低。我们将通过评价安慰剂组和治疗组患者的代谢物水平，同时控制错误发现率，确定研究代谢物的优先级，使用相关性分析来增强与这些优先代谢物相关的相关代谢模块的识别，并将离子解离光谱事后应用于代表性代谢物的途径映射，以确认途径识别。由于阿司匹林是一种多功能药物，被认为可以改变许多在致癌作用中具有潜在作用的途径，因此基于全球发现的代谢组学方法是确定其关键活性的最佳方法。这项工作的公共卫生意义是实质性的，因为了解阿司匹林抗癌作用的机制是优化其使用和开发针对代谢途径的新药的关键。