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

基本信息

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
项目类别：
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

项目摘要

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明确作用外，还具有癌症化学预防的功效。在最近对人体随机对照试验的荟萃分析中，每日服用阿司匹林可降低发病率、转移率和死亡率。阿司匹林发挥抗癌功效的机制尚不清楚，但其多种作用均依赖于环氧合酶；这项研究的目标是利用非靶向代谢组学分析（或全局代谢物分析）来阐明导致阿司匹林抗癌作用的关键代谢变化，这是一门具有变革潜力的新兴学科。我们的创新方法将使用高分辨率质谱来检测从参与者身上收集的血浆和正常结肠粘膜活检中的数千种代谢物。阿司匹林/叶酸预防息肉研究，一项阿司匹林和/或叶酸的随机、双盲、安慰剂对照试验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、每天 81 毫克或 325 毫克）。在三年的治疗期间，每天服用 81 毫克阿司匹林可降低病情。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与腺瘤相关的代谢组学特征，包括特定的代谢物和代谢途径。在随机阿司匹林治疗三年后，对参与者的血液和正常结肠粘膜组织进行阿司匹林治疗；然后评估这些代谢特征与腺瘤风险的关联，以及它们是否介导因每天服用 81 毫克阿司匹林治疗而导致的风险降低。将通过评估安慰剂组和治疗组患者的代谢水平，同时控制错误发现率，对研究的代谢物进行优先排序，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，并应用路径图谱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过程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识别其关键的最佳方法。这项工作对公共卫生意义重大，因为了解阿司匹林的抗癌作用机制是优化其使用和开发针对已确定代谢途径的新药物的关键。