Aspirin Metabolomics in Colorectal Cancer Chemoprevention

 描述(由申请人提供)：大量证据支持阿司匹林对癌症化学预防的有效性，以及它在心血管保护方面的公认作用。在最近对人类随机对照试验的荟萃分析中，每天使用阿司匹林可降低几种常见癌症的发病率、转移和死亡率，尤其是结直肠癌。阿司匹林发挥抗癌作用的机制(S)尚不确定；已经描述了许多作用，涉及环氧合酶依赖和非依赖途径。这项研究的目的是利用非靶向代谢组学分析来阐明导致阿司匹林抗癌作用的关键代谢变化。代谢组学，或全球代谢物图谱，是一门新兴学科，有可能改变药物制剂的研究。我们的创新方法将使用高分辨率质谱仪来检测血浆和正常结肠粘膜活检中的数千种代谢物，这些代谢物来自阿司匹林/叶酸息肉预防研究的参与者，这是一项阿司匹林和/或叶酸的随机、双盲、安慰剂对照试验。 预防结直肠腺瘤的补充剂。试验中的参与者被以同样的概率分配到三个阿司匹林治疗组(安慰剂、81毫克或每天325毫克)。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。目前这项提案的目的是确定在随机服用阿司匹林三年后，参与者血液和正常结肠粘膜组织中与阿司匹林治疗相关的代谢特征，包括特定的代谢物和代谢途径；然后评估这些代谢特征与腺瘤风险的关系，以及它们是否介导了每天81毫克阿司匹林治疗带来的风险降低。我们将通过评估安慰剂和治疗组患者的代谢物水平来确定研究的优先顺序，同时控制误发现率，使用相关性分析来加强与这些优先代谢物相关的代谢模块的识别，并将路径图与特殊情况下对代表性代谢物的离子解离光谱应用于路径图，以确认路径识别。由于阿司匹林是一种多功能药物，被认为可以改变许多具有潜在致癌作用的途径，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的代谢途径的新药的关键。

 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.