Precision Prevention Research Program

精准预防研究计划

• 批准号: 10053438
• 负责人: Andrew T Chan
• 金额: $ 100.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10053438
• 关键词: Advanced Malignant Neoplasm; Adverse effects; Advisory Committees; Age; Aspirin; Award; Biological Markers; Cancer Patient; Cells; Chemoprevention; Clinic; Clinical; Clinical Trials; Data; Dose; Effectiveness; Etiology; Future; Goals; Harm Reduction; Hemorrhage; Individual; Integration Host Factors; International; Intervention; Investigation; Lead; Malignant Neoplasms; Modeling; Molecular; Molecular Epidemiology; Oncology; Patients; Physicians; Population; Population Study; Prevention Research; Prevention approach; Preventive Intervention; Preventive service; Prospective cohort study; Recommendation; Reporting; Research; Research Personnel; Resolution; Risk stratification; Source; System; Target Populations; Testing; Validation; Vision; Work; anticancer activity; base; biobank; biomarker-driven; cancer prevention; career; cohort; colorectal cancer prevention; colorectal cancer risk; cost efficient; evidence base; gut microbiome; human data; human tissue; improved; individualized prevention; novel; novel strategies; personalized approach; prevent; programs; risk benefit ratio; tool

PROJECT ABSTRACT As an internationally recognized physician-investigator, I have dedicated my career to the prevention of colorectal cancer (CRC). My most substantial contributions have influenced the evidence base supporting aspirin’s effectiveness in reducing the risk of CRC and uncovered key molecular mechanisms underlying its anti- cancer activity. This work has helped advance the field to a first-if-its-kind milestone recommendation for population use of aspirin for cancer prevention by the US Preventive Services Task Force. However, growing data demonstrates that the effect of aspirin may differ according to host factors, including the gut microbiome and age, suggesting that a “one-size-fits-all” approach to aspirin chemoprevention is limited. Thus, developing novel approaches to prevention through molecular risk stratification is a high priority. Building on my expertise in molecular epidemiology, clinical trials, the gut microbiome, and clinical cancer prevention, my research vision is to develop a comprehensive Precision Prevention Research Program (PPRP) through this NCI Outstanding Investigator Award. The overarching goal of this PPRP is to leverage complementary sources of human data, including population-based studies, clinical cohorts, and “living biobanks” to study the entire continuum from healthy individuals to advanced cancer patients and with resolution from single cells to large populations to acquire a more complete, multifaceted view of how interventions can be tailored to prevent cancer. Our PPRP facilitates mechanistic discovery in population studies that can lead to rapid testing of novel, molecularly-inspired biomarkers in clinical cohorts, creating opportunity for “living biobanks” for rigorous validation and advanced mechanistic investigation. Moreover, this model is reciprocal. Our clinical cohorts and translational tools using patient-derived experimental systems may also identify novel mechanisms that can be examined within the context of our population studies to confirm their relevance to cancer and improve generalizability. Through this R35, I will develop and expand this PPRP through expansion of my work in aspirin chemoprevention. Aspirin is an exemplar agent to develop this platform since efficacy for CRC prevention has already been established and its association with adverse effects, such as bleeding, necessitate a tailored approach. As the Lancet Oncology Commission report concluded: “Perhaps the most promising precision-based approach to cancer prevention in the near future involves molecular selection for repurposed low-dose aspirin” and “in view of aspirin’s potential adverse effects (e.g., bleeding), tailoring aspirin use is a high priority”. By enhancing understanding of aspirin’s mode of action, this proposal may lead to novel mechanistic biomarkers or complementary preventative interventions that may maximize the benefits of aspirin while minimizing the harms. Over the long-term, I envision that this work will provide proof-of-concept for expansion of the PPRP program as a cost-efficient platform within which to move additional cancer preventive interventions rapidly into the clinic.

项目摘要 作为一名国际认可的医师评论者，我将职业生涯致力于预防 结直肠癌（CRC）。我最大的贡献影响了证据基础支持 阿司匹林在降低CRC的风险和发现其抗抗抗菌基础的关键分子机制方面的有效性 癌症活动。这项工作使该领域成为了第一类的里程碑建议 美国预防服务工作队预防癌症的人口使用。但是，成长 数据表明，阿司匹林的作用可能会根据宿主因素而有所不同，包括肠道微生物组 和年龄，表明对阿司匹林化学预防的“万能型”方法是有限的。那，正在发展 通过分子风险分层进行预防的新方法是高度优先级。以我的专业知识为基础 在分子流行病学，临床试验，肠道微生物组和临床癌症预防中，我的研究视觉 是通过此NCI出色的 研究者奖。该PPRP的总体目标是利用人类数据的互补来源， 包括基于人群的研究，临床人群和“生活生物库”，以研究整个连续性 健康的个体对晚期癌症患者，并从单个细胞到大种群到分辨率 获取更完整，多方面的观点，即如何定制干预措施以预防癌症。我们的PPRP 促进人口研究中的机械发现，这可能导致新型，分子启发的快速测试 临床队列中的生物标志物，为严格验证和先进的“生活生物库”创造机会 机械投资。而且，该模型是相互的。我们使用的临床人群和翻译工具使用 患者衍生的实验系统还可以识别可以在 我们的人口研究的背景是确认其与癌症相关并提高普遍性的相关性。通过这个 R35，我将通过扩展阿司匹林化学预防的工作来开发和扩展这种PPRP。阿司匹林是 由于已经建立了CRC预防效率，因此开发此平台的示例代理 它与不良影响（例如出血）的关联，必要的量身定制方法。作为柳叶刀肿瘤学 委员会的报告得出结论：“也许是最有希望的基于精确的癌症预防方法 不久的将来涉及分子选择重新利用的低剂量阿司匹林”和“鉴于阿司匹林的潜力 不利影响（例如，出血），调整阿司匹林的使用是高度优先级。通过增强对阿司匹林的理解 作用方式，该建议可能会导致新颖的机械生物标志物或完全预防措施 可以在最大程度地减少危害的同时，可以最大程度地提高阿司匹林的益处。从长远来看，我设想 这项工作将为扩展PPRP计划作为一个具有成本效益的平台提供概念证明 这可以迅速将额外的癌症预防干预措施转移到诊所中。