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 作为一名国际公认的医师研究员，我将我的职业生涯奉献给了预防 结直肠癌（CRC）。我最重要的贡献影响了支持的证据基础 阿司匹林在降低结直肠癌风险方面的有效性，并揭示了其抗结直肠癌的关键分子机制 癌症活动。这项工作帮助该领域取得了前所未有的里程碑建议： 美国预防服务工作组对阿司匹林用于预防癌症的人群使用情况进行了调查。然而，不断增长的 数据表明，阿司匹林的作用可能会因宿主因素（包括肠道微生物群）的不同而有所不同 和年龄，这表明“一刀切”的阿司匹林化学预防方法是有限的。因此，开发 通过分子风险分层进行预防的新方法是当务之急。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方面，我的研究愿景 旨在通过这项 NCI 杰出研究项目来制定全面的精准预防研究计划 (PPRP) 研究员奖。该 PPRP 的总体目标是利用人类数据的补充来源， 包括基于人群的研究、临床队列和“活体生物库”，以研究从 从健康个体到晚期癌症患者，以及从单细胞到大量细胞的分辨率 获得关于如何制定干预措施来预防癌症的更完整、多方面的观点。我们的计划 促进群体研究中的机制发现，从而快速测试新颖的、受分子启发的 临床队列中的生物标志物，为“活体生物库”创造了严格验证和先进的机会 机制调查。而且，这个模型是互惠的。我们的临床队列和转化工具使用 源自患者的实验系统还可以识别可以在内部进行检查的新机制 我们的人口研究背景，以确认其与癌症的相关性并提高普遍性。通过这个 R35，我将通过扩展我在阿司匹林化学预防方面的工作来开发和扩展这个 PPRP。阿司匹林是 由于 CRC 预防功效已经确立，因此开发该平台的典范代理 它与出血等不良反应相关，因此需要采取量身定制的方法。正如柳叶刀肿瘤学 委员会报告得出结论：“也许最有前途的基于精确的癌症预防方法 在不久的将来，涉及重新利用低剂量阿司匹林的分子选择”和“鉴于阿司匹林的潜力 不良反应（例如出血），调整阿司匹林的使用是重中之重”。通过加深对阿司匹林的了解 作用方式，该提案可能会产生新的机械生物标志物或补充性预防措施 可以最大限度地发挥阿司匹林益处同时最大限度地减少危害的干预措施。从长远来看，我设想 这项工作将为 PPRP 计划的扩展提供概念验证，作为一个具有成本效益的平台 从而将额外的癌症预防干预措施迅速推向临床。