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生和研究员，我将我的职业生涯献给了预防 结直肠癌(CRC)我最大的贡献影响了证据基础支持 阿司匹林降低结直肠癌风险的有效性及其抗肿瘤的关键分子机制 癌症活动。这项工作帮助该领域成为首个具有里程碑意义的建议 美国预防服务工作组对阿司匹林用于癌症预防的人群使用情况。然而，不断增长的 数据表明，阿司匹林的作用可能因宿主因素而异，包括肠道微生物组。 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，发展中 通过分子风险分层进行预防的新方法是一个高度优先事项。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 是开发一个全面的精密预防研究计划(PPRP)，通过这个NCI杰出的 调查员奖。这项PPRP的首要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“活生物库”，以研究整个连续体。 从健康个体到晚期癌症患者，以及从单个细胞到大量人群的分辨率 对如何为预防癌症量身定做干预措施，获得更全面、更多方面的看法。我们的PPRP 促进种群研究中的机械性发现，这可能导致快速测试新颖的、受分子启发的 临床队列中的生物标记物，为“活的生物库”创造严格验证和先进的机会 机械调查。此外，这种模式是互惠的。我们的临床队列和翻译工具使用 患者衍生的实验系统也可以识别新的机制，可以在 在我们人口研究的背景下，以确认它们与癌症的相关性，并提高普适性。通过这件事 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 开发这一平台的示范代理，因为已经建立了CRC预防的有效性，并且 它与出血等不良反应的关联，需要一种量身定制的方法。作为柳叶刀肿瘤学 委员会的报告总结道：“也许在#年最有希望的基于精确的癌症预防方法。 鉴于阿司匹林的潜力，不久的将来将涉及到对改变用途的小剂量阿司匹林的分子选择 考虑到阿司匹林的不良反应(如出血)，调整阿司匹林的使用是一个高度优先事项“。通过加强对阿司匹林的了解 作用方式，这一建议可能导致新的机械性生物标记物或补充预防 干预措施可以最大化阿司匹林的益处，同时将危害降至最低。从长远来看，我设想 这项工作将为将PPRP方案扩展为具有成本效益的平台提供概念验证 这将使更多的癌症预防干预措施迅速进入临床。