Precision Prevention Research Program

项目摘要 作为一名国际公认的医生调查员，我将自己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证据基础， 阿司匹林在降低CRC风险方面的有效性，并揭示了其抗CRC的关键分子机制。 癌症活动。这项工作有助于推动该领域成为首个里程碑式的建议， 美国预防服务工作组使用阿司匹林预防癌症。然而，成长 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。 和年龄，这表明阿司匹林化学预防的“一刀切”方法是有限的。因此，发展 通过分子危险分层进行预防的新方法是一个高度优先事项。基于我的专业知识 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 是通过这个NCI杰出的开发一个全面的精确预防研究计划（PPRP） 调查员奖。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“活生物库”，以研究从 从健康个体到晚期癌症患者，从单细胞到大群体的分辨率， 获得一个更完整的，多方面的观点，如何干预措施可以量身定制，以预防癌症。我们的PPRP 促进了人口研究中的机制发现，可以快速测试新的，分子启发的 生物标志物的临床队列，创造机会“活生物库”的严格验证和先进的 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还可以识别可以在实验室内检查的新机制。 我们的人口研究的背景下，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预防的有效性已经确立，因此是开发该平台的典范， 其与诸如出血等副作用的关联需要量身定制的方法。《柳叶刀肿瘤学》（Lancet Oncology） 委员会的报告得出结论：“也许最有希望的基于精确的癌症预防方法是在2010年。 不久的将来涉及分子选择重新利用低剂量阿司匹林”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一个高度优先事项”。通过提高对阿司匹林的认识 作用模式，该提议可能导致新的机制生物标志物或补充预防性药物。 这些干预措施可以最大限度地发挥阿司匹林的益处，同时最大限度地减少危害。从长远来看，我认为 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， 这将使更多的癌症预防干预措施迅速进入临床。

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.