Precision Prevention Research Program

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.

Grant Number: 5R35CA253185-06
NIH Institute/Center: NIH
Principal Investigator: Andrew Chan