NIH grant: PREVENT-IN-TIME: PREVENTion of colorectal cancer with INcreTIn MimEtics (1R37CA307532-01)

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NIH grant 1R37CA307532-01: PREVENT-IN-TIME: PREVENTion of colorectal cancer with INcreTIn MimEtics
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: David A Drew. Award: $673951.
Start: 2026-07-01T00:00:00.
PROJECT SUMMARY / ABSTRACT
Obesity is an established risk factor for colorectal cancer (CRC). Although underlying pathways linking obesity
to CRC remain to be fully clarified, established treatments such as bariatric surgery appear to reduce CRC risk.
A class of agents collectively known as incretin mimetics (IM), including semaglutide, a GLP-1 receptor agonist
(GLP1RA), and tirzepatide, a dual GIP/GLP1RA, have revolutionized treatment of obesity and diabetes,
becoming widely utilized owing to their effectiveness in reducing body weight and improving glycemic control.
Recent epidemiologic data have consistently shown an association of IM with reduced risk of CRC, a finding
that has been supported by experimental studies showing that IM inhibits CRC cell growth and oncogenic
signaling while suppressing pro-tumorigenic inflammation and promoting anti-tumor immunity. These agents
also influence the composition and function of the gut microbiome, which has been convincingly linked to CRC
and obesity. Taken together, there is a compelling rationale for novel, proof-of-principle studies examining the
association of IM with molecular pathways underlying CRC among individuals at high risk for CRC to establish
causal evidence supporting IM and risk of CRC and elucidate potential underlying anti-cancer mechanisms
beyond weight loss. Our overarching goal is to establish the PREVENTion of colorectal cancer with INcreTIn
MimEtics (PREVENT-IN-TIME) cohort within our established Precision Prevention Program that will enroll IM-
naïve patients with obesity/overweight after adenoma resection who are due to commence GLP1RA or dual
GIP/GLP1RA therapy for weight management to longitudinal biospecimen collection protocol at serial
timepoints over 6 months of IM therapy. We will conduct deep ‘omic profiling of these biospecimens to
determine the impact of IM on established biomarkers of CRC risk, including urinary prostaglandin metabolites
and circulating metabolic markers (Aim 1), as well as on the gut microbiome and metabolome (Aim 2). In
parallel, we will conduct co-clinical trials of IM within novel genetically engineered mouse models of CRC and
patient-derived organoid translational models to further determine causality and intensively dissect anti-
tumorigenic mechanisms (Aim 3). We anticipate that this work may lead to expanded use of IM for cancer
prevention among individuals who may not otherwise have established indications for their use (e.g. weight
management or diabetes). Moreover, our findings will provide critical insights into potential anti-cancer
mechanisms for these agents and inform the development of molecular biomarkers that can inform future
clinical trials and novel targets for cancer prevention. Our findings may also critically inform the use of IM in
prevention in other obesity-associated malignancies.

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