# Project 2: Targeting STAT3 to Prevent Colorectal Cancer (CRC) in Hereditary Syndromes and Inflammatory Bowel Disease

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $490,198

## Abstract

PROJECT 2: Summary/Abstract
Despite a variety of screening approaches, an estimated 135,000 persons will be diagnosed with colorectal
cancer (CRC) in 2017, and about 50,000 will die from it. Evidence is increasing that signal transducer and
activator of transcription (STAT) 3 contributes to patients at increased risk for CRC, such as those with
inflammatory bowel disease (IBD) and patients with hereditary syndromes, such as familial adenomatous
polyposis (FAP) and Lynch syndrome (LS). The importance of STAT3's contribution to CRC in these settings
and the effects of targeting STAT3 on CRC development and disease progression are the significant gaps in
knowledge for this project. We and others have demonstrated that colitis in mice induced by either dextran
sodium salt [DSS; ulcerative colitis (UC) model] or trinitrobenzoic acid [TNBS; Crohn's disease (CD) model] is
more severe and progresses more rapidly to CRC in transgenic mice expressing only STAT3α, the pro-
inflammatory and anti-apoptotic isoform of STAT3, compared to wild type mice. In collaboration with our
pharmaceutical partner (StemMed, Ltd.), we developed a small-molecule, C188-9, that potently inhibits STAT3
activation [phosphorylation on tyrosine (Y) 707, pY-STAT3], which prevented IBD caused by both DSS and
TNBS in mice. Others have shown that mice deficient in Stat3 in their intestinal epithelial cells have reduced
tumor size and reduced tumor incidence in a model of colitis-associated CRC [azoxymethane (AOM) plus DSS].
Also, genetically reducing levels of STAT3 in the ApcMin/+ mouse (ApcMin/+Stat3+/−) reduced the number of
intestinal polyps compared to ApcMin/+Stat3+/+ mice while STAT3 activation resulted in extra-nuclear sequestration
of hMSH3, which may further impair dMMR in enterocytes from LS patients thereby resulting in increased risk of
CRC. The long-term goal of this project is to determine if C188-9 will be of benefit in the prevention and/or
treatment of CRC. The central hypotheses are that STAT3 contributes to CRC development in patients at risk
for CRC and can be targeted successfully with C188-9. The objectives are to determine the effects of targeting
STAT3 using C188-9 to prevent CRC in mouse models of IBD, FAP, and LS and to determine the contribution
of STAT3 signaling to CRC development in corresponding patient subsets. We have formulated 3 tightly focused
Specific Aims to examine these hypotheses and to achieve these objectives. In Aim 1, we will determine the
ability of C188-9 to prevent CRC in mouse models of IBD and hereditary CRC. In Aim 2, we will audit the
contribution of STAT3 signaling to CRC development in FAP, LS and IBD patients, including in viable patient-
derived colonic organoids. Lastly, in Aim 3, we will determine the effect on pY-STAT3 and safety of chronic
exposure to C188-9 as chemopreventive agent in high-risk colorectal cancer patients diagnosed with IBD, LS
and FAP treated in the context of a Phase Ib chemopreventive clinical trial. The r...

## Key facts

- **NIH application ID:** 9999486
- **Project number:** 5P50CA221707-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** David John Tweardy
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,198
- **Award type:** 5
- **Project period:** 2019-08-20 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999486

## Citation

> US National Institutes of Health, RePORTER application 9999486, Project 2: Targeting STAT3 to Prevent Colorectal Cancer (CRC) in Hereditary Syndromes and Inflammatory Bowel Disease (5P50CA221707-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999486. Licensed CC0.

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