# Integrated approach to study early and late events in colonic neoplasia: mouse to man

> **NIH NIH R35** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $869,666

## Abstract

The EGFR contributes to the pathogenesis of many human cancers, including colorectal cancer (CRC), which
is the third most commonly diagnosed cancer and the third leading cause of cancer deaths in the US for both
men and women. The EGFR has become a major therapeutic target in many cancers. The EGFR neutralizing
monoclonal antibody, cetuximab, is approved for the treatment of advanced CRCs that contain wild-type
KRAS; however, only 15% of individuals with wild-type KRAS CRC respond to cetuximab, and individuals with
mutant KRAS CRC do not respond to cetuximab. The challenge in cancer research I propose to address is:
why has EGFR blockade in CRC (and other solid tumors) had such modest clinical benefit. I propose that the
inability to more effectively block the EGFR in CRC is due, at least in part, to three issues: 1) an incomplete
understanding of the complexity of EGFR signaling triggered by its seven mammalian ligands; 2) inadequate
predictive preclinical models and 3) the emergence of drug resistance. By addressing each of these three
issues, the overall goal of this revised application is to significantly advance the diagnosis, treatment and
monitoring of individuals with CRC. Our focus is CRC, viewed from the perspective of membrane-proximal
EGFR-related events. We anticipate that advances we make will be applicable to other solid tumors in which
EGFR signaling plays a prominent role. Based on our recent finding that the Egfr inhibitor, Lrig1, marks a
distinct population of colonic stem cells and acts as a tumor suppressor, along with the use of unique reporter
mice (Lrig1-Apple, Egfr-EmGFP), we propose to link key events in colonic neoplasia to stem cells and Egfr-
related events. Our lab has developed a robust model of colonic neoplasia: within 50 days of inducing loss of
one Apc allele in Lrig1-expressing colonic stem cells, multiple, highly dysplastic colonic adenomas arise that
can be monitored by colonoscopy and novel PET imaging probes. These mice will be treated with the first
available mouse Egfr neutralizing antibody. Findings in mouse adenomas will be related to human adenomas.
Using MulltiOmyx and DISSECT, we will examine the tumor landscape at single cell resolution and deconstruct
tumor heterogeneity. Using a newly developed 3D culture system, we have discovered a novel mode of
cetuximab resistance via increased WNT signaling due to marked upregulation of a long con-coding RNA not
previously linked to CRC. We will further elucidate the mechanism of this resistance and advance these
findings clinically. We will further examine a new mode of signaling by EGFR and its ligands via exosomes and
test whether EGFR-containing exosomes act as a decoy to reduce the amount of EGFR antibody delivered to
tumors. We will harness the tools and resources at Vanderbilt University, Vanderbilt-Ingram Cancer Center and
Vanderbilt's GI Specialized Programs of Research Excellence (SPORE) to advance this work.

## Key facts

- **NIH application ID:** 10376282
- **Project number:** 5R35CA197570-06
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Robert J. Coffey
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $869,666
- **Award type:** 5
- **Project period:** 2017-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376282

## Citation

> US National Institutes of Health, RePORTER application 10376282, Integrated approach to study early and late events in colonic neoplasia: mouse to man (5R35CA197570-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10376282. Licensed CC0.

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