# EGF Receptor and Notch Signaling in the Pathogenesis of Menetrier's Disease

> **NIH NIH K08** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $159,706

## Abstract

PROJECT SUMMARY/ABSTRACT
Ménétrier’s disease is an uncommon acquired hypoproteinemic hypertrophic gastropathy. Patients present with
a constellation of progressive signs and symptoms that include severe abdominal pain, unremitting nausea and
vomiting, peripheral edema (due to loss of protein across the gastric mucosa) and achlorhydria (due to loss of
acid-producing parietal cells), along with an increased risk of gastric cancer. Until recently, gastrectomy has
been the only therapeutic option. The lab of my mentor (Bob Coffey) has implicated increased EGFR signaling
in the pathogenesis of Ménétrier’s disease. The EGFR ligand, transforming growth factor-α (TGF-α) is
overexpressed in the gastric mucosa of Ménétrier’s disease patients, and transgenic mice that overexpress TGF-
α in the stomach phenocopy many of the features of Ménétrier’s disease. Moreover, the EGFR neutralizing
antibody, cetuximab, is the first effective medical therapy for this disorder with all seven patients treated in a
clinical trial showed objective improvement. One patient was cured but the other six ultimately required
gastrectomy, thus improved therapies are needed. From my independent work in the Coffey lab, we have
discovered that Notch signaling is upregulated and is downstream of EGFR signaling in Ménétrier’s disease
patients and MT-TGF-α mice. Preliminary data indicates that combined blockade of Notch and EGFR signaling
is more effective in treating MT-TGF-α mice than EGFR blockade alone. To investigate the role of Notch signaling
in Ménétrier’s disease, we will utilize MT-TGF-α mice, a novel endogenous EGFR reporter line, EgfrEmeraldGFP and
the first neutralizing antibodies to mouse EGFR, P1X/P2X. Aim 1 will examine the cause of the rapid loss of
parietal cells in Ménétrier’s disease. Preliminary data suggest that EGFR signaling in chief cells increases the
Jagged1 that acts in a paracrine manner to reduce parietal cell number. Aim 2 will examine the cause of massive
foveolar hyperplasia in Ménétrier’s disease. In Aim 3, we will optimize therapeutics for Ménétrier’s disease by
combining P1X/P2X and a Notch inhibitor, the γ-secretase inhibitor, dibenzazepine (DBZ), in vivo using MT-
TGF-α mice. If we can show the therapeutic efficacy of this combination in gastric organoids derived from
Ménétrier’s disease patients, we will consider advancing to a clinical trial with an optimized regimen.
Receiving this K08 award would provide the protected time, mentorship, training and support required for
achieving my goal to be an independent physician-scientist. This research proposal is well suited for the NIDDK
as it relates to the pathogenesis and treatment of a digestive disorder. Vanderbilt provides the basic and clinical
resources needed to carry out the aims of this proposal. My mentor and co-mentor have expertise in this area
and have a proven track record of successful mentoring, and I have assembled an advisory committee with
complementary expertise. I also have delinea...

## Key facts

- **NIH application ID:** 9952986
- **Project number:** 1K08DK124686-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Won Jae Huh
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $159,706
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952986

## Citation

> US National Institutes of Health, RePORTER application 9952986, EGF Receptor and Notch Signaling in the Pathogenesis of Menetrier's Disease (1K08DK124686-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952986. Licensed CC0.

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