(75) Notching down EGF receptor (EGFR) signaling: a new therapeutic approach to Ménétrier's disease

     Ménétrier’s disease (MD) is a rare premalignant hypertrophic gastropathy. Individuals present with refractory nausea and vomiting, decreased acid secretion, increased mucous secretion, and hypoalbuminemia.... [ view full abstract ]

     Ménétrier’s disease (MD) is a rare premalignant hypertrophic gastropathy. Individuals present with refractory nausea and vomiting, decreased acid secretion, increased mucous secretion, and hypoalbuminemia. Histological features include foveolar hyperplasia, glandular tortuosity and oxyntic atrophy with parietal cell loss in the involved gastric mucosa. Excess EGFR signaling contributes to MD pathogenesis: there are increased levels of EGFR and its ligand, TGF-a, in the involved gastric mucosa of MD patients and transgenic mice that overexpress TGF-a in the stomach phenocopy the disorder. The Coffey lab recently showed that cetuximab, an EGFR neutralizing monoclonal antibody (mAb), is the first effective medical therapy for MD; however, most individuals eventually required gastrectomy, suggesting more effective therapies are needed. We recently observed that the Notch ligand, Jagged1, is rapidly decreased in gastric mucosa of MD patients treated with cetuximab. Preliminary data in MT-TGF-a transgenic mice shows that HES1 staining, a Notch activity marker, is noticeably upregulated in the gastric mucosa, leading us to hypothesize that Notch signaling is increased in MD and that blocking Notch activity may be a novel treatment strategy. For further examination, we propose to block Notch signaling with the g-secretase inhibitor, DBZ, with and without EGFR mAb, in MT-TGF-a transgenic mice. These studies will be greatly enhanced by use of a novel Egfr reporter mouse we developed and use of the first EGFR mAb that blocks mouse Egfr. We predict these studies will show how dual inhibition of EGFR and Notch provide enhanced treatment efficacy, and this approach can be advanced clinically.