Targeting c-MET for Endoscopic Detection of Dysplastic Lesions within Barrett's Esophagus Using EMI-137 Fluorescence Imaging

PURPOSE: Esophageal cancer carries a poor prognosis with a 5-year overall survival of less than 20%. Barrett's esophagus increases the risk of esophageal adenocarcinoma. The aim of this study was to investigate the ability of EMI-137, a mesenchymal-epithelial transition factor (c-MET)-targeting optical imaging tracer, to detect dysplasia in Barrett's esophagus. EXPERIMENTAL DESIGN: c-MET expression in human esophageal tissue was investigated using Gene Expression Omnibus datasets, tissue microarrays, and Barrett's esophagus biopsies. EMI-137 was tested in a dual xenograft mouse model bearing OE33 (c-MET high expression) and FLO-1 (c-MET low expression) tumors. Fluorescence molecular endoscopy was performed in a mouse model of Barrett's-like metaplasia and dysplasia (L2-IL1β). Tumors and organs of interest were evaluated through ex vivo fluorescence imaging. RESULTS: MET mRNA expression analyses and c-MET immunostaining confirmed upregulation of c-MET in Barrett's esophagus and esophageal adenocarcinoma compared with normal epithelium. There was strong accumulation of EMI-137 in OE33 xenografts 3 hours after injection, decreasing by more than 50% on coinjection of a 10-fold molar excess of unlabeled EMI-137. The target-to-background ratio at 3 hours after injection for OE33 and FLO-1 tumors was 10.08 and 1.42, respectively. Fluorescence molecular endoscopy of L2-IL1β mice showed uptake of EMI-137 in dysplastic lesions within Barrett's esophagus with a target-to-background ratio of 1.9 in vivo and greater than 2 in ex vivo fluorescence imaging. CONCLUSIONS: EMI-137 accumulates in dysplastic lesions within Barrett's esophagus and also in c-MET-positive esophageal adenocarcinoma. EMI-137 imaging has potential as a screening and surveillance tool for patients with Barrett's esophagus and as a means to detecting dysplasia and esophageal adenocarcinoma.