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

Abstract

Purpose: Esophageal cancer (EC) carries a poor prognosis with 5-year overall survival of less than 20%. Barrett’s esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). 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 BE. Experimental Design: c-MET expression in human esophageal tissue was investigated using Gene Expression Omnibus (GEO) datasets, tissue microarrays and BE 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 (FME) 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 BE and EAC compared to normal epithelium. There was strong accumulation of EMI-137 in OE33 xenografts 3 h post injection decreasing by more than 50% on co-injection of a 10-fold molar excess of unlabeled EMI-137. The target-to background ratio (TBR) at 3 h p.i. for OE33 and FLO-1 tumors was 10.08 and 1.42, respectively. FME of L2-IL1β mice showed uptake of EMI-137 in dysplastic lesions within BE with a TBR of 1.9 in vivo, and greater than 2 in ex vivo fluorescence imaging. Conclusions: EMI-137 accumulates in dysplastic lesions within BE and in c-MET positive EAC. EMI-137 imaging has potential as a screening and surveillance tool for patients with BE and as a means to detecting dysplasia and EAC.