Abstract
The incidence of esophageal adenocarcinoma (EAC) is rising rapidly, and early detection within the precursor state of Barrett's esophagus (BE) is challenged by flat premalignant lesions that are difficult detect with conventional endoscopic surveillance. Overexpression of cell surface fibroblast growth factor receptor 2 (FGFR2) is an early event in progression of BE to EAC, and is a promising imaging target. We used phage display to identify the peptide SRRPASFRTARE that binds specifically to the extracellular domain of FGFR2. We labeled this peptide with a near-infrared fluorophore Cy5.5, and validated the specific binding to FGFR2 overexpressed in cells in vitro. We found high affinity kd = 68 nM and rapid binding k = 0.16 min−1 (6.2 min). In human esophageal specimens, we found significantly greater peptide binding to high-grade dysplasia (HGD) versus either BE or normal squamous epithelium, and good correlation with anti-FGFR2 antibody. We also observed significantly greater peptide binding to excised specimens of esophageal squamous cell carcinoma and gastric cancer compared to normal mucosa. These results demonstrate potential for this FGFR2 peptide to be used as a clinical imaging agent to guide tissue biopsy and improve methods for early detection of EAC and potentially other epithelial-derived cancers.
Highlights
There are over 450,000 new cases of esophageal cancer diagnosed worldwide each year, resulting in more than 400,000 deaths annually [1]
We found significantly greater peptide binding to high-grade dysplasia (HGD) versus either Barrett’s esophagus (BE) or normal squamous epithelium, and good correlation with anti-fibroblast growth factor receptor 2 (FGFR2) antibody
We performed immunohistochemistry (IHC) on specimens of human esophagus, including squamous (SQ), Barrett’s esophagus (BE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinoma (EAC), that were classified by an expert gastrointestinal pathologist (HDA) to demonstrate representative levels of FGFR2 expression, Supplementary Figure 1
Summary
There are over 450,000 new cases of esophageal cancer diagnosed worldwide each year, resulting in more than 400,000 deaths annually [1]. Esophageal adenocarcinoma (EAC) represents the majority of cases in the U.S, where the incidence and mortality continue to rise rapidly [2]. This trend is attributed to increasing obesity and chronic gastroesophageal reflux disease (GERD) [3]. Therapy includes endoscopic mucosal resection (EMR), radio-frequency ablation (RFA), and surgery for improved patient outcomes [6]. Molecular changes associated with gene alterations precede histopathological abnormalities, and may be developed for imaging as an adjunct to endoscopy for early cancer detection [8]
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