Molecular-Guided Endoscopy Targeting Vascular Endothelial Growth Factor A for Improved Colorectal Polyp Detection

Small and flat adenomas are known to carry a high miss-rate during standard white-light endoscopy. Increased detection rate may be achieved by molecular-guided endoscopy with targeted near-infrared (NIR) fluorescent tracers. The aim of this study was to validate vascular endothelial growth factor A (VEGF-A) and epidermal growth factor receptor (EGFR) targeted fluorescent tracers during ex vivo colonoscopy with a NIR endoscopy platform. Methods: VEGF-A and EGFR expression was determined by immunohistochemistry on a large subset of human colorectal tissue samples: 48 sessile serrated adenomas/polyps (SSA/P), 70 sporadic high-grade dysplastic (HGD) adenomas, 19 hyperplastic polyps (HP) and tissue derived from patients with Lynch syndrome (LS): 78 low-grade dysplastic (LGD) adenomas, 57 HGD adenomas and 31 colon cancer samples. To perform an ex vivo colonoscopy procedure, 14 mice with small intraperitoneal EGFR-positive HCT116luc tumors received intravenously bevacizumab-800CW (anti-VEGF-A), cetuximab-800CW (anti-EGFR), control tracer IgG-800CW or sodium chloride. Three days later, 8 resected HCT116luc tumors (2-5 mm) were stitched into one freshly resected human colon specimen and followed by an ex vivo molecular-guided colonoscopy procedure. Results: Immunohistochemistry showed high VEGF-A expression in 79-96% and high EGFR expression in 51-69% of the colorectal lesions. Both targets were significantly overexpressed in the colorectal lesions compared to the adjacent normal colon crypts. During ex vivo molecular-guided endoscopy all tumors could clearly be delineated for both bevacizumab-800CW and cetuximab-800CW tracers. Specific tumor uptake was confirmed with fluorescent microscopy showing respectively stromal and cell membrane fluorescence. Conclusion: VEGF-A is a promising target for molecular-guided fluorescence endoscopy as it showed a high protein expression, especially in SSA/P and LS. We demonstrate the feasibility to visualize small tumors real-time during colonoscopy using a NIR fluorescence endoscopy platform, providing the endoscopist a wide-field 'red-flag' technique for adenoma detection. Clinical studies are currently being performed in order to provide in-human evaluation of our approach.

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