Molecular Targeted Imaging in Colon Cancer

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DESCRIPTION (provided by applicant): There is an unmet need in a diagnostic procedure for colorectal cancer that relies on imaging of an early, specific, and well-understood molecular biomarker. We hypothesized that abnormally expressed receptors for vascular endothelial growth factor (VEGFR) are particularly attractive biomarkers for molecular imaging of colorectal cancerous lesions. This hypothesis is based on well-documented enhanced expression of VEGFR that begins very early in colorectal cancer progression and is associated with angiogenesis. We have recently described the first internalizable tracer for fluorescent VEGFR imaging, scVEGF/Cy, which is a genetically engineered single-chain VEGF, site- specifically labeled with near-infrared fluorescent dye, Cy5.5. We found that endothelial cells in tumor and activated host vasculature bind and internalize scVEGF/Cy via VEGFR-mediated endocytosis, leading to selective and persistent accumulation of Cy5.5 in tumor area. As a result, Cy5.5-tagged cells can be imaged in whole animals, harvested tumor-bearing organs, and on histological tissue sections. Our preliminary results indicate that scVEGF/Cy selectively and specifically accumulates in endothelial cells in tumor lesions in colon and small intestines of genetically engineered mouse model APC(Delta14/+) of spontaneous colorectal cancer. These finding suggests the feasibility of using scVEGF/Cy for early fluorescent detection of colorectal lesions and lead to focus program for Phase I. In collaboration with Dr. J. Barton (U. Arizona) we propose the following Specific Aims: Specific Aim #1. To optimize detection of colorectal lesions via VEGFR-mediated fluorescent imaging. Specific Aim #2. To establish the feasibility of early detection of colorectal lesions with scVEGF/Cy tracer. Specific Aim #3. To evaluate fluorescent colonoscopy with scVEGF/Cy tracer in Apc(Delta14/+) mouse. Accomplishing these specific aims will validate VEGFR as a molecular biomarker for fluorescent colonoscopy and and establish the feasibility of clinical development of scVEGF/Cy in Phase II. We propose to test a feasibility of using targeted molecular imaging with fluorescent tracer for early detection of colorectal cancer. The tracer will be targeted to VEGF receptors, whose enhanced expression in tumor vasculature and ability to internalize the tracer make them very attractive for diagnostic imaging. In Phase I of the project we will combine a novel targeted fluorescent tracer developed by Principal Investigator at SibTech, Inc., and a novel probe for fluorescent endoscopy developed by our collaborator at The Arizona University, and test them for detection of early cancerous lesions in a novel genetically engineered mouse model of spontaneous colorectal tumor. The success of Phase I of this project will lead to clinical development of a new imaging tracer for early diagnostic of prostate cancer in Phase II of this project.