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Targeting Tumor Endothelial Marker 8 in the Tumor Vasculature of Colorectal Carcinomas in Mice

¹ Department of Pharmacology and Therapeutics, College of Medicine, University of Florida and ² Medical Research Service, Department of Veteran Affairs Medical Center, Gainesville, Florida

Requests for reprints: Bradley S. Fletcher, Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, 1600 Southwest Archer Road, Box 100267, Gainesville, FL 32610-0267. Phone: 352-392-8558; Fax: 352-392-9696; E-mail: bsfletch{at}ufl.edu.

Key Words: TEM8 • Sleeping Beauty • Gene Therapy • Tumor Vasculature • Fusion Protein

Tumor endothelial marker 8 (TEM8) is a recently described protein that is preferentially expressed within tumor endothelium. We have developed a fusion protein that targets TEM8 and disrupts tumor vasculature by promoting localized thrombosis. Fusion protein specificity and function were evaluated using Western blot analysis, ELISA, and enzymatic assays. A xenograft model of colorectal carcinoma was used to test the efficacy of targeted and control fusion proteins. Mice treated with the gene encoding anti-TEM8/truncated tissue factor exhibited a 53% reduction in tumor volume when compared with the untreated animals (P < 0.0001; n = 10) and achieved a 49% increase in tumor growth delay by Kaplan-Meier analysis (P = 0.0367; n = 6). Immunohistochemistry confirmed tumor endothelial expression of TEM8, fusion protein homing to tumor vasculature, decrease in vessel density, and localized areas of thrombosis. These data support the hypothesis that targeting TEM8 can be an effective approach to influence tumor development by disrupting tumor vasculature. [Cancer Res 2009;69(12):5126–32]