Vascular Endothelial Growth Factor Trap Blocks Tumor Growth, Metastasis Formation, and Vascular Leakage in an Orthotopic Murine Renal Cell Cancer Model

• Published in: Clinical cancer research Vol. 13; no. 14; pp. 4201 - 4208
• Main Authors: VERHEUL, Henk M. W, HAMMERS, Hans, VAN ERP, Karen, YONFENG WEI, SANNI, Tolib, SALUMBIDES, Brenda, QIAN, David Z, YANCOPOULOS, George D, PILI, Roberto
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2007
• Subjects: angiogenesis; Animals; Antineoplastic agents; Biological and medical sciences; Carcinoma, Renal Cell - blood supply; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Disease Models, Animal; Kidney Neoplasms - blood supply; Kidney Neoplasms - pathology; Kidneys; Medical sciences; Mice; Microcirculation - drug effects; Microcirculation - pathology; Neovascularization, Pathologic - prevention & control; Nephrology. Urinary tract diseases; Pericytes - drug effects; Pericytes - pathology; Pharmacology. Drug treatments; Recombinant Fusion Proteins - therapeutic use; renal cell cancer; spontaneous metastasis formation; Tumors of the urinary system; Vascular Endothelial Growth Factor A - antagonists & inhibitors; vascular leakage; Kidney disease; Urinary system disease; Carcinoma; Orthotopic; Rodentia; Tumorigenicity; Metastasis; Malignant tumor; Carcinogenesis; Vertebrata; Mammalia; Vascular endothelium growth factor; Mouse; Tumor growth; Animal; Blood vessel; Kidney cancer; Grawitz tumor; Models; Circulatory system
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-2553

Purpose: Angiogenesis inhibitors have shown clinical benefit in patients with advanced renal cell cancer, but further therapeutic improvement is needed. Vascular endothelial growth factor (VEGF) Trap is a newly developed VEGF-blocking agent with stronger affinity and broader activity than the anti-VEGF antibody bevacizumab. In this study, we tested the activity of VEGF Trap in an orthotopic murine model of renal cancer with spontaneous lung metastases. Experimental Design: Murine syngeneic renal cell carcinoma cells (RENCA) transfected with a luciferase-expressing vector were injected into the renal capsule of BALB/c mice. I.p. treatment with VEGF Trap or control protein (10 or 25 mg/kg twice weekly) was started shortly after tumor injection to prevent tumor development (prevention model) or after established tumors were formed to inhibit tumor growth and metastasis formation (intervention model). Results: In the prevention model, VEGF Trap inhibited tumor growth by 87 ± 14% compared with control ( P = 0.007) and significantly prolonged survival. In the intervention model, VEGF Trap inhibited tumor growth by 74 ± 9% ( P < 0.001) and the formation of lung metastases was inhibited by 98% ( P < 0.004). Microvascular density was reduced by 66% due to VEGF Trap treatment ( P < 0.001). In addition, VEGF Trap prevented fibrinogen leakage into the tumor microenvironment representative for reduced vascular leaking as shown by immunohistochemical staining. Conclusions: VEGF Trap is a potent inhibitor of RENCA tumor growth and metastasis formation and blocks the biological function of VEGF in vivo . These results support further clinical development of VEGF Trap for renal cell cancer and other cancer types.