Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model

Henk M.W. Verheul, Hans Hammers, Karen Van Erp, Yonfeng Wei, Tolib Sanni, Brenda Salumbides, David Z. Qian, George D. Yancopoulos, Roberto Pili

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4201-4208
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number14
DOIs
StatePublished - Jul 15 2007

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Renal Cell Carcinoma
Vascular Endothelial Growth Factor A
Blood Vessels
Neoplasm Metastasis
Growth
Neoplasms
Lung
Angiogenesis Inhibitors
Tumor Microenvironment
Kidney Neoplasms
Luciferases
Fibrinogen
Capsules
Research Design
Therapeutics
Staining and Labeling
Kidney
Injections

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. / Verheul, Henk M.W.; Hammers, Hans; Van Erp, Karen; Wei, Yonfeng; Sanni, Tolib; Salumbides, Brenda; Qian, David Z.; Yancopoulos, George D.; Pili, Roberto.

In: Clinical Cancer Research, Vol. 13, No. 14, 15.07.2007, p. 4201-4208.

Research output: Contribution to journalArticle

Verheul, Henk M.W. ; Hammers, Hans ; Van Erp, Karen ; Wei, Yonfeng ; Sanni, Tolib ; Salumbides, Brenda ; Qian, David Z. ; Yancopoulos, George D. ; Pili, Roberto. / Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 14. pp. 4201-4208.
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AU - Hammers, Hans

AU - Van Erp, Karen

AU - Wei, Yonfeng

AU - Sanni, Tolib

AU - Salumbides, Brenda

AU - Qian, David Z.

AU - Yancopoulos, George D.

AU - Pili, Roberto

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N2 - 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.

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