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


METHODS
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.
Verheul
Henk M W
HM
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Hammers
Hans
H
van Erp
Karen
K
Wei
Yonfeng
Y
Sanni
Tolib
T
Salumbides
Brenda
B
Qian
David Z
DZ
Yancopoulos
George D
GD
Pili
Roberto
R
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007680:Kidney Neoplasms / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D020286:Pericytes / Q000187:drug effects / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A