Vascular Endothelial Growth Factor-Trap Suppresses Tumorigenicity of Multiple Pancreatic Cancer Cell Lines

Abstract

Purpose: Vascular endothelial growth factor A (VEGF-A) is a potent angiogenic agent that binds to two high affinity VEGF receptors (VEGFRs), a process facilitated by the low affinity neuropilin receptors. Although VEGF-A is overexpressed in pancreatic ductal adenocarcinoma, it is not known whether the in vivo growth of multiple pancreatic cancer cells can be efficiently blocked by VEGF-A sequestration.Experimental Design: Four human pancreatic cancer cell lines were grown s.c. in athymic nude mice. One cell line also was used to generate an orthotopic model of metastatic pancreatic cancer. The consequences of VEGF-A sequestration on tumor growth and metastasis were examined by injecting the mice with a soluble VEGFR chimer (VEGFTrap) that binds VEGF-A with high affinity.Results: VEGF-Trap, initiated 2 days after tumor cell inoculation, suppressed the s.c. growth of four pancreatic cancer cell lines and markedly decreased tumor microvessel density. Analysis of RNA from tumors generated with T3M4 cells revealed that VEGF-Trap decreased the expression of VEGFR-1 and neuropilin-1 and -2. VEGF-Trap, initiated 3 weeks after tumor implantation, also attenuated intrapancreatic tumor growth and metastasis in an orthotopic model using PANC-1 cells.Conclusions: VEGF-Trap is a potent suppressor of pancreatic tumor growth and metastasis and also may act to attenuate neuropilin-1 and -2 and VEGFR-1 expression. Therefore, VEGF-Trap may represent an exceedingly useful therapeutic modality for pancreatic ductal adenocarcinoma.

Angiogenesis: An update and potential drug approaches (Review)

“…This decoy not only binds to VEGF-A but also to PlGF and VEGF-B. In vivo studies using mice xenograft models treated with VEGF-trap have shown promising results (36). In addition, a phase I clinical dose escalation study showed acceptable tolerability (37); however, the efficacy of VEGF-trap in cancer treatment needs to be proven (38).…”

Functional evaluation of novel soluble insulin-like growth factor (IGF)-II–specific ligand traps based on modified domain 11 of the human IGF2 receptor

“…Soluble transforming growth factor-h receptor type II has been developed and shown to have a negative regulatory role in transforming growth factor-h -mediated tumor growth (53,66). The soluble vascular endothelial growth factor (VEGF)-Trap based on soluble forms of the VEGF receptor is a potent inhibitor of tumor growth, including established tumors, and is currently undergoing clinical trials (67,68). Importantly, the engineered version of the VEGF-Trap exploits homodimerization to enhance inhibitory function and affinity using Fc of human IgG1.…”

The VEGF family in cancer and antibody-based strategies for their inhibition

“…This fusion protein had improved pharmacokinetics and affinity for VEGF (approximately 1 pM) as compared to the parental mFlt(1-3)-IgG, and effectively inhibited tumor growth and angiogenesis in xenograft models. 117 Pre-clinical trials demonstrated the efficacy of VEGF-Trap in suppressing tumor growth and angiogenesis through its ability to bind both mouse and human VEGF, [118][119][120] and supported its entry into clinical trials were it is being currently evaluated in a number of cancers and in age-related macular degeneration.…”