Role of VEGF, PDGF and FGF in glioblastoma progression as determined by soluble decoy receptor expression in preclinical models

Proc Amer Assoc Cancer Res, Volume 46, 2005 3030 A number of anti-angiogenic therapies that are currently in clinical development target the vascular endothelial growth factor (VEGF) family of ligands and receptors. The VEGF family has a demonstrated role in a wide range of malignancies, particularly highly vascularized tumors such as glioblastoma (GBM), although recent research has indicated that additional growth factor pathways may also be involved. Of these factors, members of the fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) family have been implicated. Inhibition of these additional pathways, either alone or in addition to VEGF, may result in potent anti-cancer responses that may lead to tumor dormancy or regression in cancer types that are unresponsive to VEGF treatment alone. We wished to examine the relative contribution of the VEGF, PDGF and FGF growth factors in glioblastoma angiogenesis and growth using soluble decoy receptors to specifically inhibit these individual growth factor pathways for therapeutic development. Soluble decoy receptors were constructed from VEGF receptor 1 and 2 (VEGFR1 and R2), PDGF receptor α and β (PDGFRα and β) and FGF receptor 1 and 2 (FGFR1 and R2) by fusion of the extracellular Ig-like domains of the receptor to an Fc segment of human IgG1. Ligand binding affinity and in vivo bioavailability was examined on multiple variants of each growth factor receptor to determine an optimal soluble inhibitor for the VEGF, PDGF and FGF pathways. Recombinant adeno-associated virus (rAAV) gene delivery was then employed to express the optimized receptors systemically in mice. Following a single intravenous or intramusclar injection of rAAV, the soluble receptors were expressed long-term (>3 months) and at a high-level (200-2000 μg/ml depending on receptor), providing sustained inhibition of their respective growth factor signaling pathways. Preclinical efficacy was examined for each soluble receptor in the subcutaneous C6 rat glioma, 4C8 murine glioma and the human U-87 and U-251 MG glioblastoma models, allowing the relative impact of VEGF, PDGF and FGF inhibition to be assessed side-by-side. Inhibition of VEGF provided therapeutic efficacy irrespective of the glioma model examined, however, the anti-tumor efficacy of PDGF and FGF inhibition was model-dependent. Following examination of anti-tumor efficacy as a monotherapy, growth factor inhibitors were combined to examine potential synergy by targeting multiple pathways in GBM models. The development of these optimized soluble decoy receptors allows the effect of specific inhibition of growth factor pathways to be individually investigated in tumor progression and may aid in the identification of signaling pathways to inhibit in combination for the next generation of angiogenic inhibitors.