Antiangiogenic gene therapy of cancer: recent developments

Abstract

With the role of angiogenesis in tumor growth and progression firmly established, considerable effort has been directed to antiangiogenic therapy as a new modality to treat human cancers. Antiangiogenic agents have recently received much widespread attention but strategies for their optimal use are still being developed. Gene therapy represents an attractive alternative to recombinant protein administration for several reasons. This review evaluates the potential advantages of gene transfer for antiangiogenic cancer therapy and describes preclinical gene transfer work with endogenous angiogenesis inhibitors demonstrating the feasibility of effectively suppressing and even eradicating tumors in animal models. Additionally, we describe the advantages and disadvantages of currently available gene transfer vectors and update novel developments in this field. In conclusion, gene therapy holds great promise in advancing antiangiogenesis as an effective cancer therapy and will undoubtedly be evaluated in human clinical trials in the near future.

Figure 1

Antiangiogenic Inhibitors. The flowchart depicts the two major groups of antiangiogenic inhibitors, direct and indirect. It highlights the major differences between the groups and shows some representative examples in each category.

Figure 2

Antiangiogenic Gene Therapy: Recent Developments. The figure depicts different modes of gene therapy directed to tumor endothelial cell (EC) and its microenvironment. The expression of EC specific cell surface molecules like, vascular endothelial growth factor receptor (VEGFR), E selectin or angiogenic growth factors (VEGF, FGF, PDGF) produced by tumor cells can be inhibited by specific antibodies or antisense RNA or using gene specific SiRNA. The targeted gene therapy can be achieved by using either viral vectors or nanoparticles carrying ligand (RGD) to endothelial cell surface specific receptors (αvβ5, αvβ3) to target antiangiogenic genes to tumor vasculature. The inhibitors can also selectively express in EC using endothelial cell specific promoters like endothelin 1 (EDT1). Ad: adenovirus; AAV: adeno-associated virus; Retro: retrovirus; VEGF: vascular endothelial growth factor; FGF: fibroblast growth factor; PDGF: platelet derived growth factor; TNF: tumor necrosis factor; RGD: Arginine-glycine-aspartic acid; SiRNA: small interfering RNA