Blocking the interaction of vascular endothelial growth factor receptors with their ligands and their effector signaling as a novel therapeutic target for cancer: time for a new look?

Introduction: The interaction between the VEGFRs and their ligands plays an important role in tumor angiogenesis. Despite a series of problems encountered during early work on blocking growth factors, current evidence injects further vigor into researching the modulation of VEGFR activity. Emerging preclinical and clinical studies suggest that attenuating receptor activity can synergistically promote antitumor action if utilized concurrently with conventional therapies.

Areas Covered: This review presents an up-to-date assessment of the potential role of modulating receptor activities in various cancers. The sentinel work on the proof of principles in various animal models, and the current translational research on these small molecule inhibitors and receptor blocking antibodies, from Phase I to Phase III trials, has been systematically examined with an emphasis on agents in earlier stages of development.

Expert Opinion: Many clinical trials are ongoing, but early phase trials show promising results. Recently, there has been a huge explosion of research activity either in the development of new drugs or in the understanding its biology. Many current trials lend support to the rationale behind these therapies, which can function as adjuvants to conventional treatments. It has been argued that normalization of tumor-induced vasculature can promote better drug delivery and prevent resistance to radiotherapy. However, strategies involving the inhibition of the interaction of VEGFRs with ligands and their downstream pathways are not, in general, at a stage where it will be directly useful in clinical cancer treatment. A deeper understanding of these biologic therapies will help to improve the efficacy of conventional treatments and furthermore reduce dose-dependent cytotoxic activity.