VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

Abstract

Despite setbacks, the clinical development of antiangiogenic agents has accelerated remarkably over the past 3-4 years. Consequently, there are currently three direct inhibitors of the VEGF pathway approved for use in cancer therapy. Other agents that block the VEGF pathway are in advanced stages of clinical development and have shown promising results. With these exciting developments come crucial questions regarding the use of these new molecular-targeted agents, alone or in combination with standard cytotoxic or targeted agents. Importantly, the mechanisms of action of anti-VEGF therapy remain unknown. Here, we discuss several potential mechanisms of action such as tumor vascular normalization, bone marrow-derived cell recruitment blockade and cytostatic effects of anti-VEGF therapy. We review the current progress, the major stumbling blocks and the future directions for anti-cancer therapy using anti-VEGF agents, emphasizing clarification of the underlying molecular mechanisms of action and biomarker identification and validation.

FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1α and HIF1β

“…The discovery of VEGF as the key regulator of tumor angiogenesis has enabled the specific and successful repression of angiogenesis in experimental and clinical studies (33)(34)(35)(36)(37). Different agents including antibodies, aptamers, peptides, and small molecules have been shown to inhibit VEGF and its proangiogenic functions.…”

A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo

“…A system in which the investigator is able to reduce Tks5 expression after a tumor has reached a certain size may clarify how podosome formation in cancer cells may determine tumor angiogenesis. One of the major growth factors that regulate tumor angiogenesis is the vascular endothelial growth factor (VEGF) (Duda et al, 2007). Perhaps Tks5, and by implication perhaps podosomes, contribute to the release of VEGF in the microenvironment, thereby promoting angiogenesis to a greater extent in the control tumors compared to the Tks5 KD.…”

The Complex Role of Angiopoietin-2 in the Angiopoietin-Tie Signaling Pathway

“…This is in contrast to anti-VEGF agents, which provide complete growth inhibition in some of the same preclinical tumor models. Given that blockade of VEGF has proven to be beneficial but not curative in several human cancers (Duda et al 2007), several groups have examined whether Ang2 blockade can potentiate the effects of VEGF inhibitors. Combined treatment with Ang2 and VEGF blockers has been shown to provide better inhibition of tumor growth than the single agents in a number of tumor models, including some that exhibit a very strong response to VEGF blockade (Brown et al 2010;Hashizume et al 2010;Huang et al 2010).…”