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.

Figure 1

Tumor vascular normalization. (a) Antiangiogenic regimens are aimed to kill most of the vessels and starve the tumor (last column); by contrast, dosing and scheduling of the antiangiogenesis agents might be planned to transiently ’normalize’ the vasculature, making it more efficient for drug and oxygen delivery. (b) Dynamics of vascular normalization induced by VEGF-receptor-2 blockade. On the left is a two-photon image showing normal blood vessels in skeletal muscle; subsequent images show human colon carcinoma vasculature in mice at day 0, day 3 and day 5 after administration of VEGF-receptor-2-specific antibody. (c) Diagram depicting the concomitant changes in pericyte (red) and basement membrane (blue) coverage during vascular normalization. (d) These phenotypic changes in the vasculature might reflect changes in the balance of proangiogenic and antiangiogenic factors in the tissue. Reproduced, with permission, from [9].

Figure 2

Rectal tumor response to VEGF blockade evaluated by immunohistochemistry in serial biopsies. Tumor microvascular density was determined by counting CD31-positive vessels in areas of frank carcinoma. The fraction of proliferating (left plot) and apoptotic (right plot) tumor cell was determined in sections stained for proliferation cell-nuclear antigen (PCNA) and TUNEL, respectively. Note that despite significant reduction in microvascular density, there was an increase in tumor cell apoptosis, and cell proliferation tended to increase 12 days after treatment (Tx) with bevacizumab [45,46].