Building a better Trap.

A wide variety of antiangiogenic agents are now being tested in late-stage cancer patients as stand-alone agents or in combination with standard therapy (1). Although there have been mixed reviews so far, a success story appears to be emerging (2). In a recently concluded Phase III clinical trial involving patients with advanced colon cancer, Avastin [antivascular endothelial growth factor (VEGF)], in combination with chemotherapy, showed remarkable antitumor activity. These exciting clinical data breathe new life into the angiogenesis field and provide hope that Avastin and other agents now under clinical evaluation will ultimately become components of standard therapy for cancer and perhaps other diseases associated with angiogenesis. In a recent issue of PNAS, Huang et al. (3) describe a new and perhaps more effective approach to block tumor-associated VEGF. By using a high-affinity anti-VEGF therapy, VEGF-Trap (4), the investigators report the regression of large preexisting primary and metastatic tumor xenographs. By using a better or higher-affinity VEGF inhibitor, the investigators claim that VEGF levels are removed to such a degree that even preexisting tumor vessels can be destroyed. Thus, it is concluded that potent blockade of VEGF may provide a new therapeutic option for patients with bulky metastatic cancers. To grow and metastasize, tumors must stimulate the development of new vasculature through a process known as angiogenesis (5). Angiogenesis is a dynamic progression that begins with endothelial sprouting from a preexisting blood vessel and ends with the establishment of a mature vascular plexus (6). Much of the maturation of the vascular plexus occurs when mural cells such as pericytes and vascular smooth muscle cells migrate to newly formed loops of endothelial cells, sheath them, stabilize them, and thereby form arterioles, capillaries, and veins (7). This process occurs normally whenever there is a significant increase in tissue mass such as in development, growth of the corpus luteum, or accumulation of adipose tissue. However, during tumor growth, blood vessels frequently remain in a dynamically remodeling, chaotic, irregular, and leaky state with abnormal infiltration by mural cells long after endothelial loops are established (8). The distinctive properties of tumor blood vessels have made them an enticing target for tumor therapies. Although conventional therapies target neoplastic cells within a tumor, antiangiogenic therapy offers several potential advantages as an approach to cancer treatment, notably physical accessibility and genetic stability of target cells (5). Because of these advantages, several angiogenesis inhibitors have progressed to clinical trial stage, including both peptide (9) and antibody (10) integrin antagonists, antiangiogenic proteins such