Anti-angiogenesis and disintegrins

Angiogenesis is a critical process in tumor and disease progression. A number of features are central to both tumor growth and development, and the recruitment and invasion of a growing vascular network supplying the tumor with nutrients and a mechanism of escape to allow meastatic growth. One class of molecules important to both tumor growth and blood vessel recruitment are a family of cell surface receptors identified as integrins. Integrins are α/β heterodimeric glycoproteins in which the different α subunits combine with distinct β subunits resulting in a range of specificities toward various extracellular matrix (ECM) proteins. The RGD sequence found in a number of ECM proteins is recognized by several classes of integrins, allowing for linkage of cytoskeletal proteins associated with the integrins to the ECM which leads to involvement in bi-directional signaling that displays profound effects on cellular functions. Among these integrin mediated interactions are the adhesion of both endothelial cells and cancer cells to ECM proteins, an interaction that is integral to metastasis, tumor growth and angiogensis. Antibodies targeted to integrins have been shown to retard tumor growth and subsequent tumor induced angiogenesis. One concern with this approach is that the antibody targets a single integrin, which may allow the tumor to utilize other non-targeted integrins to circumvent this type of blockage. A more broad spectrum agent is available that binds to and blocks the function of several different integrins at a time, this agents is identified as a disintegrin. Originally purified from the venom of Viperidae family of snakes, a disintegrins role in nature is presumably to block platelet aggregation following envenomation based on interaction of an integrin on the activated platelet surface with an RGD sequence in the disintegrin. It has been observed that integrins overexpressed on some tumor types and angiogenic vasculature have similar affinity for RGD motifs found in ECM proteins. Based on disintegrin structure we have developed a recombinant form of a snake venom disintegrin, which we call vicrostatin (VCN). VCN is a potent anti-angiogenic/anti-tumor agent in in vitro and in vivo laboratory studies. Further development of the recombinant venom derived disintegrin along with new technology looking at additional disintegrin-like proteins may offer a novel therapeutic approach in targeting tumor induced angiogenesis.