Angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. Both stimulators and inhibitors of angiogenesis are being developed. Although inhibitors are primarily being developed for the treatment of cancer, these molecules are also receiving growing attention as a strategy for treating retinal diseases and also inflammatory conditions such as rheumatoid arthritis. Originally identified as regulators of neural development, the Eph family of receptor tyrosine kinases and their ephrin ligands are also critical for vascular development and pathological forms of angiogenesis. EphA2, a receptor for ephrin-A, is required for the formation of endothelial capillary tubes and promotes the formation of blood vessel-like structures by cancer cells. Both of these proteins are expressed in adult blood vessels but only in their "activated" state and in particular in the vasculature of human tumors. In addition to being present in tumor endothelial cells, EphA2 and ephrin-A1 are upregulated in response to a wide variety of factors in the transformed cells of a wide variety of tumors. Although EphA2 and ephrin-A1 represent excellent anti-cancer targets, these proteins belong to large families of closely related molecules and selectivity represents a potential problem. Researchers from The Burnham Institute have addressed this issue by using phage display technology to search for peptides that bind selectively to the extracellular domain of EphA2. This group identified two peptides that bind selectively to EphA2, but not other Eph receptors, and antagonize ephrin-binding. Given the restricted expression of EphA2 and the selectivity of these peptides, they may be of use in the delivery of toxins or isotopes to the tumor vasculature. At least one of the peptides has bioactive properties being able to stimulate EphA2 tyrosine phosphorylation and signaling. This was suggested to confer a further advantage in the context of drug targeting since this agonist activity should promote internalization and improve therapeutic efficacy. Antagonist peptides on the other hand may be expected to block neovascularization and should therefore be developed therapeutically or as templates for small molecule modeling of inhibitors of angiogenesis. Different Eph receptors have been implicated in various types of cancer. The positive data from the present study suggests that a similar approach should be used to exploit the therapeutic potential of molecules that bind to members of this family in general, for the treatment of both cancer and other diseases associated with pathogenic angiogenesis.

December, 2002

Adapted from Koolpe et al, J Biol Chem 2002 Dec 6;277(49):46974-9

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