EphA2: A novel target in renal cell carcinoma

Abstract

Eph receptors and their ligands, ephrins, are known to play important roles in organ development (formation of tissue boundaries, neural crest cell migration, axon guidance) and angiogenesis. In particular, EphA2 has recently attracted interest in the field of cancer research. Many observations, including our own, have demonstrated that most cancers, such as renal cell carcinoma (RCC), overexpress the EphA2 protein. EphA2 overexpression/dysregulation is associated with carcinogenesis, metastasis, and poor clinical prognosis. Indeed EphA2 is not just a marker of metastatic potential, but its overexpression is directly linked to an aggressive tumor phenotype. As a consequence, EphA2 represents a potential target for therapeutic intervention in the setting of EphA2+ cancer histologies, with several agents being developed with clinical intent. Several strategies can be contemplated in this regard, including: (1) selected promotion of EphA2 degradation or to reduce EphA2 expression and signaling (via the application of agonistic antibody, ephrin-A1 Fc fusion protein, siRNA against EphA2, or protein tyrosine phosphatases (PTP) that regulate EphA2 expression or specific EphA2 kinase inhibitors); (2) antagonism of EphA2 receptor-ligand binding (by provision of mimetic peptides or EphA2 Fc fusion protein); and/or (3) vaccination against EphA2 (using specific peptide-, protein-, or gene-based methods) to elicit specific T-cell- or Ig-mediated immunity. In this chapter, we will discuss the basic immunobiology of tumor-associated EphA2 and potential therapeutic interventions directed against EphA2 that may yield clinical benefit in the setting of (renal cell) cancer. © 2009 Humana Press.