The Eph RTK family represents an exciting new group of potential targets in cancer treatment. Eph receptors are quite distinct from 'conventional' RTKs given their involvement in bidirectional signaling and complex role in oncogenesis. The signaling cascades induced by Eph activation result in alteration of cell movement and dictates whether cell adhesion or repulsion will occur. This is in contrast to other RTKs that typically play a role in oncogenesis by affecting cell survival processes such as apoptosis. The role of the Eph family in cancer has not been fully elucidated but their expression in adult tissues is a marker of malignancy, as Ephs are quiescent in normal postembryonic tissues and their reappearance is abnormal. EPHA3 is not expressed on normal hematopoietic stem cells but is widely expressed on abnormal stem cells and more mature malignant cells within the hematological malignancies. In preclinical data, normal cells, which therefore do not express EPHA3, were unaffected by targeting of EPHA3. EPHA3 tends to be particularly highly expressed in advanced stage disease, for example, blastic phase chronic myeloid leukemia. In this regard, EPHA3 may constitute an exciting new treatment for advanced stage disease in hematological malignancies. There is a consistent positive correlation in malignancies that overexpress Ephs between the degree of overexpression and the aggressiveness and metastatic behavior of the malignancy. Targeting of EPHA3 and other Eph receptors may therefore have a role in treatment of solid tumors, particularly aggressive and metastatic disease. The combination of Eph-targeted agents with other TKIs may be particularly important.
Expert Rev Hematol. 2012;5(3):325-340. © 2012 Expert Reviews Ltd.