EPHB4 and cancer: Furthermore, since EphB4 promoting effects in cancer have been found to be variably or negligibly dependent on EphrinB2 extracellular binding (18), the block of IGF-II in cancers with confirmed dependence on IGF-II for EphB4 overexpression overcomes the potential resistance to treatment using anti-EphB4 agents targeting the extracellular/ephrinB2 binding portion of EphB4 (19).