An Ephrin Mimetic Peptide That Selectively Targets the EphA2 Receptor

Abstract

Eph receptor tyrosine kinases represent promising disease targets because they are differentially expressed in pathologic versus normal tissues. The EphA2 receptor is up-regulated in transformed cells and tumor vasculature where it likely contributes to cancer pathogenesis. To exploit EphA2 as a therapeutic target, we used phage display to identify two related peptides that bind selectively to EphA2 with high affinity (submicromolar K D values). The peptides target the ligand-binding domain of EphA2 and compete with ephrin ligands for binding. Remarkably, one of the peptides has ephrinlike activity in that it stimulates EphA2 tyrosine phosphorylation and signaling. Furthermore, this peptide can deliver phage particles to endothelial and tumor cells expressing EphA2. In contrast, peptides corresponding to receptor-interacting portions of ephrin ligands bind weakly and promiscuously to many Eph receptors. Bioactive ephrin mimetic peptides could be used to selectively deliver agents to Eph receptor-expressing tissues and modify Eph signaling in therapies for cancer, pathological angiogenesis, and nerve regeneration.

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

“…These includes downregulation of EphA2 expression by siRNA (Duxbury et al, 2004a), activating antibodies or ligand mimetic peptides to induce EphA2 endocytosis and degradation (Koolpe et al, 2002;Coffman et al, 2003), or blocking EphA2 receptor activation by soluble EphA-Fc receptor Cheng et al, 2003;Dobrzanski et al, 2004). This study provides a mechanism for effectiveness of soluble EphAFc receptor and lays foundation for future development of EphA2-specific kinase inhibitors in cancer therapeutics.…”

Differential Regulation of EphA2 in Normal and Malignant Cells

“…In particular, much recent interest has focused on approaches to mimic the actions of EphA2 ligands (ephrins) using monoclonal antibodies and peptide-based mimetics. 55,74 These reagents increase the phosphotyrosine content of EphA2 as measured in vitro. 55,74 In the case of EphA2 monoclonal antibodies, the mechanism of action appears to require receptor degradation, 55 which is consistent with evidence that antisense-based targeting of EphA2 can also inhibit the growth and invasiveness of malignant cells.…”

“…55,74 These reagents increase the phosphotyrosine content of EphA2 as measured in vitro. 55,74 In the case of EphA2 monoclonal antibodies, the mechanism of action appears to require receptor degradation, 55 which is consistent with evidence that antisense-based targeting of EphA2 can also inhibit the growth and invasiveness of malignant cells. 34,55 Altogether, these properties may provide a powerful means for selective targeting of the many cancers that overexpress EphA2.…”

Loss of EphA2 receptor tyrosine kinase reduces Apcmin/+ tumorigenesis

“…[20][21][22] Based on these observations, targeting of EphA2 via immunotherapy, soluble EphA2 receptor domains and other approaches is under clinical development. [23][24][25][26][27][28][29][30][31][32][33][34][35] Yet, there is also some evidence that EphA2 may function as a tumor suppressor, as activation of EphA2 receptors following ligand binding has been shown to lead a reduction in cell growth that is associated with inhibition of the RAS/MAPK pathways, and EphA2 2/2 gene trap mice demonstrate increased susceptibility to skin carcinogenesis. [36][37][38][39] Further, EphA2 has been reported to be a transcriptional target of the p53 tumor suppressor, 40 and expression of EphA2 was shown to negatively affect the proliferation and promote apoptosis in lung and breast cancer cells.…”

“…[20][21][22] Based on these observations, targeting of EphA2 via immunotherapy, soluble EphA2 receptor domains and other approaches is under clinical development. [23][24][25][26][27][28][29][30][31][32][33][34][35] …”