Eph receptors as therapeutic targets in glioblastoma

Abstract

The dismal outlook for patients with the most aggressive and common form of adult brain cancer, glioblastoma (GBM), motivates a search for new therapeutic strategies and targets for this aggressive disease. Here we review the findings to date on the role of Eph family receptor tyrosine kinases and their ephrin ligands in brain cancer. Expression of the Eph family of cell surface proteins is generally downregulated to very low levels in normal adult tissues making them particularly attractive for directed therapeutic targeting. Recent Eph targeting studies in pre-clinical models of GBM have been very encouraging and may provide an avenue to treat these highly refractory aggressive tumours.

Figure 1

Model of EphA/ephrin-A expression in GBM. A model has emerging suggesting that EphA receptors and ephrin-A ligands may exist within an expression gradient in GBM. EphA receptor expressing cells are poorly activated due to low ligand expression and take on a more de-differentiated mesenchymal-like GSC phenotype, whereas elevated ephrin-A expression led to a less-aggressive more-differentiated epithelial phenotype. Functionally, EphA receptors appear to maintain this GSC phenotype by limiting the duration of MAPK signalling. Cues from the microenvironment and proximity to niche may also be critical in this process; EphA receptor expression diminishes as tumour cells expanded away from the vascular niche.

Figure 2

Potential therapeutic strategies to target Eph receptors in GBM. Several approaches exist to target Eph receptors. Kinase inactivating strategies include kinase inhibitors or blocking peptides or antibodies. Kinase-activating strategies include ligand stimulation, activating antibodies or ligand peptide mimetics strategies to deliver toxic payloads following receptor activation and internalisation include coupling of cytotoxic agents or radionuclides to Eph monoclonal antibodies.