PDTB-19. EphA RECEPTOR TYROSINE KINASES AS TARGETS FOR THERAPY IN PAEDIATRIC MEDULLOBLASTOMA

Abstract

Medulloblastoma is a malignant neuroepithelial tumor that arises in the cerebellum. The overall long term survival is approximately 75%, the prospects are much less optimistic for children under five where survival is less than 50%. To achieve optimal survival, treatment involves both surgery and chemoradiotherapy. The long term effects on quality of life from radiation therapy are very significant, particularly cognitive impairment in young children. This motivates a search for novel therapies to provide better outcomes for this disease. Eph receptors and ephrin ligands are widely expressed and function normally during early embryonic development. They have been shown to be re-expressed and functional in a number of human cancers. Recent published findings have shown that EphA receptors are over expressed in glioblastoma and functionally promote a more aggressive stem cell-like phenotype in a kinase independent manner. Very little is known about Eph family receptors in medulloblastoma. We therefore undertook a study to examine EphA receptor function and to determine if these receptors might be alternative therapeutic targets in this disease. Our findings show elevated subtype-specific expression and activation of both EphA2 and EphA3 in paediatric medulloblastoma. Interestingly, EphA2 and EphA3 were most highly activated in the WNT subtype, which has the best prognosis, suggesting that EphA receptor activation may have tumor-suppressive functions in this subtype. EphA2 and EphA3 kinase function were intact, showing robust activation following stimulation with ephrin ligand. Furthermore, EphA2 activation led to a significant decrease in medulloblastoma cell migration in-vitro. Either EphA2 or EphA3 shRNA mediated knockdown attenuated medulloblastoma cell growth in-vitro and reduced tumor formation in-vivo. As a therapeutic proof of principle, we tested EphA2 and EphA3 specific monoclonal antibody drug conjugate targeting. Robust cell killing was observed in-vitro, while an EphA3-maytansine conjugate significantly reduced the size of developed orthotopic tumors in-vivo with minimal toxicity.