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OS5 - 173 Inhibition of eEF2K as a Novel Therapeutic Strategy in Neuroblastoma and Medulloblastoma

  • A Delaidelli (a1) (a2), D Khan (a1) (a3), G Leprivier (a1) (a4), SM Pfister (a5) (a6), MD Taylor (a7), JM Maris (a8) and PH Sorensen (a1)...

Abstract

Medulloblastoma and neuroblastoma are aggressive solid pediatric tumors, with 5 year survival rates lower than 50-60%. In addition, more than 80% of the survivors develop permanent neurological impairments. Hence, there is a dire need to identify and validate novel, more effective and less toxic therapeutic approaches. Tumors are continually exposed to acute changes in the micro-environment, including nutrient availability. We previously showed that eukaryotic Elongation Factor-2 Kinase (eEF2K) is a critical regulator of cellular adaptation to acute metabolic stress. Based on those findings, we hypothesize that eEF2K is a marker of outcome and mediates medulloblastoma and neuroblastoma adaptation to acute stress. METHODS – Proprietary gene expression datasets (for medulloblastoma) and the R2 genomic analysis platform (for neuroblastoma) were analyzed for links between eEF2K expression and outcome. Effects of eEF2K knockdown on cell survival were evaluated in BE(2)C neuroblastoma cells. Immunoblotting and immunohistochemistry were performed on neuroblastoma cell lines and tissue microarrays (TMAs) for key molecules in the pathway. Similar studies are underway in medulloblastoma cell lines and TMAs. RESULTS - Low eEF2K mRNA expression is predictive of improved survival in medulloblastoma and neuroblastoma. Low p-eEF2 protein expression, indicative of low eEF2K activity, improves survival in human neuroblastoma. Neuroblastoma cell lines with eEF2K knockdown are more sensitive than controls to nutrient deprivation. CONCLUSIONS - eEF2K may represent a critical mechanism for adaptation to acute metabolic stress in neuroblastoma and medulloblastoma, and is therefore a promising therapeutic target. We are currently exploring the pharmacological inhibition of eEF2K in xenograft tumor models.

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