Therapeutic targeting of protein translation in pediatric atypical teratoid/rhabdoid tumor
Mentor Name: John Presner
Protein translation is a fundamental molecular process required for all cellular life, and cancers both employ and corrupt normal translational control to achieve oncogenesis. In embryonal pediatric brain cancers specifically, there are numerous lines of evidence for the centrality of dysregulated translational control, including multiple somatic driver events (e.g. MYC or MYCN amplification in medulloblastoma, C19MC amplification in ETMR), germline predisposition syndromes that fundamentally dysregulate translational control (e.g. DICER syndrome leading to medulloblastoma and pineoblastoma), and small molecule inhibitor screens indicate exceptional lethality of protein translation inhibitors in AT/RT.
In this proposal, we seek to develop the hypothesis that protein translation inhibition represents a potential therapeutic vulnerability in pediatric embryonal brain tumors. In specific, we will investigate the particular role of protein translation inhibition in atypical teratoid/rhabdoid tumor (AT/RT). Using high-throughput drug screening, we have found that AT/RT cell lines are exceptionally susceptible to cell killing by the ribosome inhibitor, omacetaxine. We have further nominated the eukaryotic initiation factor 6 (eIF6) as potential biomarker for cell sensitivity to this drug.
The goal of this project is to provide a fruitful and enriching scientific experience for Rakesh Murugesan in pediatric neuro-oncology research. Rakesh will use this POST award to validate, optimize, and probe the utility of omacetaxine for killing AT/RT cells. He will further determine whether eIF6 is a biomarker for drug response and whether modulation of eIF6 expression results in differential cell response to omacetaxine. Lastly, Rakesh will work to characterize the downstream cellular changes that occur following treatment with omacetaxine.
