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Ribavirin as a potential therapeutic for atypical teratoid/rhabdoid tumors

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Casaos, J.; Huq, S.; Lott, T.; Felder, R.; Choi, J.; Gorelick, N.; Peters, M.; Xia, Y.; Maxwell, R.; Zhao, T.; Ji, C.; Simon, T.; Sesen, J.; Scotland, S. J.; Kast, R. E.; Rubens, J.; Raabe, E.; Eberhart, C. G.; Jackson, E. M.; Brem, H.; Tyler, B.; Skuli, N.

Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive, malignant tumors and are the most common malignant brain tumor in children under 6 months of age. Currently, there is no standard treatment for AT/RT. Recent studies have reported potential anti-tumoral properties of ribavirin, a guanosine analog and anti-viral molecule approved by the Food and Drug Administration for treatment of hepatitis C. We previously demonstrated that ribavirin inhibited glioma cell growth in vitro and in vivo. Based on these results and the fact that no pre-clinical model of ribavirin in AT/RT exists, we decided to investigate the effect of ribavirin on several human AT/RT cell lines (BT12, BT16, and BT37) both in vitro and in vivo. We provide evidence that ribavirin has a significant impact on AT/RT cell growth and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E and/or EZH2 pathways. Interestingly, using scratch wound and transwell Boyden chamber assays, we observed that ribavirin also impairs AT/RT cell migration, invasion, and adhesion. Finally, we demonstrate that ribavirin significantly improves the survival of mice orthotopically implanted with BT12 cells. Our work establishes that ribavirin is effective against AT/RT by decreasing tumoral cell growth and dissemination and could represent a new therapeutic option for children with this deadly disease.

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