Medulloblastoma is the most common malignant brain tumor in children, accounting for 18% of newly diagnosed brain tumors and 10% of all children cancer-related deaths. Despite improvement in the 5-year survival rate of medulloblastoma in recent years, only a small percentage of patients survive high-risk metastatic disease. The quality of life for those who do survive is often substantially reduced due to the toxicity associated with radiation and chemotherapy. Vincristine is a microtubule-destabilizing antimitotic drug, which is routinely administered in higher dosages to both high and average risk medulloblastoma patients. As a result, these patients suffer from devastating neurotoxic effects that include but not limited to: sensorimotor and autonomic neuropathy, hearing loss, mononeuropathy, and seizures. Using high-throughput microRNA mimic library screens, we identified a group of microRNAs that may improve the efficacy of vincristine against c-MYC amplified medulloblastoma as well as re-sensitize vincristine-resistant medulloblastoma. Our findings revealed that these microRNAs may act as tumor suppressors since their overexpression inhibited colony formation, migration and invasion ability of medulloblastoma cells. Furthermore, these microRNAs suppressed stem cell renewal/proliferation of c-MYC amplified medulloblastoma cells. Expression analysis, gene enrichment analysis and target prediction algorithms revealed that these microRNAs exert their vincristine sensitizing and tumor suppressor effect by targeting genes involved in microtubule organization, cell cycle regulation, DNA damage repair and mRNA translation. One of our most interesting targets is EIF4E3, which is a translation initiation factor. Our preliminary findings indicate that EIF4E3 may regulate medulloblastoma cell growth, progression and vincristine sensitivity by modulating c-MYC translation. Further experiments are underway to test the potential of candidate miRNA and EIF4E3 as vincristine sensitizer in vivo. In conclusion, this study may identify novel factors that have potential not only to decrease the current therapeutic dose of vincristine and therefore eliminate its side effects, but also have potential to multiply the efficacy of lower doses in order to overcome hard to treat high-risk tumors.
Citation Format: Nourhan Abdelfattah, Panneerdoss Subbarayalu, Benjamin Onyeagucha, Subapriya Rajamanickam, Hung-I Harry Chen, Manjeet Rao. MicroRNAs as novel therapeutic adjuvants to treat high-risk medulloblastoma.. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B01.