Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite recent improvements in the overall survival, only a modest percentage of patients survive Myc-driven high-risk MB. The quality of life for surviving patients is substantially reduced due to the devastating and often irreversible side effects of radiation and chemotherapy. Recently, in a large unbiased genomic screen, we uncovered a group of microRNAs (miRNAs) capable of meditating drug sensitivity in c-myc amplified high-risk MB. Our functional screen of ~1900 miRNAs identified miR-584-5p as a potent candidate that uniquely sensitizes high-risk MB to radiation as well as vincristine (VCR) (20 to 25-fold dose reduction), an anti-mitotic agent routinely administered alongside radiation and in combination with other chemotherapeutic drugs to treat medulloblastoma patients. Our studies revealed that miR-584 might act as a potent tumor suppressor as it inhibited MB growth in vivo as well as migration and invasion of c-myc amplified MB. We show that miR-584 overexpression results in defective mitosis leading to mitotic catastrophe, apoptosis, DNA damage and G2-M cell-cycle arrest in high-risk MB cells without affecting normal neural stem cell growth. Notably, we discovered that miR-584 directly regulates the expression and activity of genes including histone deacetylase 1 (HDAC1), and eukaryotic translation initiation factor 4e family member 3 (EIF4E3) that are known to play important roles in microtubule dynamics, metaphase-anaphase transition and radio-resistance. Moreover, silencing either of these two target genes resulted in significant inhibition of MB growth and enhanced sensitivity to VCR and ionizing radiation. Overexpressing miR-584 or silencing either HDAC1 or EIF4E3 also inhibited the MB stem cell proliferation and self-renewal. We report that while miR-584-5p is predominantly expressed in normal brain and cerebellum, its expression is significantly reduced in MB patient derived xenografts (PDXs). In contrast to miR-584, EIF4E3 and HDAC1 were found to be overexpressed in medulloblastoma patients. These findings are highly significant, unexpected and innovative as this miRNA and its target genes are the first to be shown to affect the therapeutic efficacy of VCR and radiation in c-myc amplified high-risk medulloblastoma.
Citation Format: Nourhan Abdelfattah, Subapriya Rajamanickam, Panneerdoss Subbarayalu, Santosh Timilsina, Benjamin Onyeagucha, Yidong Chen, Manjeet Rao. miRNAs as novel therapeutic adjuvants for improving the efficacy of vincristine and radiation therapy in treating medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5440. doi:10.1158/1538-7445.AM2017-5440