Abstract
BACKGROUND: Glioblastoma (GBM) is the most common adult malignant brain tumor. In spite of standard multi modal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy prognosis remains poor. As complexity of tumor heterogeneity is being increasingly recognized as a therapeutic hurdle, the identification of both differentiated and undifferentiated “stem cell like” populations in the tumor highlights the significance of finding novel targets that affect both cell populations. Protein arginine methyltransferase (PRMT5) is one such candidate whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of four novel PRMT5 inhibitors in the treatment of GBM. METHODS: Efficacies of these inhibitors were screened using in vitro GBM neurosphere model and in vivo intracranial zebra fish model of glioma. Standard molecular biology methods employed to investigate changes in cell cycle, growth, and senescence. RESULTS: In vitro and In vivo studies revealed that among the four PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knock down wherein it led to apoptosis of differentiated GBM cells, and drove undifferentiated primary patient derived GBM cells into a non replicative senescent state. CONCLULSION: In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.