Banasavadi-Siddegowda, Y.K., Welker, A.M., An, M., Yang, X., Zhou, W., Shi, G., Imitola, J., Li, C., Hsu, S., Wang, J., Phelps, M., Zhang, J., Beattie, C.E., Baiocchi, R., Kaur, B. (2017) PRMT5 as a druggable target for glioblastoma therapy. Neuro-Oncology. 20(6):753-763.
Background In spite of standard multi modal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy prognosis for GBM patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogenous tumor cell population. Protein arginine methyltransferase (PRMT5) is one such candidate gene 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 zebrafish model of glioma. Standard molecular biology methods were 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.
Conclusion In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.