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PRMT5 as a druggable target for glioblastoma therapy
Yeshavanth Kumar Banasavadi-Siddegowda1,2, Alessandra M Welker3,4,5, Min An3
1The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.
Background:
In spite of standard multimodal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy, prognosis for glioblastoma (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 heterogeneous tumor cell population. Protein arginine methyltransferase 5 (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 4 novel PRMT5 inhibitors in the treatment of GBM.
Methods:
Efficacies of these inhibitors were screened using an in vitro GBM neurosphere model and an 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 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated primary patient derived GBM cells into a nonreplicative senescent state.
Conclusion:
In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.
Insights
Novel Protein Arginine Methyltransferase 5 (PRMT5) inhibitors show promise for glioblastoma (GBM) treatment. Compound 5 (CMP5) effectively targets both differentiated and undifferentiated GBM cells, inducing apoptosis and senescence.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Glioblastoma (GBM) remains a challenge despite standard therapies.
- Tumor heterogeneity, including stem-like cells, necessitates novel therapeutic targets.
- Protein arginine methyltransferase 5 (PRMT5) is implicated in GBM cell survival and self-renewal.
Purpose of the Study:
- To screen novel PRMT5 inhibitors for glioblastoma (GBM) treatment efficacy.
- To evaluate the specificity and effectiveness of PRMT5 inhibition in GBM.
Main Methods:
- Screening of four novel PRMT5 inhibitors.
- Utilized in vitro GBM neurosphere models and in vivo zebrafish glioma models.
- Assessed cell cycle, growth, and senescence using molecular biology techniques.
Main Results:
- Compound 5 (CMP5) demonstrated efficacy mirroring PRMT5 knockdown.
- CMP5 induced apoptosis in differentiated GBM cells.
- CMP5 caused undifferentiated GBM cells to enter senescence.
Conclusions:
- CMP5 exhibits potent in vitro and in vivo antitumor activity against GBM.
- The specificity and efficacy of CMP5 highlight its translational potential.
- Targeting PRMT5 represents a promising therapeutic strategy for glioblastoma.
