The Role of PRMT5 in Pediatric High-Grade Gliomas

Research study background

Physician-scientists in the Neuro-Oncology Program at Children’s Hospital Colorado and researchers at the University of Colorado School of Medicine are collaborating in an urgent effort to expedite the development of new treatments for pediatric high-grade gliomas (PHGGs). These tumors are the leading cause of cancer death in children.

The interdisciplinary team’s work to improve outcomes for patients diagnosed with these aggressive and recurrent central nervous system tumors spans several years. This includes research that enhanced understanding of the factors driving heterogeneity in PHGG. In the current study, the team delved into epigenetic regulation — a biological process that controls gene activity and expression but does not alter DNA — an emerging area of cancer treatment. Epigenetic dysregulation likely plays an important role in the development of PHGG from stem-like cancer initiating cells.

A screen for known epigenetic regulators in PHGG cell lines that are vital for tumor cell survival identified protein arginine methyltransferase 5 (PRMT5) as being important to PHGG cell survival. Investigators conducted in vitro and in vivo assays to test their hypothesis that PRMT5, known to promote self-renewal in normal cells, also plays a similar role in stem cell-like PHGG tumor-initiating cells. These are crucial for tumor growth. Further, they sought to determine if targeting PRMT5 could impair the tumor's ability to sustain itself.

In experiments using cellular and murine models that mimic PHGG, they monitored survival rates and tissue changes after PRMT5 knockdown or treatment with a PRMT5 inhibitor. They found PRMT5 knockdown reduced tumor cell proliferation, increased cell death and decreased cell self-renewal. These results suggest the possibility that PRMT5 promotes PHGG through epigenetic activation of stem cell genes. In follow-up studies, PRMT5 knockdown downregulated pathways related to stem cell characteristics and upregulated differentiation pathways. These changes were accompanied by histone modifications expected to promote differentiation and reduce tumorigenesis. Based on these encouraging results in cellular models, the team turned to studies in mice.

PRMT5 knockdown in the team’s in vivo experiments resulted in a survival benefit and decreased tumor aggressiveness compared to control cells. However, pharmacological inhibition of PRMT5 in murine models using the clinical grade inhibitor LLY-283, with or without radiation therapy, didn’t show therapeutic benefits. This could possibly be due to the timing of treatment, insufficient reduction of PRMT5 activity by chemical inhibition, or perhaps because PRMT5’s non-enzymatic activities are more relevant in PHGG.

Relevance to future research

This study is the first to demonstrate the potentially important role of PRMT5 in halting the development of PHGG by preventing stem-like cells from forming tumor cells. The inability to slow tumor growth in murine models through drug intervention suggests the need for more effective inhibitors or combined treatment strategies. The team is currently working to develop and test an effective therapeutic approach that could apply to human patients.