Nagendra Chaturvedi, ph.d.

July 2023 – June 2025

PRMT5-MYC Axis as a Novel Target in Group 3 Medulloblastoma
$150,000
Update from dr. Chaturvedi | March 2024 | We have made significant progress on this project since awarded. Moving forward with this project, as proposed in Aim 1, we have performed RNA-sequencing in MYC-amplified MB cells with or without PRMT5 inhibition (using most potent PRMT5 inhibitors identified in previous experiments). Using this data, we are now further investigating to identify PRMT5-MYC interactions and key targets. As for now, we could see significant difference on overall gene expression reads in these two treatment groups, suggesting an impact of targeting PRMT5 in global gene transcription in Group 3 (MYC-amplified) MB cells.

Although several PRMT5 inhibitors are in clinical trials, it is largely unexplored if such inhibitors can cross bloodbrain barriers and reach the target in the tumor microenvironment. We have now performed animal experiments to address these issues. In our recent animals (mice) experiments, we observed that PRMT5 inhibitors, JNJ64619178 and EPZ015666, can penetrate the brain and target MB tumors in the brain tumor microenvironment. In addition, our preliminary results indicated that when nano-formulated, these inhibitors may have improved stability and brain penetration or retention in mice. Using in vitro and in vivo experiments, PK/PD and brain penetrance characteristics of a panel of clinically relevant PRMT5 inhibitors with or without nano-formulation will further be characterized in our future studies.

In summary, our in vitro and in vivo data strongly support our hypothesis that PRMT5 is a viable target in MYC-driven MB, which warrants further systematic evaluation of this target in vivo using orthotopic and PDXs models. We are now focused on targeting PRMT5 using such appropriate models.