Aaron Argall Janani Ravikrishnan Jasmine PeiJung Vinay Puduvalli Division of Neurooncology Department of Neurosurgery The Dardinger Center for Neurooncology Research The Ohio State University Comprehensive Cancer Center Columbus OH USA ID: 933663
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Inhibition of PRMT5 in Molecularly Heterogeneous Glioma Stem-like Cells
Aaron Argall
, Janani Ravikrishnan, Jasmine Pei-Jung, Vinay Puduvalli
Division of Neuro-oncology, Department of Neurosurgery, The Dardinger Center for Neuro-oncology Research, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA,
Future Directions
Glioblastoma (GBM) is a lethal brain malignancy associated with a median survival of only 15-18 months after surgery followed by chemoradiation therapy with temozolomide (TMZ), an alkylating agent.
Background
PRMT5 is overexpressed in GSC lines
Protein arginine
methyltransferase
5 (PRMT5)
symmetrically
dimethylates
histones, splicing factors and receptors to suppress
transcription
, regulate splicing
events, and is dysregulated in GBM.
PRMT5 inhibition
reduces GSC viability
Experimental Design
The lowest concentration to hit IC50
across each glioma stem-like cell was
determined to be
100nM.
Investigate PRMT5 inhibitions impact on the cellular behavior of GSCs including: proliferation (
BrdU
), cell cycle (PI), invasion (3D neurosphere assay), and angiogenesis (tube formation assay).
Test PRT808 in vivo capability to cross the BBB and reduce tumor growth.
Acknowledgements
This work is supported by the National Institute of Health (project: CA235673) and by Prelude Therapeutics Inc.
Contact: Argall.1@osu.edu
We hypothesize that PRMT5 inhibition promotes anti-tumorigenic effects across GBM molecular subtypes preferentially via p53 and MTAP dependent pathways.
PRT808 induces apoptosis after prolonged exposure
The greatest differential in apoptosis between DMSO and PRT808 treatment occurs between 6 and 9 days for wtTP53 lines.
(
Bernstock
et al., 2019. J Neurosurg)
PRT808 reduces symmetrical dimethylation marks increasingly over time
SDMA marks are shut down by day 3 and remained inhibited through day 9.
PRT808 is a specific PRMT5 inhibitor due to no changes in asymmetrical dimethylation marks - associated with other PRMT enzymes.
Compared to Normal Human Astrocytes, PRMT5 is overexpressed.
MAT2A levels are consistent across normal and glioma stem-like cell lines
.
mut
TP53 lines: GSC214 (C238Y) and GSC262 (R175H)p16 is co-deleted in MTAP null cancers.