# New Therapeutic Approaches for Stratified High-REST GBM Subtype

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $405,000

## Abstract

Summary [Print using "Actual size" (Acrobat) or "Scale: 100%" (Preview)] for proper font size (11)]
Glioblastoma (GBM), a lethal human brain tumor, is made up of multiple molecular subtypes, suggesting that
therapy could be targeted to particular subtypes. Yet all newly diagnosed GBM patients are treated with a
similar therapeutic regimen, which results in overall poor patient outcomes. GBM tumors contain stem-like cells
(GSCs) that contribute to tumor initiation, growth, and resistance to standard-of-care temozolomide (TMZ) and
ionizing radiation (IR). Thus, GSCs present an excellent system in which to study the biology of GBM and
develop and evaluate targeted therapeutic approaches to GBM. Our long-term goal is to develop mechanism-
based therapeutic approaches to significantly advance the care of GBM patients. Our laboratory discovered
the transcriptional repressor REST as a stem cell promoter, and thus a critical oncogenic regulator, in
medulloblastoma. We and others discovered that REST also regulates oncogenesis in GBM and that tumors
with GSCs expressing high levels of REST (HR-GSCs) are molecularly and biologically distinct from tumors
with GSCs expressing low levels of REST (LR-GSCs). Further, GBM patients with an HR tumor transcriptome
signature have shorter survival than patients with an LR tumor signature, similar to our results with HR-GSC
versus LR-GSC tumors in mouse models. These studies have suggested that REST is a potential therapeutic
target in HR-GBM tumors. Yet there is no REST-specific therapeutic approach for stratified HR-GSC tumors.
The goal of this project is to determine therapeutic approaches for HR-GSC tumors using mouse intracranial
tumor models. First, information obtained here will determine whether targeting HR-GBM tumors with REST-
specific inhibitor, REST-VP16, is a valuable therapeutic approach for HR-GBM. Second, Information obtained
here will determine whether targeting HR-GBM tumors with REST downstream miR targets via exosome-
mediated delivery would promote therapeutic approaches for HR-GBM. Third, we will determine the underlying
regulatory network changes and transcriptome signatures in selected tumors with and without treatment
conditions. Such regulatory networks will provide information about changes in treatment-dependent
downstream pathways and targets. The transcriptome signatures could be useful to measure treatment
progression in a clinical setting. Fourth, we will determine the homing mechanism of Exosome-mediated
delivery of miRs to HR-tumors. Information obtained here will aid in designing exosomes with enhanced
homing capabilities to HR-GBM. Thus, the project has the potential to produce a novel, mechanism-based
therapeutic approach for the HR-GBM subtype, for which such approaches are limited.

## Key facts

- **NIH application ID:** 10318992
- **Project number:** 5R01NS119162-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** SADHAN MAJUMDER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2021-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318992

## Citation

> US National Institutes of Health, RePORTER application 10318992, New Therapeutic Approaches for Stratified High-REST GBM Subtype (5R01NS119162-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10318992. Licensed CC0.

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