# Microenvironmental Regulation of Alternative Splicing Patterns Drive Aggressive GBM Biology

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $231,750

## Abstract

Glioblastoma (GBM) is the most common and lethal brain tumor in adults, claiming about 14,000 lives annually
in the U.S. alone. GBM is resistant to radiation and chemotherapy and this appears due partly to genetic diversity
and partly to a sub-population of stem-like cells (GSCs) that resist standard therapy and repopulate the tumor.
Several groups have recently identified MBNL1 as a key mediator of cellular differentiation of embryonic stem
cells. In our preliminary work we show that MBNL1 inhibits glioblastoma stem cell self-renewal in vitro and tumor
initiation and growth in vivo. Because GSC have been shown to be intrinsically more resistant to ionizing radiation
than their differentiated progenies, we propose to test if MBNL1 may sensitize GSC to ionizing radiation by
promoting their differentiation. If true, these results should have strong impact. Our long-term goal is to develop
pharmacological means to activate MBNL1 protein as effective new therapies for GBM and other malignant brain
tumors. Our findings will likely not be limited to brain tumors as MBNL1 inactivation is the mechanism in the
pathophysiology of myotonic dystrophy. Therefore, our studies should have cross-disease implications. The
central hypothesis of this proposal is that the hypoxic microenvironment inactivates MBNL1 to drive aggressive
tumor behavior (proliferation, self-renewal, invasion, and survival) and that the mechanism is a switch towards
fetal-like splicing patterns of pre-mRNA targets (Aim1). Because GSC have been previously shown to be
intrinsically resistant to radiation, we also propose that inducing MBNL1 in preformed tumors will promote adult-
like (differentiation) splicing patterns and will sensitize GBM to standard of care radiation (Aim2). Our proposal
contains two aims: Specific Aim 1: To determine the effects of the hypoxic microenvironments on MBNL1 and to
define GSC vulnerability to MBNL1 activity under these conditions. Specific Aim 2: To exploit GSC vulnerability
to MBNL1 activity as a therapeutic strategy for GBM.
 MBNL1 expression is commonly repressed in hypoxic elements of GBM and hypoxia has been linked to
negative prognosis for survival in GBM patients. We expect our studies to establish this developmentally-relevant,
key differentiation inducing splicing-factor, as a novel therapeutic target in GBM. These results are of high clinical
relevance, and will provide the rationale for the development of small molecules that can increase MBNL1 activity.
Successful completion of the proposed studies will further illuminate the biology of MBNL1 in GBM and establish
MBNL1 as a target with multiple mechanisms of action against cancer, with a strong likelihood for therapeutic
impact in patients with GBM.

## Key facts

- **NIH application ID:** 10067279
- **Project number:** 7R21NS106553-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Eli E Bar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $231,750
- **Award type:** 7
- **Project period:** 2019-12-07 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067279

## Citation

> US National Institutes of Health, RePORTER application 10067279, Microenvironmental Regulation of Alternative Splicing Patterns Drive Aggressive GBM Biology (7R21NS106553-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10067279. Licensed CC0.

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