# Exploiting Epigenetic Vulnerabilities In Glioblastoma Stem Cells Through Reprogramming

> **NIH NIH R21** · H. LEE MOFFITT CANCER CTR & RES INST · 2022 · $433,257

## Abstract

Glioblastoma (GBM) is a highly resistant cancer. Temozolomide (TMZ) is the best first-line therapy available,
but TMZ response depends on the promoter methylation status of the DNA repair gene O6-methylguanine DNA
methyltransferase (MGMT). MGMT methylated (MGMT-M) GBM patients have suppressed MGMT protein
expression which leads to TMZ sensitization and prolonged survival. In contrast MGMT unmethylated (MGMT-
UM) GBM patients are resistant to TMZ and have much shorter survivals. So far there have been no
successful treatments to render MGMT-UM susceptible to TMZ and therefore there is a desperate need for
novel treatment strategies for MGMT-UM. Our long-term goal is to devise strategies that can epigenetically
reprogram MGMT-UM GBM patients to the TMZ susceptibility of MGMT-M GBM patients. This proposal
exploits a novel epigenetic mechanism in GBM stem cells (GSCs) involving Tumor Suppressor Candidate 3
(TUSC3) that can be used to reprogram MGMT-UM to restore sensitivity to TMZ and significantly prolong
survival in experimental models of GBMs. The objective in this application is to understand how TUSC3 is
epigenetically regulated and how TUSC3 sensitizes GBMs to TMZ. We recently discovered using both
pharmacologic epigenetic reprogramming and gain-of-function strategies that: i) TUSC3 promoter regulation in
GSCs is impacted by MGMT; ii) TUSC3 significantly sensitized GSCs through suppression of DNA damage
repair and cell cycle progression; and iii) TUSC3 synergized with TMZ to produce similar survival benefits in
experimental models of MGMT-M and MGMT-UM GBMs. We will therefore test the hypothesis that epigenetic
reactivation of TUSC3 reprograms GBMs to TMZ sensitivity and prolonged survival. In Aim 1, we will determine
how TUSC3 is epigenetically regulated in GBM. In Aim 2, we will determine how TUSC3 mediates TMZ
response sensitization in GBM. Mechanistic knowledge gained from these studies will enhance our
understanding of novel epigenetic reprogramming mechanisms in GBM and contribute toward the optimal
design of impactful trials for MGMT-UM GBMs who currently do not have good chemotherapy options.

## Key facts

- **NIH application ID:** 10430928
- **Project number:** 1R21CA264635-01A1
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Arnold Etame
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $433,257
- **Award type:** 1
- **Project period:** 2022-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430928

## Citation

> US National Institutes of Health, RePORTER application 10430928, Exploiting Epigenetic Vulnerabilities In Glioblastoma Stem Cells Through Reprogramming (1R21CA264635-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10430928. Licensed CC0.

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