# Exploiting MTAP deletion for GBM therapeutics

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $344,809

## Abstract

Abstract Glioblastoma (GBM) is the most common malignant brain tumor and has a median survival of less
than 15 months, presenting an urgent clinical challenge. To overcome this challenge, our research has focused
on Methylthioadenosine phosphorylase (MTAP). MTAP deletion occurs in about half of GBM patients,
suggesting any therapeutic strategy devised based on MTAP status will significantly impact the treatment
landscape of this disease. Our preliminary study has demonstrated that MTAP deletion is associated with a
worse clinical outcome. In studying the underlying mechanism, we have elucidated that the status of MTAP
(presence or absence) affects GBM cells’ DNA methylome and the expression of genes involved in GBM
pathogenesis and in response to treatments. Furthermore, we have devised additional strategies of exploiting
MTAP status for clinical benefit. Normally, MTAP functions in the salvage pathway for adenine and methionine.
In MTAP-deficient tumor cells, the absence of this salvage pathway sensitizes cells to inhibitors of de novo
purine synthesis, providing an opportunity to specifically target cancer cells. We have devised a novel purine
starvation strategy that can effectively abrogate tumor growth. These exciting findings prompt us to further
understand the molecular mechanism of MTAP deletion in GBM and refine the promising therapeutic approach
we have developed. Our central hypothesis is that MTAP loss affects GBM progression via altering DNA
methylation, and that MTAP deletion can be exploited for GBM treatment. Specific Aim 1: Determine the
functional consequences of MTAP deletion in GBM. We will test the hypothesis that MTAP deletion affects
GBM progression via altering cancer cells’ DNA methylation patterns. Sub-Aim 1.1: Determine the mechanism
underlying the effects of MTAP deletion on GBM cells; and Sub-Aim 1.2: Determine the clinical significance of
MTAP deletion. Specific Aim 2: Develop a purine starvation-based therapeutic strategy for MTAP-null GBM.
We will test the hypothesis that purine starvation can be an effective treatment for MTAP-null GBM. Sub-Aim
2.1: We will use xenograft models derived from primary GBM cultures and test their response to purine
starvation; and Sub-Aim 2.2: We will determine the mechanism underlying GBM cells’ response to purine
starvation. This study will establish MTAP deletion as a direct therapeutic target in GBM, illuminate the
mechanism underlying the consequences of MTAP deletion in GBM progression and response to treatment,
generate novel in vitro and in vivo GBM models, and potentially lead to a new paradigm for clinical
management of GBM.

## Key facts

- **NIH application ID:** 9919011
- **Project number:** 5R01NS101074-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Yiping He
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,809
- **Award type:** 5
- **Project period:** 2017-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919011

## Citation

> US National Institutes of Health, RePORTER application 9919011, Exploiting MTAP deletion for GBM therapeutics (5R01NS101074-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9919011. Licensed CC0.

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