# Enhancing the efficacy of Radiation Therapy for brainstem glioma by targeting ATM

> **NIH NIH K08** · DUKE UNIVERSITY · 2022 · $213,541

## Abstract

Enhancing the efficacy of radiation therapy for brainstem glioma by targeting ATM
Project Summary/Abstract
Brainstem gliomas are devastating pediatric brain tumors. Brainstem gliomas include “diffuse midline gliomas
with H3K27M mutation” in the 2016 World Health Organization Classification of Tumors of the CNS, and
includie tumors previously referred to as “diffuse intrinsic pontine gliomas” or DIPG. Brainstem gliomas are
uniformly lethal to the patients. Radiation therapy is thought to be the only effective treatment for these
tumors, providing temporary relief from symptoms and from tumor progression. However, brainstem gliomas
inevitably progress after radiation therapy and result in death of the patient resulting in a median survival of
less than one year. New strategies are needed to improve the efficacy of radiation therapy to improve patient
survival. One promising investigational therapeutic strategy is to radiosensitize tumors by inactivating the
serine/threonine kinase Ataxia Telangiactasia Mutated (ATM). ATM is the master sensor for DNA damage,
and orchestrates the DNA damage response after cells are damaged by ionizing radiation or other DNA
damaging agents. ATM inactivation dramatically radiosensitizes a genetically engineered mouse model of
brainstem glioma. When ATM is inactivated in the tumor cells of our mouse model of brainstem glioma,
radiation therapy is particularly effective and extends median overall survival of the mice by approximately
threefold compared to mice bearing tumors with intact ATM. However, the specific cell populations that are
radiosensitized by ATM inactivation, and the mechanisms by which ATM inactivation radiosensitizes brainstem
gliomas, is unknown. A deeper understanding of the molecular mechansisms by which ATM inactivation can
radiosensitize brainstem gliomas is needed to enable the rational design of combination therapies that
combine ATM inhibition, radiation therapy, and other novel epigenetic and immunologic therapies to maximize
survival of patients with brainstem gliomas. Here, I will test the hypothesis that ATM inactivation specifically
radiosensitizes a population of progenitor-like tumor cells in our genetically engineered mouse model of
brainstem glioma. In parallel with this work, I will dissect type I interferon signaling pathways that are
contribute to radiosensitivity when ATM is inactivated. These experiments will map the tumor
microenvironment of a mouse model of brainstem glioma at single cell resolution for the first time. They will
also credential a genetically-engineered mouse model of brainstem glioma with an intact immune system for
preclinical investigations of immunotherapeutic approaches. Additionally, the proposed work will provide me
with critical expertise in genetically engineered mouse models and in immunologic investigations that will help
me transition to a productive independent investigator.

## Key facts

- **NIH application ID:** 10448205
- **Project number:** 1K08CA256045-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Zachary Reitman
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $213,541
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448205

## Citation

> US National Institutes of Health, RePORTER application 10448205, Enhancing the efficacy of Radiation Therapy for brainstem glioma by targeting ATM (1K08CA256045-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10448205. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*