# The DNA Damage Response and Tumorigenesis in the Brain

> **NIH NIH P01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $72,697

## Abstract

Summary - Project 2 
Brain tumors are the most common solid malignancies of childhood and are a leading cause of cancer-related 
death in children. 15-20% of pediatric CNS tumors are high-grade gliomas (HGG), and individuals with these 
tumors have a 2-year survival rate of 10-30%. Despite extensive research into the molecular basis of 
gliomagenesis, current therapies remain ineffective, and the majority of patients die from their disease. More 
effective therapeutic strategies are likely to come from a detailed understanding of glioma pathogenesis. We 
have developed a unique series of new HGG mouse models, relevant to the human disease, which are 
characterized by a range of histopathology reflective of the specific defect in the DNA damage response. In 
Aim 1 of this proposal we will determine the genomic alterations and gene expression profiles that underpin 
these gliomas, particularly in the context of human disease and other mouse glioma models, either established 
or under development in other projects in this program. We will also determine the basis for tumor 
heterogeneity in these models by ascertaining the detailed developmental origins of these gliomas and the 
relative susceptibility of different neural progenitors to transformation. These analyses will illuminate critical 
aspects of the pathogenesis of gliomas for which there is a paucity of definitive information. Finally, we will 
also determine cooperativity in these models with other mutations found in human pediatric HGG, including 
histone H3 mutations, taking advantage of novel models generated by other projects within the program. In 
Aim 2 we propose experiments to establish which DNA repair pathways are critical for genome stability at 
different cortical progenitor stages and how this is linked to chromatin. Because histone mutations and other 
epigenetic alterations have recently been identified as causative molecular changes in pediatric HGG, our 
study will be of central importance for understanding connections between DNA damage signaling, epigenetics 
and tumorigenesis. In Aim 3 we will determine if DNA breaks associated with early replicating fragile sites 
account for DNA structural alterations central to gliomagenesis. Collectively, findings from this study will 
provide fundamental new information to delineate glioma biology that will be important for developing targeted 
therapy for these diseases.

## Key facts

- **NIH application ID:** 10230056
- **Project number:** 3P01CA096832-15S1
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** PETER J MCKINNON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $72,697
- **Award type:** 3
- **Project period:** 2002-07-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230056

## Citation

> US National Institutes of Health, RePORTER application 10230056, The DNA Damage Response and Tumorigenesis in the Brain (3P01CA096832-15S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10230056. Licensed CC0.

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