# Novel Therapeutic Approaches for the Treatment of Neuroblastoma

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $410,606

## Abstract

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating
mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and
inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis.
Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages
and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated
MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic
reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative
stress. The combination of replicative stress caused by defects in the ATRX–histone chaperone
complex and that induced by MYCN-mediated metabolic reprogramming leads to synthetic lethality.
Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor
gene and activation of an oncogene are incompatible. In this proposal, we will exploit this synthetic
lethality to improve outcomes for patients with high-risk and/or recurrent neuroblastoma. Specifically,
we will use molecular targeted therapeutics to perturb ATRX-dependent processes in MYCN amplified
neuroblastomas and to disrupt MYCN-dependent processes in ATRX deficient tumors. In this
translational research proposal, we will target both the tumor cells and the tumor microenvironment.
All published and unpublished data are freely shared through the Childhood Solid Tumor Network to
accelerate discovery on neuroblastoma. The results of these studies will be used to design the next
neuroblastoma clinical trials at St. Jude.

## Key facts

- **NIH application ID:** 10130472
- **Project number:** 5R01CA248432-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Michael A Dyer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,606
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130472

## Citation

> US National Institutes of Health, RePORTER application 10130472, Novel Therapeutic Approaches for the Treatment of Neuroblastoma (5R01CA248432-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130472. Licensed CC0.

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