# Rewired Metabolism and Immunosuppression in MYCN-driven Neuroblastoma

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $431,968

## Abstract

PROJECT SUMMARY
Amplification of the oncogene MYCN drives high-risk progressive disease, resistance to therapy, and a poor
overall survival rate below 45% for high-risk neuroblastoma (NB) patients. Further, more than half of all high-risk
patients will relapse, and the post-relapse survival rate is only 10%. MYCN-driven NB tumors have poor immune
responses due to a relatively low mutational load, low MHC-I expression, and reduced immune cell infiltration.
As a result, NB is often immunologically quiescent, thus limiting immunotherapy approaches. MYCN amplification
has a central role in orchestrating the metabolic reprogramming that favors NB growth and adaptation to its
microenvironment. Tumor cells and immune cells exist in a complex environment where they share and compete
for specific nutrients. Through unbiased transcriptomics, metabolomics, and immune profiling of TH-MYCN GEM
and syngeneic mouse models of NB, we have identified cysteine metabolism as a selective vulnerability in
MYCN-driven NB. We have also found that MYCN drives an immune suppressive tumor microenvironment
(TME) during oncogenesis, and reprograms NB tumors to create a cysteine-poor TME. By lacking de novo
biosynthetic enzymes, T cells are exquisitely vulnerable to cysteine starvation, while cysteine supplementation
restores T-cell activation, expansion, and effector functions. Our central hypothesis is that MYCN-driven tumor
intrinsic metabolism and recruitment of other cysteine-consuming cells (such as PMN-MDSCs) deplete
extracellular cysteine, thus blocking T cell anti-tumor activity. This proposal aims to: (1) elucidate how oncogenic
MYCN rewires the metabolic environment of NB to drive immune suppression; and (2) modulate the metabolic
environment of NB to enhance immune-based approaches for high-risk MYCN-amplified disease.

## Key facts

- **NIH application ID:** 10978992
- **Project number:** 1R01CA283369-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Eveline Barbieri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $431,968
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978992

## Citation

> US National Institutes of Health, RePORTER application 10978992, Rewired Metabolism and Immunosuppression in MYCN-driven Neuroblastoma (1R01CA283369-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10978992. Licensed CC0.

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