# Towards Novel Differentiation Therapies for Neuroblastoma.

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $348,888

## Abstract

Neuroblastoma (NB) is a neural crest-derived malignancy that accounts for approximately 15% of pediatric
cancer deaths. Importantly, NB arises from a failure of sympathoadrenal progenitors to differentiate.
Furthermore, the degree of tumor differentiation strongly correlates with NB outcome, as the most
undifferentiated tumors are predictive of poor overall survival. We have recently identified a novel pathway that
is capable of restricting NB differentiation, and this pathway involves de-regulation of the histone chaperone
CHAF1A (chromatin assembling factor-1A). CHAF1A is a major epigenetic and transcriptional regulator and its
aberrant expression has recently been linked to tumorigenesis in numerous cancers. We found that high
CHAF1A expression strongly predicts poor NB survival and an undifferentiated phenotype. Importantly, we show
that CHAF1A is necessary for in vivo tumor establishment and growth, restricts NB differentiation, and rewires
distinct metabolic programs. Thus, our guiding hypothesis is that NB remains frozen in a highly undifferentiated
state in part due to CHAF1A-mediated suppression of differentiation programs and metabolic reprogramming.
Our working model is that by blocking CHAF1A functions, we can drive NB to differentiate. The specific aims of
this proposal will test these hypotheses and determine: 1) the contribution of CHAF1A to NB resistance to
differentiation therapy, 2) the molecular mechanisms through which CHAF1A blocks NB differentiation and
reprograms tumor metabolism, and 3) how CHAF1A metabolic reprogramming alters NB tumorigenesis and
response to differentiation therapy. We expect to uncover the molecular mechanisms by which CHAF1A opposes
NB differentiation and to identify genes and pathways that alter tumor metabolism in CHAF1A-driven
tumorigenesis. We expect that the proposed research will also more generally provide new insight into the
transcriptional regulation of NB differentiation and energy metabolism in NB progression and resistance to
therapy. These studies will be significant as these findings will lead to develop novel differentiation therapies for
NB.

## Key facts

- **NIH application ID:** 10408043
- **Project number:** 5R01CA222224-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Eveline Barbieri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $348,888
- **Award type:** 5
- **Project period:** 2019-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10408043

## Citation

> US National Institutes of Health, RePORTER application 10408043, Towards Novel Differentiation Therapies for Neuroblastoma. (5R01CA222224-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10408043. Licensed CC0.

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