# Dissecting high-risk cell states in neuroblastoma

> **NIH NIH R37** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $613,054

## Abstract

PROJECT SUMMARY/ABSTRACT:
Relapsed disease is a key challenge in cancer biology and medicine. Cancer cells are dynamic and exist in
flexibly interconverting and epigenetically-specified states regulated by master transcription factors (mTFs).
These mTFs determine the transcriptome and resultant malignant phenotype, including controlling striking
differences in sensitivity to chemotherapies. The presence of cellular heterogeneity within tumors, driven by
epigenetic control of cell state is a mechanism by which tumor cells may escape from treatment. This has been
challenging to study, since tumors are commonly marked by a high mutational load, which may obscure the
contribution of cell state. Intriguingly, the pediatric high-risk tumor neuroblastoma (NB) is a heterogenous and
lethal tumor associated with epigenetically-plastic cell states, and is marked by a low mutational burden. This
makes NB an ideal system to study the contribution of cell state to chemosensitivity. Our long-term goal is to
use epigenomic control of cell state to develop mechanistically-based, targeted cancer therapies. The objective
of this proposal is to interrogate how mTFs control cell state and chemosensitivity in NB. Our central
hypothesis is that chemoresistance and sensitivity are controlled by the mTFs that establish the NB
transcriptome and cell state. This hypothesis is formulated based on preliminary data using new systems
including cell state reporters and genome engineering coupled with chemical biology to dissect these flexibly-
interconverting cell states, termed the “adrenergic (ADRN)” and “mesenchymal (MES)” – states. The rationale
for this work is that the MES and ADRN NB cell states display differential sensitivity to chemotherapies and
reflect mechanisms by which NB cells evade conventional therapy, driving lethal tumor relapse. This hypothesis
will be tested in two parallel specific aims: 1) Interrogating the transcriptional controllers of the MES NB state
and leveraging this for therapeutic benefit; and 2) Dissecting the transcriptional maintenance of the ADRN state.
First, we will use our reporters, with gene editing and re-expression models, to determine how candidate mTFs
initiate and maintain the MES state. We will identify and interrogate MES-specific catalytic targets, to disrupt this
chemoresistant, high-risk state. Second, we will use chemical biology approaches in new models of ADRN NB
to dissect how mTFs maintain the ADRN chemosensitive state. Using epigenomics and nascent transcriptomics,
we will determine and validate the targets regulated by each mTF that establish chemosensitivity. These
approaches are innovative as they use new approaches including cell state reporters and chemical degradation
to dissect cell state heterogeneity in NB, to illuminate mechanisms of cell state and chemoresistance control. As
a result, we expect to identify new vulnerabilities, thereby achieving new research horizons. This approach is
significant because it wil...

## Key facts

- **NIH application ID:** 10781488
- **Project number:** 1R37CA286444-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Adam David Durbin
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $613,054
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10781488

## Citation

> US National Institutes of Health, RePORTER application 10781488, Dissecting high-risk cell states in neuroblastoma (1R37CA286444-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10781488. Licensed CC0.

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