# Dissecting the contribution of the transcriptional regulators of SNS fate to neuroblastoma oncogenesis

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $347,700

## Abstract

Project Summary/Abstract:
Neuroblastoma (NB) is the most common cancer of infancy and arises from immature cells of the sympathetic
nervous system (SNS) that derive from neural crest stem cells (NCCs). NB is responsible for 15% of pediatric
cancer deaths with the majority of high-risk NB patients eventually relapsing with resistant disease. Finding
novel treatments, especially for relapse disease, is desperately needed for high-risk neuroblastoma. The
standard model of neuroblastoma initiation assumes a block in differentiation. We propose that SNS factors
important for the growth and establishment of the SNS are co-opted by neuroblastoma mutations to instead
support the growth and establishment of the tumor. Further based on our preliminary findings we propose a
class of drugs called BET inhibitors, which were found to be very effective against neuroblastoma, partially
function by suppressing important SNS factors. Here, we hypothesize that SNS cell fate regulators, are
critical for NB oncogenesis and responsible for NB sensitivity to BET inhibitors. The two aims we
will pursue in this proposal: Aim 1: Are regulators of cell fate critical targets of BET inhibition in NB? Aim 2:
Does cell identity/developmental stage contribute to malignant transformation of primary NCCs? For the first
aim we will determine in neuroblastoma cell lines, if BET inhibitors work through turning off critical SNS
factors. Thus, here we will: 1) Interrogate the impact of BET inhibitors on SNS lineage factors expression. 2)
Investigate loss of the BET protein BRD4 binding in response to the BET inhibitor JQ1, in human NB cell lines.
3) Test if silencing SNS lineage factors individually or in combination interferes with growth of human NB cell
lines and NB tumors. 4) Determine if lineage factors expressed in trans from the JQ1-insensitive MSCV
promoter conveys resistance to BET inhibitors in human NB cell lines and patient derived xenograft tumors.
Aim 1 will establish if SNS lineage factors are necessary for NB maintenance. In Aim 2, we will interrogate if
these factors are functionally required for NB oncogenesis. To test the second aim we will use a unique system
we have developed for turning normal immature SNS mouse cells, the NCCs, into neuroblastoma to determine
if the important SNS factors can contribute to initiating neuroblastoma. For the second aim we will: 1)
Determine if the SNS core factors block NCC differentiation into sympathetic neurons. 2) We will determine if
the SNS core transcription factors promote tumorigenic behavior in vitro. 3) Determine if the SNS core
transcription factors promotes the formation of NCC-derived NB tumors alone or in combination with N-Myc
or 1p36 loss of heterozygosity, two common mutations in NB. Overall, our work will inform us of whether
factors important for SNS development also contribute to neuroblastoma. Further our ability to engineer
neuroblastoma tumors from immature SNS mouse cells uniquely enables us to illuminate n...

## Key facts

- **NIH application ID:** 10179331
- **Project number:** 5R01CA216394-05
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Kevin W. Freeman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $347,700
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179331

## Citation

> US National Institutes of Health, RePORTER application 10179331, Dissecting the contribution of the transcriptional regulators of SNS fate to neuroblastoma oncogenesis (5R01CA216394-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10179331. Licensed CC0.

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