# Identifying and targeting oncogenic Myc enhancer control in pediatric tumors

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $382,301

## Abstract

Myc deregulation is a hallmark of cancer and promotes tumor aggression across multiple tumor types.
When deregulated, levels of the full length Myc (MYC, MYCN, or MYCL) transcription factor are drastically
increased, leading to a global remodeling of gene expression that is poorly understood. Here we show
evidence for and propose “Myc enhancer invasion” as a novel mechanism in which excess Myc protein
invades distal cis-regulatory enhancers that are not normally bound at physiological Myc levels. As enhancers
control tissue specific gene expression, Myc invasion creates aberrant regulatory interactions that drive tumor
progression and can be targeted as a therapeutic strategy.
 Specifically, we have developed and provide evidence for a model of Myc enhancer invasion in which
1) a subset of enhancers contain weak Myc binding motifs that are accessed when Myc is deregulated. 2)
Invaded enhancers act as reservoirs for excess Myc binding and drive the Myc responsive transcription of
target genes. 3) Tumor specific enhancer landscapes specify the context of Myc enhancer invasion leading to
different enhancer invasion responsive genes in different tumors. 4) Enhancer invaded pathways and other
transcription factors that form enhancers can be targeted to interdict tumor specific Myc transcriptional control.
 To investigate this model for Myc enhancer invasion, we propose the following specific aims. 1) To map
and model Myc enhancer invasion in neuroblastoma and osteosarcoma in order to identify genomic
parameters that predicate enhancer invasion. 2) To investigate transcriptional consequences of Myc enhancer
invasion in vitro and in vivo in order to functionally validate that tumor specific Myc enhancer invaded target
genes are dynamically and selectively responsive to Myc perturbation. 3) To identify and target oncogenic Myc
enhancer regulation to establish proof of concept for the therapeutic targeting of Myc enhancer regulation.
 We will perform this work in pediatric neuroblastoma and osteosarcoma models and primary tumors. In
these diseases, Myc deregulation is associated with high risk disease, metastasis, increased tumor
aggression, and poor responsiveness to existing treatments. As no targeted therapies exist for Myc
deregulated neuroblastoma or osteosarcoma, there is a critical unmet need for novel strategies to identify
dependencies and effectors of Myc deregulation. In our preliminary data, we find that the enhancer
transcription factor TWIST1 acts as a co-factor of MYCN enhancer invasion and is a specific dependency of
MYCN driven neuroblastoma. These data highlight the utility of the proposed approach to connect mechanistic
investigation of Myc transcriptional regulation to novel frameworks for the identification and validation of tumor
specific therapeutic targets in Myc driven neuroblastoma and osteosarcoma.

## Key facts

- **NIH application ID:** 9891027
- **Project number:** 5R01CA215452-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Thomas Westbrook
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,301
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891027

## Citation

> US National Institutes of Health, RePORTER application 9891027, Identifying and targeting oncogenic Myc enhancer control in pediatric tumors (5R01CA215452-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9891027. Licensed CC0.

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