# Genotypic Interactions in Brain Cancer Heterogeneity

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $345,169

## Abstract

Project Summary
Minimal improvement in the 12-15 month average survival of patients with glioblastoma multiforme (GBM) has
been achieved despite decades of advances in neurosurgery and radiation therapy, many clinical trials for
novel therapeutics, and increased understanding of the driving molecular mechanisms. A central issue that
confounds successful treatment is the heterogeneous nature of this aggressive tumor. This heterogeneity
presents phenotypically as mixed cytological subtypes, genotypically as mutations and gene amplifications,
and transcriptionally as regional differences in gene expression. As a result, multiple and spatially distinct
heterotypic populations exist within a single GBM, making any lesion- or pathway-specific therapy less
effective. While considerable effort has been placed on understanding cell intrinsic mechanisms conferring
therapeutic resistance, much less is known about the interactions between heterogeneous tumor cells within
these neoplasms that contribute to the recalcitrant nature of this cancer. In GBM, amplification of the
epidermal growth factor receptor, a hallmark mutation present in 60% of cases, often occurs in a
heterogeneous manner and is frequently associated with structural alterations. The most common of these
alterations, EGFRvIII, (also known as ∆EGFR) results in a constitutively active mutant receptor with tumor
enhancing capability. This ability is lacking from amplified wtEGFR despite its more pervasive tumor
expression. By modeling this type of genetic heterogeneity in vivo, we have determined that an IL-6 paracrine
signaling mechanism driven by EGFRvIII activity can not only recruit wtEGFR-expressing cells into accelerated
proliferation, but also promote EGFR-targeted therapeutic resistance through activation of a pro-survival
inflammatory NF-κB/BRD4 signaling axis. Given the central role of NF-κB/BRD4 in the remodeling of
chromatin super enhancers we postulate that EGFRvIII/wtEGFR sub-population interactions not only enhance
aggressive tumor growth, but also prompt the synchronization of aspects of gene expression in these
heterotypic cells through shared enhancer remodeling.
The overall goal of this renewal project is to dissect and target the mechanisms whereby GBM EGFR/EGFRvIII
heterogeneity drives therapeutic resistance through orchestration of NF-κB/BRD4-mediated remodeling of the
epigenetic landscape. The following lines of experimentation will be carried out: 1) genome editing to create a
drug-selective BRD4 allele for mechanistic chemical biology studies; 2) use of this modified BRD4 allele as a
tool for chromatin structure and functional analysis of the cytokine-stimulated NF-κB/BRD4 enhancer
landscape in heterotypic and subpopulation-ablated gliomas; 3) genetic and pharmacological inhibition of
identified NF-κB/BRD4-mediated genetic or epigenetic vulnerabilities shared among EGFR and EGFRvIII
heterotypic cells to enhance therapeutic efficacy.

## Key facts

- **NIH application ID:** 10109153
- **Project number:** 5R01NS080939-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Frank Furnari
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,169
- **Award type:** 5
- **Project period:** 2012-09-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109153

## Citation

> US National Institutes of Health, RePORTER application 10109153, Genotypic Interactions in Brain Cancer Heterogeneity (5R01NS080939-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10109153. Licensed CC0.

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