# Genotypic Interactions in Brain Cancer Heterogeneity

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $536,694

## Abstract

Project Summary
Minimal improvement in the 12-15-month median survival of patients with IDHwt glioblastoma (GBM) has
occurred despite advances in neurosurgery, radiation therapy, and clinical trials for novel therapeutics. A central
issue confounding successful treatment is the heterogeneous nature of this aggressive tumor. Multi-omics
analyses have provided granularity into GBM cellular composition, illustrating that these malignancies can be
classified into three molecular subtypes - classical (CL), mesenchymal (MES), and proneural (PN) - with
individual tumors typically harboring mixtures of all three subtypes. As a result, multiple spatially distinct,
heterotypic populations exist within 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 interactions between heterotypic GBM cells that contribute to its
recalcitrant nature. A hallmark mutation present in 60% of GBM cases is amplification and mutation of the
epidermal growth factor receptor (EGFR). The most common EGFR alteration, EGFRvIII, results from structural
deletion within its extracellular domain (ECD) yielding a constitutively active receptor which conveys tumor
enhancing and therapy resisting functions. Furthermore, EGFRvIII-expressing cells can transmit these properties
to amplified EGFRwt cells through pro-survival, paracrine factors,1 akin to TNFα inflammatory signaling. Like
TNFα, EGFRvIII activity, specifically in the context of PTEN inactivation, results in NF-κB RelA/p65 nuclear
localization, association with members of the acetylated lysine-binding BET (bromodomain and extra terminal
domain) family of enhancer proteins, and activation of inflammatory transcription.1 Given the requirement of RelA
K310 acetylation (acK310-RelA) for BET bromodomain interactions2 and central role of NF-κB in driving a PN/CL
to MES phenotype transition (MESt),3 we postulate that RelA K310 acetylation acts as a regulatory switch
controlling MESt and therapy resistance associated with tumors enriched for MES gene signatures.4
The overall goal of this renewal project is to dissect and target mechanisms whereby GBM PN or EGFR-driven
CL tumors transition to MES gene expression (collectively referred to here as MES transition (MESt)) and acquire
therapeutic resistance through activation of acK310-RelA/BET-mediated inflammatory gene expression. The
following lines of experimentation will be employed: 1) biochemical interrogation of the PTEN signaling pathway
to determine effectors mediating RelA K310 acetylation and associated MESt, tumor abundance of microglia
and macrophages, and resistance to DNA damage; 2) functional analysis of BET family members, BRD2, 3 and
4, through inducible protein degradation, gene editing, bromodomain (BD1, BD2) pharmacological targeting, and
assessment of transcription coupled with acK310-RelA/BET enhancer landscape...

## Key facts

- **NIH application ID:** 10799994
- **Project number:** 2R56NS080939-12A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Frank Furnari
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $536,694
- **Award type:** 2
- **Project period:** 2012-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799994

## Citation

> US National Institutes of Health, RePORTER application 10799994, Genotypic Interactions in Brain Cancer Heterogeneity (2R56NS080939-12A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10799994. Licensed CC0.

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