# Project 3: A New Therapeutic Target for TERT Promoter Mutant Glioma

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $363,524

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of this project is to develop GABP as a therapeutic target to reverse immortality of tumors harboring a
mutant telomerase reverse transcriptase (TERT) promoter. TERT promoter mutation is the third most common
mutation in human cancer, affecting over 80% of GBM and oligodengroglioma (OD). Due to a lack of TERT
transcription in somatic cells, telomeres shorten with each successive cell division until they reach a critical
level that triggers senescence and limits cell lifespan. Reactivation of TERT expression overcomes these
barriers, enabling tumor cells to proliferate indefinitely. Although proteins controlling mutant TERT promoter
reactivation and tumor cell immortalization may be ideal therapeutic targets, the exact identity of these
molecules remained unknown. We discovered that a single ubiquitously expressed transcription factor, GABP,
uniquely bound to the mutant TERT promoter and drove TERT reactivation in TERT-promoter-mutant glioma
and other cancers. GABP binds DNA as a heterodimer or a heterotetramer which regulate functionally distinct
transcriptional programs. In our preliminary data, we identify a specific heterotetramer forming GABPβ1
isoform (GABPβ1L) that is dispensable in normal cells but may be critical for mutant TERT promoter activation
and tumor cell immortalization. If the mutant TERT promoter is uniformly present throughout each tumor, and if
GABPβ1L modulation leads to tumor cell death while sparing normal cells, the GABP pathway may represent a
new therapeutic option for mutant TERT promoter-driven malignancies. We will test this hypothesis with three
specific aims: In Aim 1, we will determine the extent to which the TERT promoter mutation is clonal at
diagnosis and recurrence. We devised a robust system to collect and analyze clonality in 10 spatially mapped
samples from each GBM and OD, representing maximal tumor geography. In Aim 2, we will determine if the
GABP heterotetramer is required to maintain cellular immortality in TERT promoter mutant CNS tumors. We
will use CRISPR-Cas9 genetic targeting of the GABPB1L isoform to determine the consequences on TERT
expression, telomere length, cell viability and tumor formation. The transcriptome effects and death mechanism
of GABPβ1L deficient tumor cells will be determined to identify vulnerabilities to exploit with existing therapies.
In Aim 3, we will identify therapies that will increase cell death in TERT promoter mutant tumors deficient in
GABPβ1L. In our preliminary data, failure of GBM cells to fully activate TERT expression by a GABP
heterotetramer culminates in telomere dysfunction and DNA damage. We will perform a focused, exploratory
screen of DNA damaging and DNA damage response-inhibiting agents on GABPβ1L deficient cells to identify
therapies that will increase cell death and decrease tumor formation. These studies could establish the
GABPβ1L isoform as a valuable therapeutic target specifically for TERT promoter mutant CNS tum...

## Key facts

- **NIH application ID:** 9999431
- **Project number:** 5P50CA097257-18
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Joseph F Costello
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,524
- **Award type:** 5
- **Project period:** 2002-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999431

## Citation

> US National Institutes of Health, RePORTER application 9999431, Project 3: A New Therapeutic Target for TERT Promoter Mutant Glioma (5P50CA097257-18). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999431. Licensed CC0.

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