# In vivo regulators of TERT promoter mutant glioblastoma

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $48,914

## Abstract

Project Summary/Abstract
A crucial step in the development of human cancer is the ability of cells to undergo immortalization by avoiding
senescence and apoptosis that result from repeated cell divisions. To accomplish this, 90% of cancers
reactivate telomerase reverse transcriptase (TERT), the catalytically active and rate-limiting subunit of
telomerase. Telomerase functions to maintain telomeres, which cap the ends of chromosomes, protecting
chromosomal DNA from the end replication problem. Normally, TERT is expressed in stem cells, but is
transcriptionally silenced in somatic cells. However, recent work has demonstrated that many cancer subtypes,
including 83% of primary glioblastoma (GBM) tumors, contain activating mutations in the TERT promoter.
These mutations result in binding of the transcription factor GA binding protein (GABP), and reactivation of
TERT, through incompletely understood mechanisms. Understanding and targeting genes and pathways
related to these phenomena has the potential to open major future therapeutic avenues for GBM, the most
common and most severe form of adult brain cancer. The current proposal will make use of a focused in vivo
CRISPRi growth-based screen using an intracranial xenograft model of GBM to uncover factors that regulate
immortality of TERT promoter mutant GBM cells. The targeted screen will be performed in both control and
GABP mutant cell lines, in order to elucidate genes that function both synergistically with and independently of
GABP. In parallel, the proposal aims to engineer Cas9 ribonucleoprotein (RNP) complexes that target GBM
cells specifically, using receptor-mediated uptake. Cas9 RNP complexes are currently being developed with
future therapeutic intent, given the tendency for reduced toxicity and off-target effects as compared to other
methods of CRISPR editing. These GBM-specific RNPs will be designed with the ultimate goal of editing genes
to reverse cellular immortality in TERT promoter mutant GBM cells, both in vitro and in vivo. Overall, this work
will develop CRISPR-based technologies for both in vivo screening and targeting of GBM cells, with the goal of
elucidating and inhibiting major factors that underlie GBM cellular immortality.

## Key facts

- **NIH application ID:** 9918280
- **Project number:** 5F32CA228365-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** ALEXANDRA M AMEN
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $48,914
- **Award type:** 5
- **Project period:** 2018-06-01 → 2021-02-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918280

## Citation

> US National Institutes of Health, RePORTER application 9918280, In vivo regulators of TERT promoter mutant glioblastoma (5F32CA228365-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9918280. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*