# Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $355,705

## Abstract

Project Summary/Abstract
Glioblastoma (GBM) is the most common and most malignant primary brain tumor and
has a dismal prognosis. Abundant evidence now indicates that a small subset of
neoplastic cells, referred to as Glioma Stem Cells (GSCs), governs biologic behavior
and resistance to therapy. GSCs inhabit specific biologic niches and have properties of
self-renewal, pluripotency and high tumorigenicity. They can be identified by expression
of markers, such as CD133, CD15 and nestin, yet molecular mechanisms responsible
for their specific stem-like behavior in glioblastomas have not been fully defined. This
proposal aims to define mechanisms underlying fundamental biological properties of
GSCs, including: 1) their marked accumulation following the development of necrosis
and tendency to localize to the hypoxic niche; and 2) a disrupted program of asymmetric
cell division that favors self-renewing division over differentiation. We have developed
novel in vitro and in vivo models and analytic techniques to study the differential
behavior of stem and non-stem glioma cells within the tumor micro-environment,
especially as it relates to their accumulation in regions of hypoxia. These include an in
vivo orthotopic xenograft model in which stem cells are interrogated for patterns and
mechanisms of accumulation following the induction of necrosis using a photo-activated
dye. We also dissect pathways that direct asymmetric cellular division in Drosophila
nervous system provide clues to understand the stem/non-stem dynamics in malignant
gliomas. We have previously demonstrated that the human ortholog of Drosophila Brat,
Trim3, is a tumor suppressor that regulates glioma stem cell dynamics and promotes
stemness when lost. Here we propose to investigate novel regulatory mechanisms that
arise during transition to the stem cell phenotype that can be antagonized
therapeutically. Regulatory networks and potential therapeutic targets are further
explored in xenografts and genetically engineered mouse models that recapitulates
human gliomas to show efficacy.

## Key facts

- **NIH application ID:** 10434100
- **Project number:** 5R01CA214928-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** DANIEL J BRAT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $355,705
- **Award type:** 5
- **Project period:** 2018-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434100

## Citation

> US National Institutes of Health, RePORTER application 10434100, Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma (5R01CA214928-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10434100. Licensed CC0.

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