# Targeting Glioblastoma Stem Cells

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $722,890

## Abstract

PROJECT SUMMARY/ABSTRACT
Glioblastoma represents one of the most lethal types of cancers. Despite extensive molecular
characterization, precision medicine efforts have largely failed for glioblastoma therapy, suggesting that these
complex tumors are resilient ecosystems that overcome singular therapeutic approaches. Aging is strongly
associated with increased incidence and mortality of most cancers, including glioblastoma. However, the
cellular and molecular mechanisms by which aging promotes tumor initiation and progression remain poorly
understood. Tissue-specific stem cells contribute to development, renewal, and regeneration of most organs.
Neural stem cells (NSCs) undergo little to no cell division during normal homeostasis but become activated
by tissue injury with wound responses. NSCs reside in specialized niches that provide maintenance cues
and regulate the balance between quiescence and proliferation. Inflammation and nutrient constraints in NSC
niches in the aging brain promotes quiescence and decreased regenerative potential.
Like the normal brain, glioblastomas contain cellular hierarchies with stem-like tumor cells at the apex. While
controversial, these cancer stem cells contribute to therapeutic resistance, invasion into normal brain,
generation of new vasculature, and evasion of anti-tumor immunity. Cancer stem cells display remarkable
plasticity, rendering therapeutic targeting strategies challenging. In the proposed studies, the Rich laboratory
will leverage insights from aging in the nervous system and the molecular circuitry of cancer stem cells to
understand how aging promotes tumor growth through cell autonomous mechanisms and interactions with
the microenvironment. We will leverage preliminary observations that cancer stem cells reprogram essential
metabolic pathways through integration of extrinsic signals from tumor-infiltrating immune cells and
vasculature to promote epigenetic reprogramming, empowering sustained proliferation, self-renewal, and
immune evasion. Based on this background, we hypothesize that aging promotes reprogramming of the
tumor immune microenvironment and cell autonomous nuclear structural regulation that will inform the
development of novel brain tumor treatments. Using spatial transcriptomics and metabolomics of patient
tumors and organoids, we will investigate the metabolic alterations within the aging tumor microenvironment
to derive multi-modal therapies that disrupt the dynamic growth and survival mechanisms within tumors.

## Key facts

- **NIH application ID:** 11330379
- **Project number:** 7R35CA283998-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** JEREMY N RICH
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $722,890
- **Award type:** 7
- **Project period:** 2024-09-01 → 2031-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11330379

## Citation

> US National Institutes of Health, RePORTER application 11330379, Targeting Glioblastoma Stem Cells (7R35CA283998-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11330379. Licensed CC0.

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