# Dual Targeting of Brain Tumor Initiating Cells through Inhibition of BMI1 and EZH2 (R01NS103434)

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $128,590

## Abstract

The most prevalent primary brain tumor, glioblastoma (GBM), ranks among the most lethal of human
cancers. Like the normal brain, GBMs contain cellular hierarchies with self-renewing, multi-lineage cells at
the apex. These brain tumor initiating cells (BTICs), or GBM stem cells, display therapeutic resistance,
promote tumor angiogenesis, and invade into normal tissues. BTICs are not uniformly distributed, but
rather concentrated in specific regions, or niches, including around blood vessels (the perivascular niche)
and in perinecrotic (hypoxic) regions. These niches provide essential cues that maintain stem-like tumor
cells through several pathways that appear specific for each location. In preliminary studies, we find that
biopsies of specific GBM regions contain tumor cells with divergent transcriptional profiles and precursor
markers. Cellular differentiation states reflect the cumulative regulation of chromatin, so we examined the
expression and activity of two core epigenetic regulatory nodes: polycomb repressive complexes 1 and 2
(PRC1/2). Vascular tumor regions were associated with PRC2 activity, whereas hypoxic regions were
associated with measures of PRC1. Collectively, these results suggest that stem-like cancer cells residing
in different locations may be regulated by different epigenetic programs.
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme that serves as the
enzymatic component of PRC2. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) is an essential
component of PRC1. Both EZH2 and BMI1 have been linked to normal and neoplastic stem cells, as well
as therapeutic resistance. Clinical relevance for BMI1 and EZH2 is supported by the development of
targeted therapies against each molecule. We find that mesenchymal BTICs display preferential activity
and dependence on BMI1, whereas proneural BTICs display preferential activity and dependence on
EZH2. As GBMs contain a mixture of proneural and mesenchymal tumor cells, we hypothesized that
combined targeting of BMI1 and EZH2 will offer improved tumor control with acceptable toxicity. Further,
we have identified a novel molecular regulatory mechanism of BMI1 linked to the hypoxic
microenvironment that may inform patient selection for precision (personalized) medicine application of
epigenetic targeting. Finally, additional studies will determine the potential of this therapeutic regimen to
synergize with conventional therapies against glioblastoma. Collectively, these studies will investigate novel
molecular regulation by the tumor microenvironment of neoplastic stem cells that can be directly translated
into clinical trials.

## Key facts

- **NIH application ID:** 10450285
- **Project number:** 7R01NS103434-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JEREMY N RICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $128,590
- **Award type:** 7
- **Project period:** 2017-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450285

## Citation

> US National Institutes of Health, RePORTER application 10450285, Dual Targeting of Brain Tumor Initiating Cells through Inhibition of BMI1 and EZH2 (R01NS103434) (7R01NS103434-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450285. Licensed CC0.

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