# Selective targeting of ependymoma progenitor cells via BMI1 inhibition

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2023 · $218,089

## Abstract

PROJECT SUMMARY
Ependymoma (EPN) is fatal in 50% of children and has not seen any therapeutic
improvements in over 30 years. Standard therapy remains limited to surgery, radiation,
and chemotherapy in limited situations. In the past decade our understanding of the
molecular biology of EPN has been advanced by molecular analysis of patient samples
but these advances have failed to improve outcomes. Genomic studies clearly define
multiple subgroups including Posterior fossa A and B as well as supratentorial subgroups.
Despite these advances the heterogeneity in EPN remains a problem. To address this
problem, we performed single cell RNA sequencing analysis of EPN patient samples and
identified an undifferentiated progenitor population that expresses high levels of
pluripotent cell markers. In parallel we performed an unbiased epigenome-wide RNAi
screen targeting 410 chromatin regulators to identify novel epigenetic regulators critical
for EPN cell growth. We identified the Polycomb repressive complex 1 (PRC1) protein
BMI1 as a top hit, that when depleted or chemically inhibited severely suppressed EPN
cell growth. Interestingly BMI1 is most highly expressed in the undifferentiated population
identified by our scRNA-seq and associated with worse outcomes. Importantly the
functional significance of BMI1 has not previously been evaluated in EPN. We
hypothesize that high expression of BMI1 promotes de-differentiation and self-renewal of
the UEC subpopulation, thereby locking the cells in a highly tumorigenic stem-like state.
To address our hypothesis, we will first investigate the inhibition of BMI1 function on PFA
tumor cell self-renewal and differentiation of aggressive PFA subpopulations in vitro. We
will then establish the therapeutic efficacy of targeting BMI1 with novel small molecule
inhibitors in EPN in vivo. Completion of this work will establish a direct role for BMI1 in
EPN stem cell differentiation and provide justification for use of BMI1 inhibitors in human
pediatric clinical trials.

## Key facts

- **NIH application ID:** 10648408
- **Project number:** 1R21CA280148-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Rajeev Vibhakar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $218,089
- **Award type:** 1
- **Project period:** 2023-04-20 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10648408

## Citation

> US National Institutes of Health, RePORTER application 10648408, Selective targeting of ependymoma progenitor cells via BMI1 inhibition (1R21CA280148-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10648408. Licensed CC0.

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