# Role of FACT in ZFTA-RelA fusion driven ependymoma

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $657,440

## Abstract

PROJECT SUMMARY / ABSTRACT
Ependymomas are tumors that occur in the brain or spinal cord and are incurable in nearly half of all patients.
Recent molecular classification has identified numerous molecular subgroups of ependymoma with
supratentorial ependymoma ZFTA-RELA fusion positive (ZFTA-RELA) accounting for over 70% of all
supratentorial ependymomas. ZFTA-RELA, a mainly pediatric brain tumor, has also been identified as one of
the subgroups with the worst prognosis. These tumors arise from the oncogenic fusion between a central gene
in the NF-κB pathway, RELA, and a gene with undescribed function, ZFTA. The resulting fusion protein, ZRfus,
aberrantly recruits transcriptional and chromatin remodeling machinery to drive neoplastic transcriptional
programs that includes constitutive activation of NF-κB signaling, activation of inflammatory gene expression
programs, and stem cell programs. To date, chemotherapy has not become standard of care for any of the
subtypes of ependymoma. All targeted therapies tested in ependymoma clinical trials have failed. Therefore,
there is an urgent need to capitalize on the more recent molecular understanding of ZFTA-RELA to develop
novel therapeutic paradigms that increase survival outcomes for these patients. In the search for co-regulatory
proteins as candidate tumor dependencies and targets, we identified the chromatin remodeling complex, FACT
(FAcilitates Chromatin Transcription), as a ZRfus interacting protein. Moreover, FACT is elevated in ZFTA-RELA
compared to normal brain tissue and other ependymoma disease subtypes. Project goal: To thoroughly
investigate FACT as a driver of ZFTA-RELA and to reveal it as a promising therapeutic target for this devastating
disease. FACT, a heterodimer of SPT16 and SSRP1, mainly serves to reorganize nucleosomes to facilitate RNA
polymerase II-mediated transcription. In tumors, we and others have shown that FACT is essential for
maintaining an undifferentiated stem-like state necessary for tumor growth. This is relevant for ZFTA-RELA
tumors as they are characterized as having undifferentiated transcriptional profiles. Project hypothesis: FACT
regulates ZRfus oncogenic and inflammatory genes to maintain an undifferentiated cell state. Compromising
FACT function will lead to reduced tumor growth, modulate tumor inflammation, and improve survival in
orthotopic murine tumor models. Aim 1: Determine if FACT is essential for sustaining transcription of ZRfus
targets (including oncogenes and inflammatory genes) and stem cell identity genes that may be important for
tumorigenicity. Impact: These studies will reveal how FACT regulates ZRfus transcription and tumor cell identity.
Aim 2: Evaluate the impact of genetic and pharmacological disruption of FACT on tumor progression, immune
landscape, overall survival, and normal neurogenesis. Impact: These studies will reveal preclinical insight into
FACT as a therapeutic target, and the efficacy of our candidate small molecule anti-neopl...

## Key facts

- **NIH application ID:** 10808119
- **Project number:** 5R01CA280203-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Stephen C Mack
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $657,440
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808119

## Citation

> US National Institutes of Health, RePORTER application 10808119, Role of FACT in ZFTA-RelA fusion driven ependymoma (5R01CA280203-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10808119. Licensed CC0.

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