# Discovering the mechanisms underlying oncogenesis by ZFTA-RELA and pinpointing therapeutic targets.

> **NIH NIH U01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $601,250

## Abstract

PROJECT SUMMARY:
Ependymoma (EPN) is an aggressive and chemo-resistant pediatric brain tumor, with treatment remaining
surgery and radiation. There are no targeted therapies available to EPN patients at diagnosis or relapse. Over
95% of EPN that arise in the cortex are driven by gene fusions of ZFTA, with ZFTA-RELA fusions (denoted
ZRFUS) being the most common. We and others have developed mouse models of ZRFUS EPN and found that
ZRFUS binds novel genomic loci to activate oncogenic gene expression and drive tumor formation. Despite these
advances, key knowledge gaps regarding ZRFUS biology remain, including: 1) The precise mechanisms of
oncogenic gene expression, including recruitment of co-regulatory factors, following ZRFUS DNA binding, 2) How
the structured domains and intrinsically disordered regions (IDRs) within the ZRFUS protein synergistically
contribute to oncogene activation, and 3) How ZRFUS interaction partners contribute to oncogenesis and whether
they represent therapeutic vulnerabilities. Emerging evidence from us and others across multiple pediatric
cancers has linked fusion oncoprotein (FO) expression to biomolecular condensate formation, possibly through
a phase separation (PS) mechanism, as a possible unifying model of oncogenic gene expression. We
demonstrate that ZRFUS forms dynamic, nuclear condensates, and that key ZRFUS IDRs are necessary for
condensate formation, oncogenic gene expression and tumorigenesis. In addition to identifying several long
IDRs within ZRFUS, we have discovered that the ZFTA zinc finger (ZF) domains in ZRFUS dominantly influence
DNA binding, condensate formation, and oncogenic gene expression. Based on these preliminary data, we
hypothesize that: ZRFUS forms chromatin-associated, liquid-like condensates that are necessary for oncogenic
gene expression and tumor development. To address this hypothesis, we propose the following three
objectives/aims, to (1) Understand how ZRFUS condensates regulate oncogenic expression and tumor
development, (2) Discover the structural basis of ZFTA zinc finger DNA binding and its role in tumorigenesis,
and (3) Interrogate ZRFUS interacting proteins as cancer dependency proteins and therapeutic targets. Overall,
we anticipate that deciphering the mechanisms underlying oncogenesis by ZRFUS, including the biophysics of
condensate formation and functional roles of its condensate interaction partners, may yield novel therapeutic
targets for this aggressive disease.

## Key facts

- **NIH application ID:** 10987405
- **Project number:** 1U01CA294103-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** RICHARD W KRIWACKI
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $601,250
- **Award type:** 1
- **Project period:** 2024-09-13 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987405

## Citation

> US National Institutes of Health, RePORTER application 10987405, Discovering the mechanisms underlying oncogenesis by ZFTA-RELA and pinpointing therapeutic targets. (1U01CA294103-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10987405. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*