# EXPLORE AND TARGET THE EPIGENETIC VULNERABILITY OF PAX3-FOXO1-DRIVEN RHABDOMYOSARCOMA

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $656,854

## Abstract

ABSTRACT
The genetic abnormalities that drive tumorigenesis are usually coupled with epigenetic alterations such as
aberrant histone lysine methylations due to deregulation of histone methyltransferases and histone lysine
demethylases(KDMs). Our long-term goal is to investigate the mechanism by which oncogenic
transcription factors “hijack” KDMs in tumorigenesis and disease progression, and develop new therapies
to block the functions of these oncoproteins by targeting KDMs. Rhabdomyosarcoma (RMS) is a
devastating soft tissue cancer in children and adolescent young adults. The alveolar RMS (aRMS) is a
more aggressive subtype, with a higher rate of metastasis. aRMS is primarily driven by the pathognomonic
fusion oncoprotein PAX3-FOXO1 or its variant PAX7-FOXO1 through chromosomal translocations of
t(2;13)(q35;q14) or t(1;13)(p36;q14). Despite the fact that current treatment modalities have steadily
improved survival of low-risk RMS patients, the outcome for the fusion positive aRMS patients with
metastasis remains dismal. Even for patients with favorable outcomes, the aggressive chemotherapy and
radiotherapy may lead to long-term adverse effects as children may be particularly vulnerable to long-term
toxicity. These clinical challenges underscore a pressing need to identify new therapeutic targets and
develop better therapies for these patients. However, one obstacle is much less is known about
vulnerabilities that arise in transformed cells by PAX3-FOXO1 that could be exploited therapeutically. In
this application, we will investigate the functional impact of KDM4 in tumorigenesis driven by PAX3-
FOXO1 (Aim 1); dissect the molecular mechanism of KDM4 inhibition on PAX3-FOXO1-driven aRMS (Aim
2), and translate KDM4 inhibitors into novel therapeutic approaches for PAX3-FOXO1 positive aRMS (Aim
3). This innovative study integrates multiple approaches to identify and validate new therapeutic targets
and explore small molecules to dually inhibit oncoproteins in the context of a disease that is driven by a
undruggable fusion oncoprotein. The proposed research will be impactful for its translational relevance for
the treatment of children with high-risk RMS and have the potential to shed new light on the molecular
mechanism of PAX3-FOXO1-driven aRMS.

## Key facts

- **NIH application ID:** 10878910
- **Project number:** 5R01CA266600-03
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Xiang Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $656,854
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878910

## Citation

> US National Institutes of Health, RePORTER application 10878910, EXPLORE AND TARGET THE EPIGENETIC VULNERABILITY OF PAX3-FOXO1-DRIVEN RHABDOMYOSARCOMA (5R01CA266600-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10878910. Licensed CC0.

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