# Clinical & Mechanistic underpinnings to reducing PAX:FOXO1 for alveolar rhabdomyosarcoma

> **NIH NIH R01** · CHILDREN'S CANCER THERAPY DEVELOP/INST · 2024 · $288,592

## Abstract

SUMMARY
The childhood muscle cancer alveolar rhabdomyosarcoma (ARMS) is generally not survivable when metastatic.
However, ARMS does usually respond clinically to chemotherapy initially. With respect to the cause of
recurrences, clinicians observe that the PAX3:FOXO1 oncogene present in most ARMS cases mediates
treatment resistance, causing a 45% drop in 10-year survival. In explanation, we reported that PAX3:FOXO1
facilitates G2/M checkpoint adaptation (tolerance of DNA breaks & mitotic catastrophe). Thus, the driving clinical
challenge is to overcome recurrence by counteracting PAX3:FOXO1. We published that PAX3:FOXO1 can be
pharmacologically silenced by entinostat, a novel histone deacetylase inhibitor. We find entinostat dramatically
improves ARMS sensitivity to frontline chemotherapy. Mechanistically, our recently published studies implicate
an HDAC3 – SMARCA4 – miR-27a – PAX3:FOXO1 regulatory circuitry in ARMS. In parallel we have uncovered
that SMARCA4 expression is uniquely elevated in fusion positive ARMS, and that ARMS-selective SMARCA4
expression is a pivotal long-term susceptibility in tumor cell survival. These results point to SMARCA4 having a
key role in fusion positive ARMS – controlling PAX3:FOXO1 and chemotherapy sensitivity in the short-term and
tumor cell maintenance long-term. We hypothesize that PAX3:FOXO1+ ARMS can be made more
chemosensitive at relapse and less likely to recur by epigenetically silencing PAX3:FOXO1. Thus, our aims are
to: (1) Delineate the atypical role of SMARCA4 as an oncogene in ARMS via the SWI/SNF BAF complex,
and (2) Test efficacy of direct PAX3:FOXO1 inhibition versus upstream SMARCA4/A2 inhibition versus
entinostat when combined with relapse chemotherapy and non-chemotherapy agents. From these
results, we hope to understand rhabdomyosarcoma molecular underpinnings.

## Key facts

- **NIH application ID:** 10834223
- **Project number:** 5R01CA258720-04
- **Recipient organization:** CHILDREN'S CANCER THERAPY DEVELOP/INST
- **Principal Investigator:** CHARLES KELLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $288,592
- **Award type:** 5
- **Project period:** 2021-05-14 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834223

## Citation

> US National Institutes of Health, RePORTER application 10834223, Clinical & Mechanistic underpinnings to reducing PAX:FOXO1 for alveolar rhabdomyosarcoma (5R01CA258720-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10834223. Licensed CC0.

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