# Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $402,394

## Abstract

Project Summary/Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Despite rigorous clinical trials
the survival for children with high-risk RMS has not changed for three decades. The children that do survive
often suffer from life-long disfigurements as a result of the aggressive treatment. RMS is subdivided into two
major classes, fusion-positive (FP-RMS) and fusion-negative (FN-RMS), based on the presence or absence of
the PAX3-FOXO1 or PAX7-FOXO1 gene fusions. RMS resembles developing skeletal muscle and has been
speculated to originate from genetically compromised skeletal muscle progenitors. Despite the expression of
skeletal muscle master regulator proteins MYOD1 and MYOGENIN, RMS tumors and cells fail to terminally
differentiate, suggesting that RMS is an arrested state of muscle development. The molecular underpinnings of
the differentiation arrest in RMS and therapeutics to drive differentiation are unknown. The long-term goal is to
elucidate the mechanisms that determine the basis for developmental arrest in RMS and design novel, directed
drug therapies for RMS. A study recently identified PTEN promoter hypermethylation with decrease PTEN
expression in over 90% of FN-RMS tumors. In a RMS genetically engineered mouse model (GEMM), PTEN loss
decreased tumor latency, increased tumor penetrance, and much less differentiated tumors more closely
resembling the embryonal RMS in children. PTEN loss did not increase mTOR signaling but was localized in the
nucleus and increased PAX7 expression and ectopic DBX1 expression. DBX1 is a neuronal specific
transcriptional repressor that is ectopically expressed across both human FN-RMS and FP-RMS. Forced DBX1
expression blocks myogenic differentiation in cultured myoblasts. The central hypothesis is that the PTEN-PAX7-
DBX1 axis provides a key node in the developmental arrest in RMS and that DBX1 functions as a transcriptional
repressor blocking differentiation in RMS. The objective of this proposal is to leverage our robust RMS mouse
models coupled with in vitro assays to define the role of PTEN and DBX1 in RMS. To accomplish this objective,
we propose the following Specific Aims: 1) Define the role of PTEN loss in RMS. 2) Determine the mechanism
of DBX1 regulation in RMS. 3) Identify role of DBX1 in blocking myogenic differentiation in RMS. The proposed
studies leverage a simple, rapid RMS GEMM to dissect genes that contribute to RMS biology in vivo and provide
insight into the mechanism maintaining an arrested state of differentiation in RMS. We will use gain- and loss-
of-function approaches both in vivo and in vitro to dissect the roles of AKT1, mTORC1, PAX7 and DBX1 in
modulation of the PTEN loss phenotype. Differentiation therapy of embryonal tumors has proven an efficacious
venue for therapy with 13-cis-retinoic acid for neuroblastoma and all-trans-retinoic acid for acute promyelocytic
leukemia. Molecular and developmental dissection of RMS will reveal new vuln...

## Key facts

- **NIH application ID:** 10331082
- **Project number:** 5R01CA251436-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Mark Edward Hatley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,394
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10331082

## Citation

> US National Institutes of Health, RePORTER application 10331082, Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma (5R01CA251436-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10331082. Licensed CC0.

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