Friday, October 31, 2025 10/31/2025

Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma

Award Number: R01CA251436
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma - 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 vulnerabilities to develop new therapeutics to drive terminal differentiation of RMS. These studies will have broad impact as DBX1 is highly expressed in pediatric brain tumors and PTEN perturbations are involved in many cancers.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $410,606 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	5	1/13/2025	NON-COMPETING CONTINUATION	$369,546
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	001	5	5/30/2025	NON-COMPETING CONTINUATION	$41,060
														Subtotal = $410,606

Issue Date FY: 2024 ( Subtotal = $390,077 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$20,531
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	4	1/5/2024	NON-COMPETING CONTINUATION	$369,546
														Subtotal = $390,077

Issue Date FY: 2023 ( Subtotal = $402,394 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	3	1/26/2023	NON-COMPETING CONTINUATION	$402,394
														Subtotal = $402,394

Issue Date FY: 2022 ( Subtotal = $402,394 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	001	2	5/5/2022	NON-COMPETING CONTINUATION	$32,849
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	2	2/1/2022	NON-COMPETING CONTINUATION	$369,545
														Subtotal = $402,394

Issue Date FY: 2021 ( Subtotal = $410,606 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	1	1/20/2021	NEW	$410,606
														Subtotal = $410,606

Grand Total All Awards = $2,016,077

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Mediators Of Arrested Differentiation In Pediatric Rhabdomyosarcoma

Award Number: R01CA251436

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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