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Targeting defective differentiation in the treatment of pediatric rhabdomyosarcoma invasion and metastasis

Award Number: R00CA273296
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Targeting defective differentiation in the treatment of pediatric rhabdomyosarcoma invasion and metastasis - PROJECT SUMMARY Rhabdomyosarcoma (RMS) is a cancer of the skeletal muscle that affects around 350 children each year. Despite advances in the treatment of localized disease, the outcomes for patients with advanced or metastatic disease have not improved in more than forty years. This is partly due to a lack of understanding of the processes driving RMS invasion and metastasis. RMS is characterized in part by a block in differentiation of skeletal muscle (myogenic) precursor cells. My mentor, Dr. Yohe discovered that differentiation can be induced with MEK1/2 inhibitors in PAX/FOXO1 fusion negative RMS (FN-RMS) tumors with oncogenic RAS mutations slowing FN-RMS tumor growth and extending survival in preclinical models. However, because dynamic modulation of differentiation is a mechanism by which many cancers promote metastasis and escape therapy, a deeper understanding of the effect of differentiation on RMS invasion and metastasis is needed for the effective translation of differentiation therapy. This Pathway to Independence (K99/R00) proposal outlines experiments to test the hypothesis that YAP/TAZ-mediated perturbations of FN-RMS differentiation programs drive local invasion and metastasis. This hypothesis will be tested in three Aims. Aim 1 Identify mechanisms by which late myogenic differentiation is dysregulated in FN-RMS in a mechanistic study of NF-kB activity complimented by single cell transcriptomic analysis, innovative differentiation reporter cell lines, and a drug screen to identify targetable perturbations of myogenic differentiation in FN-RMS. Aim 2 investigates tumor-stromal interactions to determine the mechanisms driving invasion in differentiation therapy-resistant cells using both in vitro spheroid invasion assays and in vivo zebrafish tumor invasion studies. Aim 3 utilizes a novel orthotopic xenograft mouse model of spontaneous FN-RMS metastasis and spatial transcriptomics to study dynamic regulation of differentiation on FN-RMS metastasis. The proposed studies will 1) develop novel tools that will benefit the larger community in the investigation of RMS invasion and metastasis, 2) advance our understanding of the mechanisms driving FN-RMS invasion and metastasis, 3) identify new therapeutic strategies for the treatment of patients with advanced FN-RMS. My robust publication and funding record demonstrates my potential as an independent scientist. The exceptional research, training, and career development opportunities at the NIH Intramural Research Program will be complemented by the mentorship of Dr. Marielle Yohe, Dr. Kandice Tanner, and Dr. Corinne Linardic. With the help of my advisory committee (Dr. Jack Shern, Dr. John Brognard, and Dr. Troy McEachron) during the K99 phase, I will develop a strong skill set in transcriptomic data analysis, animal modeling, advanced imaging, and translational research. This technical skill set will be complemented by training in leadership, communication, personnel management, and mentoring. Upon transition to the R00 phase, I will launch a career as an independent investigator leading a translational research program studying invasion and metastasis in advanced sarcomas.


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: 2026 ( Subtotal = $249,000 )
2026	2026	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	000	2	9/3/2026	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2026	2026	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	001	2	9/18/2026	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $249,000

Grand Total All Awards = $249,000

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Targeting defective differentiation in the treatment of pediatric rhabdomyosarcoma invasion and metastasis

Award Number: R00CA273296

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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