Friday, April 26, 2024
4/26/2024
ABSTRACT Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, harbingers a poor prognosis. Alveolar rhabdomyosarcoma (aRMS) generally presents during the teen years and is myogenic, affecting the larger skeletal muscles of the arms, legs, or torso. In aRMS the chimeric fusion genes, PAX3-FOXO1A and PAX7-FOXO1A (PAX-FKHR), are prevalent genetic abnormalities. However, the key effector genes of PAX- FKHR and the mechanisms of how these target genes contribute to malignant transformation in aRMS remain poorly defined. The rewiring of metabolic programs to meet the demands of growth and proliferation is a characteristic hallmark of all cancers. We have revealed an enriched metabolo-transcriptome signature in the ¿-aminobutyric acid (GABA) metabolic shunt that links to the glutamine and arginine catabolic pathways. GABA transaminase (ABAT) encodes a rate-limiting enzyme in the GABA shunt and is one of the top targets of PAX- FKHR. Our preliminary data show that ABAT is required for maintaining the myogenic lineage identity in aRMS cell lines. Hence, our central hypothesis is that the ABAT is a key metabolic effector of PAX-FKHR that drives metabolic rewiring to ensure myogenic and malignant phenotypes of aRMS. We propose to 1) determine the role of ABAT in driving aRMS development in a mouse model, and 2) coordinately assess the PAX-FKHR dependent metabolic programs in aRMS and determine the metabolic dependency (“addiction”) of aRMS cells on these metabolic pathways. Our long-term goal is to understand the oncogenic function of PAX- FKHR and discover novel therapeutic approaches targeting metabolic alterations and to assess the prognostic value of measuring metabolic enzymes and metabolites in RMS.
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