Date of Award
Fall 2025
Document Type
Thesis
Degree Name
Master of Science (MS) in Biology
Department
Biology
Committee Chair
Dr. Le Su
Abstract
CIC-DUX4 sarcoma (CDS) is a rare, aggressive round-cell tumor that primarily affects children and young adults and is associated with poor clinical outcomes. Current treatments borrow from Ewing sarcoma regimens but offer limited benefit, underscoring the need for targeted therapeutic strategies. Transcriptomic analysis of CDS cell lines revealed a striking overrepresentation of ribosome biogenesis genes, indicating that CDS relies heavily on hyperactive RNA Polymerase I (Pol I)–driven rRNA synthesis. To evaluate this vulnerability, the Pol I inhibitors CX-5461 and BMH-21 were tested across multiple functional assays, including rRNA transcription, proliferation, migration, and 3-dimensional spheroid growth. Both inhibitors reduced rRNA synthesis and suppressed tumor cell growth in a dose-dependent manner, with BMH-21 consistently demonstrating superior potency. BMH-21 also produced stronger nucleolar stress responses, including greater suppression of 45S rRNA and robust p53 stabilization. These results collectively show that CDS cells are highly dependent on Pol I activity for survival, migration, and 3D tumor architecture. Targeting Pol I represents a promising therapeutic strategy, with BMH-21 emerging as a particularly effective candidate for further preclinical development in CIC-DUX4 sarcoma.
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