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RESEARCH PAPER ANALYSIS

Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.

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PMID40408469
JournalScience advances
Publication Date2025-05-23
Ingested2026-08-02 12:04 AM
EXECUTIVE SUMMARY

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ABSTRACT

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Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRTs). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved antimalarial drug, atovaquone (AVO). We then establish the utility of oxygen-enhanced-multispectral optoacoustic tomography, a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment that results in complete elimination of tumors in all tested mice when combined with 10-gray radiotherapy, a dose several times lower than the current clinic standard. Last, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual patient cohort. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

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PATIENT-FRIENDLY SUMMARY

Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.

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