Image-Guided Targeting of Mitochondrial Metabolism Sensitizes Pediatric Malignant Rhabdoid Tumors to Low Dose Radiotherapy

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRT). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved anti-malarial drug, Atovaquone (AVO). We then establish the utility of Oxygen-Enhanced-Multispectral Optoacoustic Tomography (OE-MSOT), 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 which results in complete elimination of tumors in all tested mice when combined with 10 Gy radiotherapy, a dose several times lower than the current clinic standard. Finally, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual clinical patient population. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.