Image-Guided Targeting of Mitochondrial Metabolism Sensitizes Pediatric Malignant Rhabdoid Tumors to Low Dose
Abstract:
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.
Insights
Repurposing the anti-malarial drug Atovaquone (AVO) targets metabolic vulnerabilities in pediatric malignant rhabdoid tumors (MRT). Combining AVO with radiotherapy significantly enhances tumor oxygenation and elimination, offering a novel treatment strategy.
Area of Science:
- Oncology
- Biochemistry
- Medical Imaging
Background:
- Tumor hypoxia is a key driver of radioresistance and poor outcomes in pediatric malignant rhabdoid tumors (MRT).
- Mitochondrial oxidative phosphorylation (OXPHOS) represents a critical metabolic vulnerability in MRT.
Purpose of the Study:
- To identify and exploit metabolic vulnerabilities in MRT to overcome hypoxia-induced radioresistance.
- To evaluate the efficacy of Atovaquone (AVO), an anti-malarial drug, as a radiosensitizer for MRT.
- To utilize Oxygen-Enhanced-Multispectral Optoacoustic Tomography (OE-MSOT) for monitoring tumor oxygenation changes.
Main Methods:
- Transcriptomics and bioenergetic profiling to identify MRT metabolic vulnerabilities.
- In vivo studies using Atovaquone (AVO) combined with radiotherapy.
- Oxygen-Enhanced-Multispectral Optoacoustic Tomography (OE-MSOT) for non-invasive hypoxia assessment.
- Translational mathematical modeling for optimizing treatment regimens.
Main Results:
- Atovaquone (AVO) treatment transiently increases tumor oxygenation by targeting OXPHOS.
- Combination therapy of AVO and a reduced radiotherapy dose (10 Gy) led to complete tumor elimination in mice.
- OE-MSOT effectively visualized and quantified hypoxia changes in response to AVO treatment.
Conclusions:
- Atovaquone (AVO) is a promising radiosensitizer for pediatric malignant rhabdoid tumors (MRT) by targeting metabolic vulnerabilities.
- Image-guided metabolic radiosensitization using OE-MSOT offers a safe and effective therapeutic framework.
- This approach holds potential for improved pediatric cancer treatment outcomes.
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