Co-Hyperpolarized Dehydroascorbate and Pyruvate MRI Predicts Radiation Response in Glioblastoma Models

Glioblastoma (GBM) remains the most aggressive and treatment-resistant primary malignant brain tumor in adults. Current imaging assessments fail to capture early metabolic responses to therapy, underscoring the need for biomarkers that reflect treatment efficacy in real time. Radiation critical component of GBM treatment, increasing oxidative stress on the cell through numerous mechanisms. This study investigates metabolic reprogramming in response to oxidative stress as an indicator of radiosensitivity and evaluates co-hyperpolarized (HP) [1- ¹³ C] dehydroascorbate and [1- ¹³ C] pyruvate (HP DHA/PA) magnetic resonance imaging as a quantitative approach to assess redox and glycolytic flux changes in GBM. In vitro analyses across four human GBM cell lines revealed that glutathione depletion sensitizes some GBM cells to radiation, with corresponding upregulation of the pentose phosphate pathway (PPP) and pyrimidine synthesis. Leveraging both radiosensitive and radioresistant orthotopic xenograft GBMs, co-hyperpolarized DHA/PA imaging detected reductions in both DHA-to-vitamin C and pyruvate-to-lactate conversion in radiosensitive tumors in vivo , reflecting diminished reductive capacity and oxidative stress following radiation. Metabolomic profiling confirmed increased pyrimidine metabolism in responsive tumors and purine metabolism in resistant ones, aligning with known mechanisms of radioresistance. Collectively, these findings establish HP DHA/PA imaging as the first non-invasive method to quantify oxidative stress and identify radiation responders in GBM prior to anatomical changes.