Hyperpolarized [2-13C]pyruvate provides an early readout of response to precision therapy in mutant IDH gliomas

Motivation: Mutations in isocitrate dehydrogenase (IDHm) define a distinct molecular class of gliomas. IDHm produces the oncometabolite D-2-hydroxyglutarate, which downregulates the activity of pyruvate dehydrogenase (PDH). The IDHm inhibitor vorasidenib was recently approved for treatment of IDHm glioma patients. However, reliable methods of imaging tumor response to therapy are lacking. Goal(s): Assess if hyperpolarized [2-13C]pyruvate provides a readout of response to therapy. Approach: Utilize hyperpolarized [2-13C]pyruvate in cell and rat tumor models. Results: Tracing glutamate production from [2-13C]pyruvate using hyperpolarized 13C-MRI provides an early non-invasive readout of response to vorasidenib that precedes MRI-detectable volumetric alterations in rats bearing intracranial IDHm gliomas in vivo. Impact: Our studies indicate that hyperpolarized [2-13C]pyruvate MRI interrogates early response to targeted therapy in IDHm gliomas. Clinical translation of hyperpolarized [2-13C]pyruvate will provide clinicians with a much-needed tool to monitor disease progression in IDHm glioma patients, which is currently challenging.