Deuterium metabolic imaging of response to precision therapy in BRAF-V600E mutant gliomas

Motivation: Oncogenic BRAF-V600E mutations are common in gliomas in adults and children. The combination of the BRAF-V600E inhibitor dabrafenib and the MEK1/2 inhibitor trametinib improves patient survival. However, there is considerable variation in the durability of response, underscoring the need for early biomarkers of treatment response. Goal(s): To determine whether dabrafenib/trametinib induces alterations in glucose metabolism that can be leveraged for non-invasive imaging. Approach: Usage of DMI in clinically relevant BRAF-V600E models Results: We show that DMI-detectable lactate production from [6,6'-2H]-glucose provides an early readout of response to therapy that precedes volumetric alterations and predicts extended survival in vivo. Impact: Our studies mechanistically link BRAF/MEK inhibition with downregulation of glycolysis and identify [6,6'-2H]-glucose as a novel contrast agent for imaging early response to therapy. Clinical translation of our studies will enable precision imaging of response to therapy for BRAF-mutant gliomas.