IMG-31. DEUTERIUM METABOLIC IMAGING OF RESPONSE TO PRECISION THERAPY IN BRAF-V600E MUTANT GLIOMAS

Oncogenic BRAF-V600E mutations are frequently observed in low- and high-grade gliomas in children. BRAF transduces signals from receptor tyrosine kinases to downstream effectors such as MEK1/2 and ERK, which regulate metabolism and proliferation. The combination of the BRAF-V600E inhibitor dabrafenib and the MEK1/2 inhibitor trametinib (Dab/Tra) improves patient survival. However, there is considerable variation in response durability, underscoring the need for early biomarkers of treatment response. Magnetic resonance imaging (MRI), which is the gold standard for patient management, does not reliably assess response to therapy. Since the BRAF/MEK pathway regulates metabolism, the goal of this study was to determine whether Dab/Tra induces alterations in glucose metabolism that can be leveraged for non-invasive imaging of response to therapy.

We performed gene expression profiling, in vivo metabolomics, stable isotope tracing, and deuterium metabolic imaging in patient-derived and syngeneic BRAF-V600E mutant models (AM38, 2341).

Our studies indicate that Dab/Tra downregulates glucose metabolism to lactate in AM38 and 2341 cells. In vivo infusion with [U-¹³C]-glucose in mice bearing intracranial AM38 tumors confirmed that Dab/Tra downregulates ¹³C-lactate production in the tumor. Mechanistically, Dab/Tra destabilizes hypoxia inducible factor-1a and downregulates glycolytic genes, including SLC2A1, HK2, PFKFB3, and LDHA. Importantly, deuterium metabolic imaging using [6,6’-²H]-glucose, which is a clinical stage method of imaging glycolysis, shows a reduction in lactate production within 48h of treatment with Dab/Tra in AM38 tumor-bearing mice.

Our studies mechanistically link BRAF/MEK inhibition with reduced glycolysis and identify [6,6’-²H]-glucose as a novel, non-invasive agent for imaging early response to therapy. Since [6,6’-²H]-glucose is a safe, orally administered agent, our studies can be rapidly translated to the clinic, where they will provide physicians with a much-needed tool to determine whether patients are responding to therapy at an early timepoint that predicts extended survival.