Abstract
BACKGROUND
Diffuse midline gliomas (DMGs) harboring histone H3K27M mutations are devastating pediatric brain tumors. ONC201 is the first drug in decades to extend survival in DMG patients and is likely to be widely used for treatment of DMGs. However, magnetic resonance imaging (MRI), the gold standard for patient management, does not provide a reliable readout of response to therapy. The Warburg effect describes the propensity of tumor cells to increase glucose uptake and conversion to lactate. Deuterium metabolic imaging of the Warburg effect using [6,6’-2H]-glucose provides the unparalleled opportunity to obtain a biologically meaningful readout of treatment response. Therefore, the goal of this study was to assess the utility of [6,6’-2H]-glucose for DMG imaging.
METHODS
We performed expression profiling and deuterium metabolic imaging in patient-derived and syngeneic DMG models.
RESULTS
Our studies indicate that DMG cells upregulate key components of the Warburg effect, including SLC2A1, SLC2A3, HK2, PFKFB3, PGK1, and LDHA relative to normal astrocytes. Silencing the H3K27M mutation in DMG cells reduced glycolytic gene expression. Spatially resolved 2D chemical shift imaging at 3T showed that lactate produced from [6,6’-2H]-glucose was localized to tumor vs. normal brain in mice bearing intracranial tumors. ONC201 downregulated glycolytic gene expression in DMG cells, an effect that was accompanied by reduced lactate production from [6,6’-2H]-glucose. Importantly, lactate production from [6,6’-2H]-glucose was reduced following treatment with ONC201 in mice bearing intracranial tumors at 3T, at an early timepoint independent of MRI-detectable volumetric alterations and predictive of extended survival.
CONCLUSIONS
Our studies mechanistically link the H3K27M mutation with the Warburg effect. Importantly, they identify [6,6’-2H]-glucose as a novel contrast agent for visualizing the metabolic lesion and imaging early response to therapy in DMGs. Since [6,6’-2H]-glucose is a safe, orally administered agent, our studies have the potential to be rapidly translated to the clinic, where they will provide physicians with a much-needed tool to determine whether DMG patients are responding to therapy.