Mapping of choline uptake and metabolism in brain tumors with deuterium metabolic imaging (DMI)

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PROJECT SUMMARY While neuro-oncologists rely heavily on medical imaging, particularly magnetic resonance imaging (MRI) for detection and sizing of brain tumors, they do not have access to a robust method that shows the active metabolism of tumor lesions. Positron emission tomography (PET) detection of the radioactive glucose analog 18F-deoxyglucose (FDG) is widely used for metabolic imaging of many solid cancers outside of the brain. FDG- PET detects high glucose uptake, which is often a sign of active and growing tissue, such as in proliferating tumors. However, when used for scanning tumors in the brain FDG-PET has shown to be often inconclusive. This is not due to any technical limitation, but merely the consequence of the high glucose uptake of normal brain, leading to high background signal and thus low metabolic image contrast between brain and tumor. Choline is an essential nutrient, and proliferating cells need choline for phospholipid and membrane synthesis. As a result, many types of cancer have evolved with a high capacity for choline uptake and metabolism. In contrast, choline uptake in normal brain is in comparison very low. Our preliminary data indicate that the detection of deuterated choline uptake and metabolism using the novel technique Deuterium Metabolic Imaging (DMI) can provide high brain tumor-specific image contrast with surrounding brain. DMI of deuterium (2H)-labeled choline allows detection of choline uptake and/or choline metabolism, simply by varying the timing of the scan in relation to the start of the choline administration. These features make choline DMI a very promising metabolic imaging technique for use in brain tumors. The overall objective is to investigate the potential of choline DMI as a metabolic imaging method for brain cancer. In this R03 research project we propose to investigate the value of mapping choline uptake and metabolism with DMI as correlate for brain tumor grade and prognosis (Aim 1), and evaluating treatment effect (Aim 2). We will use two established mouse models of brain tumor grade 3, and grade 4 glioma, and test the effect of temozolomide, the standard of care chemotherapeutic, on tumor choline uptake and metabolism. Choline is an essential nutrient and used as a nutritional supplement within and outside of clinical settings, at very high but safe doses. Deuterium is a stable isotope and commonly used as a tracer for metabolic studies. Finally, DMI is a highly translatable imaging technique, already applied in clinical research settings. Therefore, if the potential of mapping of choline uptake and metabolism is established in these rodent models, rapid translation of DMI for detection of deuterium-labeled choline in human patients is relatively straightforward.