Metabolic imaging detects low levels of glycolytic activity that vary with levels of c-Myc expression in patient-derived xenograft models of glioblastoma

13C magnetic resonance imaging (MRI) of hyperpolarized [1-13C]pyruvate metabolism has been used in oncology to detect disease, investigate disease progression, and monitor response to treatment with a view to guiding treatment in individual patients. This technique has translated to the clinic with initial studies in prostate cancer. Here we use the technique to investigate its potential uses in patients with glioblastoma (GB). We assessed the metabolism of hyperpolarized [1-13C]pyruvate in an orthotopically implanted cell line model (U87) of GB and in patient-derived tumors, where these were produced by orthotopic implantation of cells derived from different patients. Lactate labeling was higher in the U87 tumor when compared to patient-derived tumors, which displayed inter-tumoral heterogeneity, reflecting the intra- and inter-tumoral heterogeneity in the patients' tumors from which they were derived. Labeling in some patient-derived tumors could be observed before their appearance in morphological images, while in other tumors it was not significantly greater than the surrounding brain. Increased lactate labeling in tumors correlated with c-Myc driven expression of hexokinase 2 (HK2), lactate dehydrogenase A (LDHA) and the monocarboxylate transporters (MCT) and was accompanied by increased radio-resistance. Since c-Myc expression correlates with glioma grade, this study demonstrates that imaging with hyperpolarized [1-13C]pyruvate could be used clinically with GB patients to determine disease prognosis, to detect early responses to drugs that modulate c-Myc expression and to select tumors, and regions of tumors, for increased radiotherapy dose.

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