Reversed metabolic reprogramming as a measure of cancer treatment efficacy in rat C6 glioma model

BACKGROUND: Metabolism in tumor shifts from oxidative phosphorylation to inefficient glycolysis resulting in overproduction of lactate (Warburg effect), and cancers may be effectively treated if this imbalance were corrected. The aim of this longitudinal study of glioblastoma in a rat model was to determine whether the ratio of lactate (surrogate marker for glycolysis) to bicarbonate (for oxidative phosphorylation), as measured via in vivo magnetic resonance imaging of hyperpolarized (13)C-labeled pyruvate accurately predicts survival. METHODS: C6 Glioma implanted male Wistar rats (N = 26) were treated with an anti-vascular endothelial growth factor antibody B20.4.1.1 in a preliminary study to assess the efficacy of the drug. In a subsequent longitudinal survival study, magnetic resonance spectroscopic imaging (MRSI) was used to estimate [1-(13)C]Lactate and [1-(13)C]Bicarbonate in tumor and contralateral normal appearing brain of glioma implanted rats (N = 13) after injection of hyperpolarized [1-(13)C]Pyruvate at baseline and 48 hours post-treatment with B20.4.1.1. RESULTS: A survival of ~25% of B20.4.1.1 treated rats was noted in the preliminary study. In the longitudinal imaging experiment, changes in (13)C Lactate, (13)C Bicarbonate and tumor size measured at baseline and 48 hours post-treatment did not correlate with survival. (13)C Lactate to (13)C Bicarbonate ratio increased in all the 6 animals that succumbed to the tumor whereas the ratio decreased in 6 of the 7 animals that survived past the 70-day observation period. CONCLUSIONS: (13)C Lactate to (13)C Bicarbonate ratio (Lac/Bic) at 48 hours post-treatment is highly predictive of survival (p = 0.003). These results suggest a potential role for the (13)C Lac/Bic ratio serving as a valuable measure of tumor metabolism and predicting therapeutic response.