CNS Tumor Metabolism: Targets, Markers, and Challenges

Introduction: There is a lack of robust metabolic imaging techniques that can be routinely applied to characterize lesions in patients with brain tumors. Here we explore in an animal model of glioblastoma the feasibility to detect uptake and metabolism of deuterated choline and describe the tumor-to-brain image contrast.

Methods: RG2 cells were incubated with choline and the level of intracellular choline and its metabolites measured in cell extracts using high resolution ¹H NMR. In rats with orthotopically implanted RG2 tumors deuterium metabolic imaging (DMI) was applied in vivo during, as well as 1 day after, intravenous infusion of ²H₉-choline. In parallel experiments, RG2-bearing rats were infused with [1,1′,2,2′-²H₄]-choline and tissue metabolite extracts analyzed with high resolution ²H NMR to identify molecule-specific ²H-labeling in choline and its metabolites.

Results: In vitro experiments indicated high uptake and fast phosphorylation of exogenous choline in RG2 cells. In vivo DMI studies revealed a high signal from the ²H-labeled pool of choline + metabolites (total choline, ²H-tCho) in the tumor lesion but not in normal brain. Quantitative DMI-based metabolic maps of ²H-tCho showed high tumor-to-brain image contrast in maps acquired both during, and 24 h after deuterated choline infusion. High resolution ²H NMR revealed that DMI data acquired during ²H-choline infusion consists of free choline and phosphocholine, while the data acquired 24 h later represent phosphocholine and glycerophosphocholine.

Discussion: Uptake and metabolism of exogenous choline was high in RG2 tumors compared to normal brain, resulting in high tumor-to-brain image contrast on DMI-based metabolic maps. By varying the timing of DMI data acquisition relative to the start of the deuterated choline infusion, the metabolic maps can be weighted toward detection of choline uptake or choline metabolism. These proof-of-principle experiments highlight the potential of using deuterated choline combined with DMI to metabolically characterize brain tumors.

2,141 views

14 citations

Review

09 November 2023

Differential metabolic alterations in IDH1 mutant vs. wildtype glioma cells promote epileptogenesis through distinctive mechanisms

Darrian McAfee

, 6 more and

Alexander Ksendzovsky

3,536 views

1 citations

Inhibition of the pyruvate dehydrogenase (PDH) complex by pyruvate dehydrogenase kinase (PDK) is responsible for the aerobic glycolysis observed in cancer, also known as the Warburg phenomenon. Accumulation of cytosolic pyruvate is converted to lactate which contributes to the acidification of the extracellular environment or utilized for anabolic processes necessary for cancer cell growth and proliferation. DCA inhibits PDK, activating the PDH complex and thus forcing the cancer cell to allow pyruvate to enter the tricarboxylic acid cycle and eventually terminal oxidation to generate ATP and restore the apoptotic machinery of the mitochondrion. The metabolic consequence is a rapid reduction of extra and intracellular lactate as well as increase of glutamate as the cell no longer has to rely on the latter as an alternative carbon source for the TCA cycle. (B) Representative 1H-MRS spectra from a low-grade glioma (left) normal appearing brain from the same patient (middle) and healthy normal volunteer (right). The signals from glutamate (Glu, blue) and lactate (Lac, orange) can be monitored after DCA administration to assess efficacy of drug delivery.

Mini Review

17 March 2023

In-vivo magnetic resonance spectroscopy of lactate as a non-invasive biomarker of dichloroacetate activity in cancer and non-cancer central nervous system disorders

David O. Kamson

, 5 more and

Georg Oeltzschner

The adverse effects of lactic acidosis in the cancer microenvironment have been increasingly recognized. Dichloroacetate (DCA) is an orally bioavailable, blood brain barrier penetrable drug that has been extensively studied in the treatment of mitochondrial neurologic conditions to reduce lactate production. Due to its effect reversing aerobic glycolysis (i.e., Warburg-effect) and thus lactic acidosis, DCA became a drug of interest in cancer as well. Magnetic resonance spectroscopy (MRS) is a well-established, non-invasive technique that allows detection of prominent metabolic changes, such as shifts in lactate or glutamate levels. Thus, MRS is a potential radiographic biomarker to allow spatial and temporal mapping of DCA treatment. In this systematic literature review, we gathered the available evidence on the use of various MRS techniques to track metabolic changes after DCA administration in neurologic and oncologic disorders. We included in vitro, animal, and human studies. Evidence confirms that DCA has substantial effects on lactate and glutamate levels in neurologic and oncologic disease, which are detectable by both experimental and routine clinical MRS approaches. Data from mitochondrial diseases show slower lactate changes in the central nervous system (CNS) that correlate better with clinical function compared to blood. This difference is most striking in focal impairments of lactate metabolism suggesting that MRS might provide data not captured by solely monitoring blood. In summary, our findings corroborate the feasibility of MRS as a pharmacokinetic/pharmacodynamic biomarker of DCA delivery in the CNS, that is ready to be integrated into currently ongoing and future human clinical trials using DCA.

2,946 views

7 citations

Original Research

28 February 2023

Identification and validation of a risk model and molecular subtypes based on tryptophan metabolism-related genes to predict the clinical prognosis and tumor immune microenvironment in lower-grade glioma

Wenxia Li

, 3 more and

Wei Yue

3,262 views

2 citations

Original Research

07 February 2022