Deuterium metabolic imaging differentiates glioblastoma metabolic subtypes and detects early response to chemoradiotherapy.
Jacob Chen Ming LowJianbo CaoFriederike HesseAlan J WrightAnastasia TsybenIslam AlshamlehRichard MairKevin M BrindlePublished in: Cancer research (2024)
Metabolic subtypes of glioblastoma have different prognoses and responses to treatment. Deuterium metabolic imaging with 2H-labeled substrates is a potential approach to stratify patients into metabolic subtypes for targeted treatment. Here, we used 2H magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) measurements of [6,6'-2H2]glucose metabolism to identify metabolic subtypes and their responses to chemoradiotherapy in patient-derived glioblastoma xenografts in vivo. The metabolism of patient-derived cells was first characterized in vitro by measuring the oxygen consumption rate, a marker of mitochondrial TCA cycle activity, as well as the extracellular acidification rate and 2H-labeled lactate production from [6,6'-2H2]glucose, which are markers of glycolytic activity. Two cell lines representative of a glycolytic subtype and two representative of a mitochondrial subtype were identified. 2H MRS and MRSI measurements showed similar concentrations of 2H-labeled glucose from [6,6'-2H2]glucose in all four tumor models when implanted orthotopically in mice. The glycolytic subtypes showed higher concentrations of 2H-labeled lactate than the mitochondrial subtypes and normal-appearing brain tissue, whereas the mitochondrial subtypes showed more glutamate/glutamine labeling, a surrogate for TCA cycle activity, than the glycolytic subtypes and normal-appearing brain tissue. The response of the tumors to chemoradiation could be detected within 24 hours of treatment completion, with the mitochondrial subtypes showing a decrease in both 2H-labeled glutamate/glutamine and lactate concentrations and glycolytic tumors showing a decrease in 2H-labeled lactate concentration. This technique has the potential to be used clinically for treatment selection and early detection of treatment response.
Keyphrases
- oxidative stress
- high resolution
- rectal cancer
- type diabetes
- locally advanced
- risk assessment
- metabolic syndrome
- computed tomography
- signaling pathway
- brain injury
- white matter
- drug delivery
- blood brain barrier
- cross sectional
- multiple sclerosis
- mass spectrometry
- molecular docking
- climate change
- patient reported outcomes
- molecular dynamics simulations
- glycemic control
- pet ct
- patient reported
- cerebral ischemia
- wild type