Glucose fluxes in glycolytic and oxidative pathways detected in vivo by deuterium magnetic resonance spectroscopy reflect proliferation in mouse glioblastoma

Simões, Rui V.; Henriques, Rafael Neto; Cardoso, Beatriz M.; Fernandes, Francisca F.; Carvalho, Tânia; Shemesh, Noam

doi:10.1016/j.nicl.2021.102932

Cited by 21 publications

(46 citation statements)

References 57 publications

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“…Following our initial work on human brain at 7 T with a small surface coil transceiver, 7 we report 3D DMI at 7 T with whole‐brain coverage that allows the detection of glucose metabolism in brain of healthy control subjects following the oral intake of [6,6′‐ 2 H 2 ]‐glucose. The focus of the current DMI study was not on dynamic mapping of glucose metabolism, 5,8–10 but rather on detecting signals during approximate isotopic steady state circa 60 to 120 min following glucose administration as has previously been used to study patient populations 1 . Emphasis is given to the achievable spatial resolution and data quality of 3D DMI at 7 T, as well at the feasibility of using ultra‐high field strengths for DMI research and clinical applications.…”

Section: Introductionmentioning

confidence: 99%

“…When DMI data are acquired in a dynamic way, capturing the increase in 2 H-labeling of the glucose metabolites over time with a sufficiently high temporal resolution, the data can be used as input for metabolic models to calculate metabolic rates. 5,9,10 If instead spatial resolution is prioritized, DMI acquisitions can benefit from increased signal averaging across a time during which the level of 2 H-labeled compounds is relatively constant. This period of approximate isotopic steady state can be used to visualize regional metabolic differences such as those observed in brain tumors.…”

Section: Introductionmentioning

confidence: 99%

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Deuterium metabolic imaging of the human brain in vivo at 7 T

Roig

Feyter

Nixon

et al. 2022

Magnetic Resonance in Med

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Purpose To explore the potential of deuterium metabolic imaging (DMI) in the human brain in vivo at 7 T, using a multi‐element deuterium (2H) RF coil for 3D volume coverage. Methods 1H‐MR images and localized 2H MR spectra were acquired in vivo in the human brain of 3 healthy subjects to generate DMI maps of 2H‐labeled water, glucose, and glutamate/glutamine (Glx). In addition, non‐localized 2H‐MR spectra were acquired both in vivo and in vitro to determine T1 and T2 relaxation times of deuterated metabolites at 7 T. The performance of the 2H coil was assessed through numeric simulations and experimentally acquired B1+ maps. Results 3D DMI maps covering the entire human brain in vivo were obtained from well‐resolved deuterated (2H) metabolite resonances of water, glucose, and Glx. The T1 and T2 relaxation times were consistent with those reported at adjacent field strengths. Experimental B1+ maps were in good agreement with simulations, indicating efficient and homogeneous B1+ transmission and low RF power deposition for 2H, consistent with a similar array coil design reported at 9.4 T. Conclusion Here, we have demonstrated the successful implementation of 3D DMI in the human brain in vivo at 7 T. The spatial and temporal nominal resolutions achieved at 7 T (i.e., 2.7 mL in 28 min, respectively) were close to those achieved at 9.4 T and greatly outperformed DMI at lower magnetic fields. DMI at 7 T and beyond has clear potential in applications dealing with small brain lesions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deuterium metabolic imaging of the human brain in vivo at 7 T

Roig

Feyter

Nixon

et al. 2022

Magnetic Resonance in Med

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“…2 H MRS, also referred to as deuterium metabolic imaging DMI ( 23 , 32 – 42 ), monitors the metabolic products of administered deuterated substrates. 2 H MRS monitoring of the glycolytic conversion of Glc to Lac has shown the tumor-signature Warburg effect in rat ( 23 ) and mouse ( 40 ) glioblastoma models and clinically in human patients with malignant gliomas ( 23 ). Inhibited glycolytic conversion of Glc to Lac following chemotherapy (etoposide) was demonstrated by 2 H MRS in a mouse lymphoma tumor model ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, we note that the SPECIAL single-voxel 2 H spectroscopy pulse sequence employed a short (4.27 ms) but finite TE, which could hamper the detection of lower abundance 2 H-labeled metabolites compared to 2 H MRS pulse-and-acquire approaches, as employed recently in normal rodent brain ( 36 ) and GL261 mouse tumors ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Distinguishing Tumor Admixed in a Radiation Necrosis (RN) Background: 1H and 2H MR With a Novel Mouse Brain-Tumor/RN Model

Song

Engelbach

et al. 2022

Front. Oncol.

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PurposeDistinguishing radiation necrosis (RN) from recurrent tumor remains a vexing clinical problem with important health-care consequences for neuro-oncology patients. Here, mouse models of pure tumor, pure RN, and admixed RN/tumor are employed to evaluate hydrogen (1H) and deuterium (2H) magnetic resonance methods for distinguishing RN vs. tumor. Furthermore, proof-of-principle, range-finding deuterium (2H) metabolic magnetic resonance is employed to assess glycolytic signatures distinguishing RN vs. tumor.Materials and MethodsA pipeline of common quantitative 1H MRI contrasts, including an improved magnetization transfer ratio (MTR) sequence, and 2H magnetic resonance spectroscopy (MRS) following administration of 2H-labeled glucose, was applied to C57BL/6 mouse models of the following: (i) late time-to-onset RN, occurring 4–5 weeks post focal 50-Gy (50% isodose) Gamma Knife irradiation to the left cerebral hemisphere, (ii) glioblastoma, growing ~18–24 days post implantation of 50,000 mouse GL261 tumor cells into the left cerebral hemisphere, and (iii) mixed model, with GL261 tumor growing within a region of radiation necrosis (1H MRI only). Control C57BL/6 mice were also examined by 2H metabolic magnetic resonance.ResultsDifferences in quantitative 1H MRI parametric values of R1, R2, ADC, and MTR comparing pure tumor vs. pure RN were all highly statistically significant. Differences in these parameter values and DCEAUC for tumor vs. RN in the mixed model (tumor growing in an RN background) are also all significant, demonstrating that these contrasts—in particular, MTR—can effectively distinguish tumor vs. RN. Additionally, quantitative 2H MRS showed a highly statistically significant dominance of aerobic glycolysis (glucose ➔ lactate; fermentation, Warburg effect) in the tumor vs. oxidative respiration (glucose ➔ TCA cycle) in the RN and control brain.ConclusionsThese findings, employing a pipeline of quantitative 1H MRI contrasts and 2H MRS following administration of 2H-labeled glucose, suggest a pathway for substantially improving the discrimination of tumor vs. RN in the clinic.

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“…Like many other types of cancer, glioblastoma multiforme is characterized by a significantly rewired metabolism. GBM exhibits markedly elevated glycolysis (as well as mitochondrial respiration) [ 75 ] which is at least partially due to enhanced RAS signaling [ 76 ] and amplification of MYC and MYCN genes [ 77 ]. In addition, the tumor is highly dependent on de novo fatty acid and lipid biosynthesis [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

2-Deoxyglucose, an Inhibitor of Glycolysis, Enhances the Oncolytic Effect of Coxsackievirus

Vorobyev

Kochetkov

Chumakov

et al. 2022

Cancers

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Glioblastoma multiforme (GBM) is one of the most common types of brain tumor. Despite intensive research, patients with GBM have a poor prognosis due to a very high rate of relapse and significant side effects of the treatment, with a median survival of 14.6 months. Oncolytic viruses are considered a promising strategy to eliminate GBM and other types of cancer, and several viruses have already been introduced into clinical practice. However, identification of the factors that underly the sensitivity of tumor species to oncolytic viruses or that modulate their clinical efficacy remains an important target. Here, we show that Coxsackievirus B5 (CVB5) demonstrates high oncolytic potential towards GBM primary cell species and cell lines. Moreover, 2-deoxyglucose (2DG), an inhibitor of glycolysis, potentiates the cytopathic effects of CVB5 in most of the cancer cell lines tested. The cells in which the inhibition of glycolysis enhanced oncolysis are characterized by high mitochondrial respiratory activity and glycolytic capacity, as determined by Seahorse analysis. Thus, 2-deoxyglucose and other analogs should be considered as adjuvants for oncolytic therapy of glioblastoma multiforme.

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Glucose fluxes in glycolytic and oxidative pathways detected in vivo by deuterium magnetic resonance spectroscopy reflect proliferation in mouse glioblastoma

Cited by 21 publications

References 57 publications

Deuterium metabolic imaging of the human brain in vivo at 7 T

Deuterium metabolic imaging of the human brain in vivo at 7 T

Distinguishing Tumor Admixed in a Radiation Necrosis (RN) Background: 1H and 2H MR With a Novel Mouse Brain-Tumor/RN Model

2-Deoxyglucose, an Inhibitor of Glycolysis, Enhances the Oncolytic Effect of Coxsackievirus

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