Imaging tumour cell metabolism using hyperpolarized 13C magnetic resonance spectroscopy

2010 ◽  
Vol 38 (5) ◽  
pp. 1220-1224 ◽  
Author(s):  
Timothy H. Witney ◽  
Kevin M. Brindle
Keyword(s):  
Magnetic Resonance ◽  
Treatment Response ◽  
Tumour Cell ◽  
Cell Metabolism ◽  
Resonance Spectroscopy ◽  
Early Assessment ◽  
Drug Induced ◽  
Hyperpolarized 13C ◽  
New Treatments

Patients with similar tumour types frequently show different responses to the same therapy. The development of new treatments would benefit, therefore, from imaging methods that allow an early assessment of treatment response in individual patients, allowing rapid selection of the most effective treatment. We have been using 13C MRSI (magnetic resonance spectroscopic imaging) of tumour cell metabolism, using hyperpolarized 13C-labelled cellular metabolites, to detect treatment response. Nuclear spin hyperpolarization can increase sensitivity in the magnetic resonance experiment >10000 times, allowing us to image labelled cell substrates in vivo and their subsequent metabolism. We showed that exchange of hyperpolarized 13C label between lactate and pyruvate, catalysed by lactate dehydrogenase, was decreased in treated tumours undergoing drug-induced cell death, and that tissue pH could be imaged from the ratio of the signal intensities of hyperpolarized H13CO3− and 13CO2 following intravenous injection of hyperpolarized H13CO3. Tumour cell glutaminase activity, a potential measure of cell proliferation, can be determined using hyperpolarized [5-13C]glutamine, and treatment-induced tumour cell necrosis can be imaged in vivo from measurements of the conversion of hyperpolarized [1,4-13C2]fumarate into malate. Since these substrates are endogenous and, in some cases, have already been safely infused into patients, these techniques have the potential to translate to the clinic.

BIOM-10. PRECLINICAL PLATFORM FOR THE IDENTIFICATION OF DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY-BASED BIOMARKERS OF BRAIN TUMOR METABOLISM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi12-vi12
Author(s):  
Georgios Batsios ◽  
Meryssa Tran ◽  
Céline Taglang ◽  
Anne Marie Gillespie ◽  
Sabrina Ronen ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Brain Tumors ◽  
Treatment Response ◽  
Lactate Production ◽  
Cell Suspensions ◽  
Response To Therapy ◽  
Resonance Spectroscopy

Abstract Metabolic reprogramming is a fundamental hallmark of cancer, which can be exploited for non-invasive tumor imaging. Deuterium magnetic resonance spectroscopy (2H-MRS) recently emerged as a novel, translational method of interrogating flux from 2H-labeled substrates to metabolic products. However, to date, preclinical studies have been performed in vivo, an endeavor which suffers from low-throughput and potential wastage of animal life, especially when considering studies of treatment response. Developing in vitro assays for monitoring metabolism of 2H-labeled substrates will enhance throughput, lead to the rapid evaluation of new 2H-based probes and enable identification of treatment response biomarkers, thereby allowing the best 2H-based probes to be translated for further in vivo assessment. The goal of this study was to develop a preclinical cell-based platform for quantifying metabolism of 2H-labeled probes in brain tumor models. Since the Warburg effect, which is characterized by elevated glycolytic production of lactate, is a metabolic phenotype of cancer, including brain tumors, we examined metabolism of 2H-glucose or 2H-pyruvate in patient-derived glioblastoma (GBM6) and oligodendroglioma (BT88) cells and compared to normal human astrocytes (NHACONTROL). Following incubation in media containing [6,6’-2H]glucose or [U-2H]pyruvate, 2H-MR spectra obtained from live cell suspensions showed elevated 2H-lactate production in GBM6 and BT88 cells relative to NHACONTROL. Importantly, 2H-lactate production from [6,6’-2H]glucose or from [U-2H]pyruvate was reduced in GBM6 or BT88 cells subjected to irradiation and temozolomide, which is standard of care for glioma patients, pointing to the utility of this method for detecting response to therapy. Collectively, we have, for the first time, demonstrated the ability to quantify metabolism of 2H-MRS probes in live cell suspensions and validated the utility of our assay for differentiating tumor from normal cells and assessing response to therapy. Our studies will expedite the identification of novel 2H-MRS probes for imaging brain tumors and potentially other types of cancer.

scholarly journals Evaluation of LDH-A and Glutaminase Inhibition In Vivo by Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy of Tumors

2013 ◽  
Vol 73 (14) ◽  
pp. 4190-4195 ◽  
Author(s):  
Prasanta Dutta ◽  
Anne Le ◽  
David L. Vander Jagt ◽  
Takashi Tsukamoto ◽  
Gary V. Martinez ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Resonance Spectroscopy ◽  
Hyperpolarized 13C

scholarly journals Author Correction: Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elisabeth Bliemsrieder ◽  
Georgios Kaissis ◽  
Martin Grashei ◽  
Geoffrey Topping ◽  
Jennifer Altomonte ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Resonance Spectroscopy ◽  
Metabolic Phenotyping ◽  
Hyperpolarized 13C

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals O8.02 * MONITORING OF TREATMENT RESPONSE IN IDH-MUTANT GLIOMAS WITH IN-VIVO 3D MAGNETIC RESONANCE SPECTROSCOPY

2014 ◽  
Vol 16 (suppl 2) ◽  
pp. ii18-ii18
Author(s):  
D. P. Cahill ◽  
F. Loebel ◽  
W. Bogner ◽  
M. Marjanska ◽  
E. Gerstner ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Treatment Response ◽  
Resonance Spectroscopy

TAMI-40. PEDIATRIC H3K27M MUTANT GLIOMAS UNDERGO METABOLIC REPROGRAMMING THAT CAN BE LEVERAGED FOR NON-INVASIVE METABOLIC IMAGING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi206-vi207
Author(s):  
Meryssa Tran ◽  
Georgios Batsios ◽  
Céline Taglang ◽  
Anne Marie Gillespie ◽  
Javad Nazarian ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Phospholipid Metabolism ◽  
Metabolic Reprogramming ◽  
Metabolic Imaging ◽  
Resonance Spectroscopy ◽  
1H Mrs ◽  
Hyperpolarized 13C ◽  
Non Invasive ◽  
13C Mrs

Abstract Diffuse midline gliomas (DMGs) are a universally lethal form of childhood cancer. The infiltrative nature of DMGs makes them difficult to visualize by conventional magnetic resonance imaging. Genomics studies indicate that DMGs are driven by unique histone H3K27M mutations that result in broad epigenetic dysregulation. Many of the resulting changes in gene expression have the potential to induce metabolic reprogramming, which has been identified as a hallmark of cancer. The goal of this study was to dissect metabolic reprogramming in preclinical DMG models in order to identify novel magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers that can be exploited for non-invasive imaging. First, we used 1H-MRS, which reports on steady-state metabolism, to examine H3K27M mutant SF7761 cells and H3 wild-type normal human astrocytes (NHA). Lactate, glutathione and phosphocholine, which are involved in glycolysis, redox and phospholipid metabolism respectively, were elevated in SF7761 cells relative to NHAs. Mechanistically, these metabolic alterations were associated with upregulation of key enzymes including hexokinase 2, glutamate cysteine ligase and choline kinase a. Importantly, in vivo 1H-MRS showed elevated lactate, glutathione and total choline (combined signal from choline, phosphocholine and glycerophosphocholine) in mice bearing orthotopic SF7761 tumors relative to tumor-free controls. We then examined alterations in dynamic metabolic pathways in our models. Using thermally-polarized 13C-MRS, we identified elevated production of [2-13C]-lactate from [2-13C]-glucose in SF7761 cells relative to NHAs. Hyperpolarized 13C-MRS is a method of enhancing the 13C-MR signal such that metabolic fluxes can be interrogated with high sensitivity. Hyperpolarized [1-13C]-pyruvate flux to [1-13C]-lactate non-invasively monitors glycolysis and is in clinical trials in adult glioma patients. Importantly, hyperpolarized [1-13C]-pyruvate metabolism to lactate was elevated in SF7761 cells relative to NHAs. Collectively, our studies suggest that H3K27M mutant DMGs undergo reprogramming of glucose, redox and phospholipid metabolism that can be leveraged for non-invasive 1H- and hyperpolarized 13C-MRS-based imaging.

Spectroscopic imaging of human disease

1996 ◽  
Vol 54 ◽  
pp. 884-885
Author(s):  
D.J. Meyerhoff
Keyword(s):  
Magnetic Field ◽  
Magnetic Resonance ◽  
Field Gradient ◽  
Human Disease ◽  
Morphological Changes ◽  
Magnetic Field Gradient ◽  
Spectroscopic Imaging ◽  
Resonance Spectroscopy ◽  
Tissue Water

Magnetic Resonance Imaging (MRI) observes tissue water in the presence of a magnetic field gradient to study morphological changes such as tissue volume loss and signal hyperintensities in human disease. These changes are mostly non-specific and do not appear to be correlated with the range of severity of a certain disease. In contrast, Magnetic Resonance Spectroscopy (MRS), which measures many different chemicals and tissue metabolites in the millimolar concentration range in the absence of a magnetic field gradient, has been shown to reveal characteristic metabolite patterns which are often correlated with the severity of a disease. In-vivo MRS studies are performed on widely available MRI scanners without any “sample preparation” or invasive procedures and are therefore widely used in clinical research. Hydrogen (H) MRS and MR Spectroscopic Imaging (MRSI, conceptionally a combination of MRI and MRS) measure N-acetylaspartate (a putative marker of neurons), creatine-containing metabolites (involved in energy processes in the cell), choline-containing metabolites (involved in membrane metabolism and, possibly, inflammatory processes),

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