In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors

Salamanca-Cardona, Lucia; Shah, Hardik; Poot, Alex J.; Correa, Fabian; Gialleonardo, Valentina Di; Lui, Hui; Miloushev, Vesselin Z.; Granlund, Kristin L.; Tee, Sui Seng; Cross, Justin R.; Thompson, Craig B.; Keshari, Kayvan R.

doi:10.1016/j.cmet.2017.10.001

Cited by 79 publications

(73 citation statements)

References 49 publications

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“…Several recent studies have reported metabolic alterations driven by accumulation of 2‐HG in IDH‐mutated tumours, showing that: ( i ) when available, the major source of 2‐HG production is glutamine, which is rapidly metabolized by glutaminase and IDH1 (Salamanca‐Cardona et al , ); ( ii ) in acidic pH conditions accumulation of 2‐HG may be required for HIF‐1α stabilization (Nadtochiy et al , ); and ( iii ) in hypoxic conditions increased levels of L‐2‐HG inhibit electron transport and glycolysis in order to mitigate reductive stress (Oldham et al , ).…”

Section: Oncometabolites and Their Related Metabolic Enzymesmentioning

confidence: 99%

Oncometabolites in cancer aggressiveness and tumour repopulation

et al. 2019

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Tumour repopulation is recognized as a crucial event in tumour relapse where therapy-sensitive dying cancer cells influence the tumour microenvironment to sustain therapy-resistant cancer cell growth. Recent studies highlight the role of the oncometabolites succinate, fumarate, and 2-hydroxyglutarate in the aggressiveness of cancer cells and in the worsening of the patient's clinical outcome. These oncometabolites can be produced and secreted by cancer and/or surrounding cells, modifying the tumour microenvironment and sustaining an invasive neoplastic phenotype. In this review, we report recent findings concerning the role in cancer development of succinate, fumarate, and 2-hydroxyglutarate and the regulation of their related enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. We propose that oncometabolites are crucially involved in tumour repopulation. The study of the mechanisms underlying the relationship between oncometabolites and tumour repopulation is fundamental for identifying efficient anti-cancer therapeutic strategies and novel serum biomarkers in order to overcome cancer relapse.

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Section: Oncometabolites and Their Related Metabolic Enzymesmentioning

confidence: 99%

Oncometabolites in cancer aggressiveness and tumour repopulation

et al. 2019

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“…Subsequent work improved the preparation of glutamine for the hyperpolarization process and showed a treatment response in cell culture . The difference in chemical shift between C1‐labeled glutamate and glutamine is even smaller, but rapid exchange between [1– 13 C]glutamine and [1– 13 C]2HG can still be monitored with HP imaging . This paper demonstrates a primary strength of HP‐based imaging kinetics.…”

Section: Biochemical Aspects Of Hp 13c Studies Of Cancer Metabolismmentioning

confidence: 90%

“…Unlike HP pyruvate, however, the optimal choice of glutamine isotopomer is less clear. Both the C1 and C5 positions of glutamine have only α‐protons as a primary source of relaxation, and hence their T 1 values are relatively long in solution (>15 s), but show a strong field dependence associated with the chemical shift anisotropy of the carbonyls . However, the relatively small changes in chemical shift upon metabolic transformation to glutamate make ready measurement of reaction kinetics more problematic.…”

Section: Biochemical Aspects Of Hp 13c Studies Of Cancer Metabolismmentioning

confidence: 99%

Cancer in the crosshairs: targeting cancer metabolism with hyperpolarized carbon‐13 MRI technology

Morze

Merritt

2018

NMR in Biomedicine

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Magnetic resonance (MR)-based hyperpolarized (HP) C metabolic imaging is under active pursuit as a new clinical diagnostic method for cancer detection, grading, and monitoring of therapeutic response. Following the tremendous success of metabolic imaging by positron emission tomography, which already plays major roles in clinical oncology, the added value of HP C MRI is emerging. Aberrant glycolysis and central carbon metabolism is a hallmark of many forms of cancer. The chemical transformations associated with these pathways produce metabolites ranging in general from three to six carbons, and are dependent on the redox state and energy charge of the tissue. The significant changes in chemistry associated with flux through these pathways imply that HP imaging can take advantage of the underlying chemical shift information encoded into an MR experiment to produce images of the injected substrate as well as its metabolites. However, imaging of HP metabolites poses unique constraints on pulse sequence design related to detection of X-nuclei, decay of the HP magnetization due to T , and the consumption of HP signal by the inspection pulses. Advancements in the field continue to depend critically on customization of MRI systems and pulse sequences for optimized detection of HP C signals, focused largely on extracting the maximum amount of information during the short lifetime of the HP magnetization. From a clinical perspective, the success of HP C MRI of cancer will largely depend upon the utility of HP pyruvate for the detection of lactate pools associated with the Warburg effect, though several other agents are also under investigation, with novel agents continually being formulated. In this review, the salient aspects of HP C imaging will be highlighted, with an emphasis on both technological challenges and the biochemical aspects of HP experimental design.

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“…Salamanca-Cardona et al also used the hyperpolarized 1-13 C glutamine to identify the IDH mutant tumors 36 . However, the transition of this technique to the clinic has not been forthcoming because of the short T1 half-life of 1-13 C glutamine 36 and slow glutamine uptake by cells 31 . Correlation spectroscopy (COSY) has been employed in-vivo setting to detect 2-HG 30, 37 .…”

Section: Discussionmentioning

confidence: 99%

Robust detection of oncometabolic aberrations by ¹H-¹³C heteronuclear single quantum correlation in live cells and intact tumors ex-vivo

Barekatain

Yan

Arthur

et al. 2019

Preprint

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Extensive efforts have been made to use non-invasive 1 H magnetic resonance (MR) spectroscopy to quantify metabolites that are diagnostic of specific disease states. Within the realm of precision oncology, these efforts have largely centered on quantifying 2hydroxyglutarate (2-HG) in tumors harboring isocitrate dehydrogenase 1 (IDH1) mutations. As many metabolites have similar chemical shifts, the resulting 1 H spectra of intact biological material are highly convoluted, limiting the application of 1 H MR to high abundance metabolites. Hydrogen-Carbon Heteronuclear single quantum correlation 1 H-13 C HSQC is routinely employed in organic synthesis to resolve complex spectra but has received limited attention for biological studies. Here, we show that 1 H-13 C HSQC offers a dramatic improvement in sensitivity compared to one-dimensional (1D) 13 C NMR and dramatic signal deconvolution compared to 1D 1 H spectra in an intact biological setting.Using a standard NMR spectroscope without specialized signal enhancements features such as magic angle spinning, metabolite extractions or 13 C-isotopic enrichment, we obtain well-resolved 2D 1 H-13 C HSQC spectra in live cancer cells, in ex-vivo freshly dissected xenografted tumors and resected primary tumors. We demonstrate that this method can readily identify tumors with specific genetic-driven oncometabolite alterations such as IDH mutations with elevation of 2-HG as well as PGD-homozygously deleted tumors with elevation of gluconate. These data support the potential of 1 H-13 C HSQC as a non-invasive diagnostic tool for metabolic precision oncology.IDH1/2 mutations have been the foci of a number of experimental and clinical studies 4 .Both cytoplasmic IDH1 and mitochondrial IDH2 enzymes catalyze the conversion of isocitrate to ⍺-ketoglutarate 5 . Recurrent mutations in the active site of these enzymes result in a neomorphic activity that enables NADPH-dependent reduction of ⍺ketoglutarate to the oncometabolite R-2-hydroxyglurate (2-HG) 6,7 . Thus, the accumulation of 2-HG inside IDH1/2 mutant tumors can reach millimolar level and is the molecular hallmark of this mutation. In glioma, patients harboring IDH mutations have better prognoses compared to the IDH-wildtype group 8,9 , and would be the candidate for targeted therapies such as IDH1 mutant inhibitor, AGI-120 (NCT03564821).The demand driving the development of drugs targeting tumor metabolism extends beyond IDH mutations. An emerging metabolic vulnerability-based precision oncology is collateral lethality 10,11 . Homozygous deletion of major tumor suppressor genes can result in the collateral deletion of chromosomal neighboring metabolic housekeeping genes such as the pentose phosphate shunt enzyme 6-phosphogluconate dehydrogenase (PGD) at the 1p36 locus 10-12 . PGD enzyme catalyzes the oxidative conversion of 6phosphogluconate (6-PG) in the oxidative arm of the pentose phosphate pathway, and its deletion results in >100-fold increased accumulation of 6-phosphogluconate and its hydrolysis product gluconate 12 . ...

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In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors

Cited by 79 publications

References 49 publications

Oncometabolites in cancer aggressiveness and tumour repopulation

Oncometabolites in cancer aggressiveness and tumour repopulation

Cancer in the crosshairs: targeting cancer metabolism with hyperpolarized carbon‐13 MRI technology

Robust detection of oncometabolic aberrations by ¹H-¹³C heteronuclear single quantum correlation in live cells and intact tumors ex-vivo

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In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors

Cited by 79 publications

References 49 publications

Oncometabolites in cancer aggressiveness and tumour repopulation

Oncometabolites in cancer aggressiveness and tumour repopulation

Cancer in the crosshairs: targeting cancer metabolism with hyperpolarized carbon‐13 MRI technology

Robust detection of oncometabolic aberrations by 1H-13C heteronuclear single quantum correlation in live cells and intact tumors ex-vivo

Contact Info

Product

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Robust detection of oncometabolic aberrations by ¹H-¹³C heteronuclear single quantum correlation in live cells and intact tumors ex-vivo