First hyperpolarized [2-13C]pyruvate MR studies of human brain metabolism

Chung, Brian T.; Chen, Hsin‐Yu; Gordon, Jeremy W.; Mammoli, Daniele; Sriram, Renuka; Autry, Adam; Page, Lydia M. Le; Chaumeil, Myriam M.; Shin, Peter; Slater, James B.; Tan, C. T.; Suszczynski, Chris; Chang, Susan M.; Li, Yan; Bok, Robert; Ronen, Sabrina M.; Larson, Peder E. Z.; Kurhanewicz, John; Vigneron, Daniel B.

doi:10.1016/j.jmr.2019.106617

Cited by 68 publications

(88 citation statements)

References 22 publications

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“…Hyperpolarized 13 C-MRS requires both additional expertise and equipment that is currently only available in large research and medical centers. Nonetheless, over the past decade, several hyperpolarized 13 C agents have been developed and applied to the imaging of normal and diseased cells, animal models and patients in vivo 18 - 20 , 35 , 47 , 71 - 73 . Most notably, hyperpolarized [1- 13 C] pyruvate and [2- 13 C] pyruvate are currently in clinical trials for glioma patients 20 , 74 .…”

Section: Discussionmentioning

confidence: 99%

MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma

et al. 2020

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Mutations in isocitrate dehydrogenase 1 (IDH1mut) are reported in 70-90% of low-grade gliomas and secondary glioblastomas. IDH1mut catalyzes the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite which drives tumorigenesis. Inhibition of IDH1mut is therefore an emerging therapeutic approach, and inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. However, detection of response to these therapies prior to changes in tumor growth can be challenging. The goal of this study was to identify non-invasive clinically translatable metabolic imaging biomarkers of IDH1mut inhibition that can serve to assess response. Methods: IDH1mut inhibition was confirmed using an enzyme assay and 1 H- and 13 C- magnetic resonance spectroscopy (MRS) were used to investigate the metabolic effects of AG-120 and AG-881 on two genetically engineered IDH1mut-expressing cell lines, NHAIDH1mut and U87IDH1mut. Results: 1 H-MRS indicated a significant decrease in steady-state 2-HG following treatment, as expected. This was accompanied by a significant 1 H-MRS-detectable increase in glutamate. However, other metabolites previously linked to 2-HG were not altered. 13 C-MRS also showed that the steady-state changes in glutamate were associated with a modulation in the flux of glutamine to both glutamate and 2-HG. Finally, hyperpolarized 13 C-MRS was used to show that the flux of α-KG to both glutamate and 2-HG was modulated by treatment. Conclusion: In this study, we identified potential 1 H- and 13 C-MRS-detectable biomarkers of response to IDH1mut inhibition in gliomas. Although further studies are needed to evaluate the utility of these biomarkers in vivo , we expect that in addition to a 1 H-MRS-detectable drop in 2-HG, a 1 H-MRS-detectable increase in glutamate, as well as a hyperpolarized 13 C-MRS-detectable change in [1- 13 C] α-KG flux, could serve as metabolic imaging biomarkers of response to treatment.

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Section: Discussionmentioning

confidence: 99%

MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma

et al. 2020

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“…Schroeder et al 23 95 and increased glutamate, acetoacetate and acetylcarnitine production was observed post-injection of an anti-cancer agent in rats. 96 The first clinical MR spectroscopy and imaging data of HP [2-13 C]pyruvate in the healthy human brain was reported at the 2019 ISMRM meeting; 97 however, application of the probe remains challenging due to the relatively low concentration of downstream metabolites generated; in one study, none were detectable. 66 [1-13 C]urea, the first hyperpolarized 13 C molecular MR imaging agent demonstrated by the d-DNP method, 11 is metabolically inert and shows promise as a HP MRI agent for perfusion assessment.…”

Section: D-dnp Beyond [1-13 C]pyruvate: Other Candidate Molecular Probesmentioning

confidence: 99%

Biomedical Applications of the Dynamic Nuclear Polarization and Parahydrogen Induced Polarization Techniques for Hyperpolarized <sup>13</sup>C MR Imaging

Stewart

Matsumoto

2021

magn reson med sci

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Since the first pioneering report of hyperpolarized [1-13 C]pyruvate magnetic resonance imaging (MRI) of the Warburg effect in prostate cancer patients, clinical dissemination of the technique has been rapid; close to 10 sites worldwide now possess a polarizer fit for the clinic, and more than 30 clinical trials, predominantly for oncological applications, are already registered on the US and European clinical trials databases. Hyperpolarized 13 C probes to study pathophysiological processes beyond the Warburg effect, including tricarboxylic acid cycle metabolism, intra-cellular pH and cellular necrosis have also been demonstrated in the preclinical arena and are pending clinical translation, and the simultaneous injection of multiple co-polarized agents is opening the door to high-sensitivity, multi-functional molecular MRI with a single dose. Here, we review the biomedical applications to date of the two polarization methods that have been used for in vivo hyperpolarized 13 C molecular MRI; namely, dissolution dynamic nuclear polarization and parahydrogeninduced polarization. The basic concept of hyperpolarization and the fundamental theory underpinning these two key 13 C hyperpolarization methods, along with recent technological advances that have facilitated biomedical realization, are also covered.

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“…With this selection, we choose to put special focus on 13 C human brain imaging, a challenging clinical case, which has attracted much interest lately. In fact, the first studies of hyperpolarized [1- 13 C]pyruvate and [2- 13 C]pyruvate in human brain have already been presented [10] , [11] , [12] , [13] with results suggesting a need for tailored receive coils.…”

Section: Introductionmentioning

confidence: 99%