Deuterium magnetic resonance spectroscopy enables noninvasive metabolic imaging of tumor burden and response to therapy in low-grade gliomas

Abstract

Background The alternative lengthening of telomeres (ALT) pathway is essential for tumor proliferation in astrocytomas. The goal of this study was to identify metabolic alterations linked to the ALT pathway that can be exploited for non-invasive magnetic resonance spectroscopy (MRS)-based imaging of astrocytomas in vivo. Methods Genetic and pharmacological methods were used to dissect the association between the ALT pathway and glucose metabolism in genetically-engineered and patient-derived astrocytoma models. 2H-MRS was used for non-invasive imaging of ALT-linked modulation of glycolytic flux in mice bearing orthotopic astrocytomas in vivo. Results The ALT pathway was associated with higher activity of the rate-limiting glycolytic enzyme phosphofructokinase-1 and concomitantly elevated flux of glucose to lactate in astrocytoma cells. Silencing the ALT pathway or treating with the poly (ADP-ribose) polymerase inhibitor niraparib that induces telomeric-fusion in ALT-dependent astrocytoma cells abrogated glycolytic flux. Importantly, this metabolic reprogramming could be non-invasively visualized by 2H-MRS. Lactate production from [6,6’- 2H]-glucose was higher in ALT-dependent astrocytoma tumors relative to normal brain in vivo. Furthermore, treatment of orthotopic astrocytoma-bearing mice with niraparib reduced lactate production from [6,6’- 2H]-glucose at early timepoints when alterations in tumor volume could not be detected by anatomical imaging, pointing to the ability of [6,6’- 2H]-glucose to report on pseudoprogression in vivo. Conclusions We have mechanistically linked the ALT pathway to elevated glycolytic flux and demonstrated the ability of [6,6’- 2H]-glucose to non-invasively assess tumor burden and response to therapy in astrocytomas. Our findings point to a novel, clinically translatable method for metabolic imaging of astrocytoma patients.

Current state of pediatric neuro-oncology imaging, challenges and future directions

“…Deuterium metabolic imaging (DMI) is a novel MRI molecular imaging technique that can be performed with oral intake or intravenous infusion of nonradioactive 2H-labeled substrates followed by deuterium magnetic resonance spectroscopic imaging and enables noninvasive metabolic imaging of gliomas [92] . DMI has been used [6,6′-2H2]glucose to monitor flux to lactate and glx (sum of glutamine and glutamate) and to visualize tumor burden in glioblastoma patients [94] . In addition, a recent animal study demonstrated that DMI can be used to non-invasively assess alternative lengthening of telomeres (ALT)-linked modulation of glycolytic flux and to monitor response to ALT-inhibitor therapy [94] .…”

“…DMI has been used [6,6′-2H2]glucose to monitor flux to lactate and glx (sum of glutamine and glutamate) and to visualize tumor burden in glioblastoma patients [94] . In addition, a recent animal study demonstrated that DMI can be used to non-invasively assess alternative lengthening of telomeres (ALT)-linked modulation of glycolytic flux and to monitor response to ALT-inhibitor therapy [94] . Chemical exchange saturation transfer (CEST) is a molecular MRI imaging technique that is based on applying an off-resonance that can detect very low concentrations of molecules by the presence of groups with exchangeable protons, such as hydroxyls, amides, and amines [95] .…”

Deuterium metabolic imaging for 3D mapping of glucose metabolism in humans with central nervous system lesions at 3T

“…45 In preclinical animal models, Kreis, et al, showed that dynamic DMI acquisitions at 9.4T could be used to acquire quantitative and spatially resolved measurements of glycolytic flux in tumors, 15 which can be used to assess treatment response. 46 Batsios et al demonstrated DMI using [U-2 H]-pyruvate for assessing early treatment response in a preclinical model for reporting on telomerase reverse transcriptase expression via assessing the production of lactate in mice with patient-derived gliomas. 47 If successfully demonstrated, DMI at 3T would accelerate clinical translation due to the ubiquity of clinical 3T scanners.…”

“…In addition to the seminal DMI study in patients with glioma at 4T by de Feyter et al, multiple other sites have begun DMI studies in healthy human subjects at 3T, 43 7T 44 as well as at 9.4T 45 . In preclinical animal models, Kreis, et al, showed that dynamic DMI acquisitions at 9.4T could be used to acquire quantitative and spatially resolved measurements of glycolytic flux in tumors, 15 which can be used to assess treatment response 46 . Batsios et al demonstrated DMI using [U‐ 2 H]‐pyruvate for assessing early treatment response in a preclinical model for reporting on telomerase reverse transcriptase expression via assessing the production of lactate in mice with patient‐derived gliomas 47 …”

Subcutaneous deuterated substrate administration in mice: An alternative to tail vein infusion

“…Deuterium ( 2 H) MRS (DMRS) and imaging (DMRI) of 2 H‐labeled substrates and their subsequent downstream metabolites is an emerging arena of metabolic imaging 1–28 . With small‐animal models, tail vein catheterization is a common in‐magnet route of substrate administration.…”