scholarly journals Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 109
Author(s):  
Marina Radoul ◽  
Donghyun Hong ◽  
Anne Marie Gillespie ◽  
Chloé Najac ◽  
Pavithra Viswanath ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Genetically Engineered ◽  
Response To Treatment ◽  
Driver Mutations ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
1H Mrs ◽  
Metabolic Biomarkers

Approximately 80% of low-grade glioma (LGGs) harbor mutant isocitrate dehydrogenase 1/2 (IDH1/2) driver mutations leading to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Thus, inhibition of mutant IDH is considered a potential therapeutic target. Several mutant IDH inhibitors are currently in clinical trials, including AG-881 and BAY-1436032. However, to date, early detection of response remains a challenge. In this study we used high resolution 1H magnetic resonance spectroscopy (1H-MRS) to identify early noninvasive MR (Magnetic Resonance)-detectable metabolic biomarkers of response to mutant IDH inhibition. In vivo 1H-MRS was performed on mice orthotopically-implanted with either genetically engineered (U87IDHmut) or patient-derived (BT257 and SF10417) mutant IDH1 cells. Treatment with either AG-881 or BAY-1436032 induced a significant reduction in 2-HG. Moreover, both inhibitors led to a significant early and sustained increase in glutamate and the sum of glutamate and glutamine (GLX) in all three models. A transient early increase in N-acetylaspartate (NAA) was also observed. Importantly, all models demonstrated enhanced animal survival following both treatments and the metabolic alterations were observed prior to any detectable differences in tumor volume between control and treated tumors. Our study therefore identifies potential translatable early metabolic biomarkers of drug delivery, mutant IDH inhibition and glioma response to treatment with emerging clinically relevant therapies.

EXTH-46. MRS BASED BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO THE IDH INHIBITOR BAY-1436032

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi173-vi173
Author(s):  
Donghyun Hong ◽  
Noriaki Minami ◽  
Céline Taglang ◽  
Georgios Batsios ◽  
Anne Marie Gillespie ◽  
...  
Keyword(s):  
Animal Models ◽  
Animal Studies ◽  
Response To Treatment ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
1H Mrs ◽  
Hyperpolarized 13C ◽  
13C Mrs ◽  
Mutant Idh1

Abstract Gliomas are the most prevalent type of brain tumor in the central nervous system. Mutations in the cytosolic enzyme isocitrate dehydrogenase 1 (IDH1) are a common feature of primary low-grade gliomas, catalyzing the conversion of α-ketoglutarate (αKG) to the oncometabolite 2-hydroxyglutarate (2HG), and mutant IDH1 is a therapeutic target for these tumors. Several mutant IDH inhibitors are currently in clinical trials, nonetheless, complementary non-invasive early biomarkers to assess drug delivery and potential therapeutic response are still needed. The goal of this study was therefore to determine the potential of 1H and hyperpolarized 13C magnetic resonance spectroscopy (MRS)-based biomarkers as indicators of mutant IDH1 low-grade glioma response to treatment with the clinically-relevant IDH1 inhibitor BAY-1436032 in cells and animal models. Immortalized human astrocytes engineered to express mutant IDH1 were treated with 500nM (IC50 value) of BAY-1436032 and BT257 tumors implanted in rats were treated with 150mg/kg of BAY-1436032. To assess steady-state metabolite levels, 1H MRS spectra were acquired on a 500 MHz MRS cancer for cells and a 3 T scanner for animal studies. To assess metabolic fluxes, we used hyperpolarized 13C MRS and probed the fate of hyperpolarized [1-13C]αKG. 1H MRS showed a significant decrease in 2HG as well as a significant increase in glutamate (Glu) and phosphocholine (PCh) following BAY-1436032 treatment in both cell and animal models compared to controls. Furthermore, hyperpolarized 13C MRS showed that hyperpolarized 2HG production from hyperpolarized [1-13C]αKG was decreased and hyperpolarized glutamate production from hyperpolarized [1-13C]αKG was increased in the BAY-1436032 treated groups compared to controls. These findings are consistent with our previous study, which investigated the MRS-detectable consequences of two other mutant IDH inhibitors: AG120 and AG881. Collectively, our work identifies translatable MRS-based metabolic biomarkers of mutant IDH1 inhibition.

scholarly journals CBMT-10. MUTANT ISOCITRATE DEHYDROGENASE 1 INHIBITION INDUCES A UNIQUE MRS-DETECTABLE METABOLIC SIGNATURE IN LOW-GRADE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi34-vi35
Author(s):  
Abigail Molloy ◽  
Aliya Lakhani ◽  
Chloé Najac ◽  
Elavarasan Subramani ◽  
Anne Marie Gillespie ◽  
...  
Keyword(s):  
Cell Lines ◽  
Isocitrate Dehydrogenase ◽  
Phase 1 ◽  
Genetically Engineered ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
1H Mrs ◽  
Low Grade Gliomas ◽  
Non Invasive

Abstract Mutations in isocitrate dehydrogenase 1/2 (IDHmut) are reported in 70–90% of low-grade gliomas and secondary glioblastomas. IDHmut catalyzes the reduction of a-ketoglutarate (a-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite that drives tumorigenesis. Inhibition of IDHmut is therefore a rapidly emerging therapeutic approach and IDHmut inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. The goal of this study was to identify early non-invasive metabolic biomarkers of IDHmut inhibition that can serve to moniter response to these therapies. We used 1H and 13C magnetic resonance spectroscopy (MRS) to investigate the response of two genetically-engineered IDHmut cell lines (U87-based and normal human astrocyte-based) to AG-120 and AG-881 treatment. As expected, in both cell lines, our 1H-MRS data indicated that AG-120 and AG-881 induced a significant decrease in 2-HG. Interestingly however, we also observed a significant increase in phosphocholine and glutamate, pointing to broader changes in the metabolism of treated cells and a unique MRS signature. To further investigate the increase in glutamate induced by AG-120 and AG-881 in our models, we used 13C-MRS and quantified the flux of [1-13C] glucose and [3-13C] glutamine to 13C-labeled glutamate. Our results indicate that both AG-120 and AG-881 significantly increase the flux of 13C-labeled glutamine to 13C glutamate, while the flux of 13C-labeled glucose to 13C glutamate remained unchanged. Further studies are currently underway to explore the utility of using hyperpolarized [1-13C]-glutamine and hyperpolarized [1-13C]-a-KG for monitoring flux to glutamate and 2-HG, and to validate these probes as additional biomarkers of response to IDHmut inhibition. Taken together, our studies indicate that IDHmut inhibition induces a unique MRS-detectable metabolic profile that can potentially be exploited for early non-invasive, clinically translatable detection of response to emerging IDHmut inhibitors.

scholarly journals BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING 2H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i2-i2
Author(s):  
Georgios Batsios ◽  
Celine Taglang ◽  
Meryssa Tran ◽  
Anne Marie Gillespie ◽  
Joseph Costello ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
In Vivo Imaging ◽  
Lactate Production ◽  
Telomere Maintenance ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Non Invasive ◽  
Tert Expression

Abstract Telomere shortening constitutes a natural barrier to uncontrolled proliferation and all tumors must find a mechanism of maintaining telomere length. Most human tumors, including high-grade primary glioblastomas (GBMs) and low-grade oligodendrogliomas (LGOGs) achieve telomere maintenance via reactivation of the expression of telomerase reverse transcriptase (TERT), which is silenced in normal somatic cells. TERT expression is, therefore, a driver of tumor proliferation and, due to this essential role, TERT is also a therapeutic target. However, non-invasive methods of imaging TERT are lacking. The goal of this study was to identify magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers of TERT expression that will enable non-invasive visualization of tumor burden in LGOGs and GBMs. First, we silenced TERT expression by RNA interference in patient-derived LGOG (SF10417, BT88) and GBM (GS2) models. Our results linked TERT silencing to significant reductions in steady-state levels of NADH in all models. NADH is essential for the conversion of pyruvate to lactate, suggesting that measuring pyruvate flux to lactate could be useful for imaging TERT status. Recently, deuterium (2H)-MRS has emerged as a novel, clinically translatable method of monitoring metabolic fluxes in vivo. However, to date, studies have solely examined 2H-glucose and the use of [U-2H]pyruvate for non-invasive 2H-MRS has not been tested. Following intravenous injection of a bolus of [U-2H]pyruvate, lactate production was higher in mice bearing orthotopic LGOG (BT88 and SF10417) and GBM (GS2) tumor xenografts relative to tumor-free mice, suggesting that [U-2H]pyruvate has the potential to monitor TERT expression in vivo. In summary, our study, for the first time, shows the feasibility and utility of [U-2H]pyruvate for in vivo imaging. Importantly, since 2H-MRS can be implemented on clinical scanners, our results provide a novel, non-invasive method of integrating information regarding a fundamental cancer hallmark, i.e. TERT, into glioma patient management.

scholarly journals 81 IN VIVO PROTON MAGNETIC RESONANCE SPECTROSCOPY (1H-MRS) IN CYSTIC LEUCOMALACIA OF INFANCY

1994 ◽  
Vol 36 (1) ◽  
pp. 16A-16A
Author(s):  
Floris Groenendaal ◽  
Paula Eken ◽  
Jeroen Van Der Grond ◽  
Karin Rademaker ◽  
Linda S De Vries
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Proton Magnetic Resonance ◽  
Proton Magnetic Resonance Spectroscopy ◽  
Resonance Spectroscopy ◽  
1H Mrs

scholarly journals Non-Invasive Prediction of IDH Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo 1H-Magnetic Resonance Spectroscopy and Machine Learning

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3406
Author(s):  
Elisabeth Bumes ◽  
Fro-Philip Wirtz ◽  
Claudia Fellner ◽  
Jirka Grosse ◽  
Dirk Hellwig ◽  
...  
Keyword(s):  
Machine Learning ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Support Vector ◽  
Resonance Spectroscopy ◽  
Idh Mutation ◽  
1H Mrs ◽  
1H Magnetic Resonance Spectroscopy ◽  
Non Invasive

Isocitrate dehydrogenase (IDH)-1 mutation is an important prognostic factor and a potential therapeutic target in glioma. Immunohistological and molecular diagnosis of IDH mutation status is invasive. To avoid tumor biopsy, dedicated spectroscopic techniques have been proposed to detect D-2-hydroxyglutarate (2-HG), the main metabolite of IDH, directly in vivo. However, these methods are technically challenging and not broadly available. Therefore, we explored the use of machine learning for the non-invasive, inexpensive and fast diagnosis of IDH status in standard 1H-magnetic resonance spectroscopy (1H-MRS). To this end, 30 of 34 consecutive patients with known or suspected glioma WHO grade II-IV were subjected to metabolic positron emission tomography (PET) imaging with O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) for optimized voxel placement in 1H-MRS. Routine 1H-magnetic resonance (1H-MR) spectra of tumor and contralateral healthy brain regions were acquired on a 3 Tesla magnetic resonance (3T-MR) scanner, prior to surgical tumor resection and molecular analysis of IDH status. Since 2-HG spectral signals were too overlapped for reliable discrimination of IDH mutated (IDHmut) and IDH wild-type (IDHwt) glioma, we used a nested cross-validation approach, whereby we trained a linear support vector machine (SVM) on the complete spectral information of the 1H-MRS data to predict IDH status. Using this approach, we predicted IDH status with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2–99.9%) and a specificity of 75.0% (95% CI, 42.9–94.5%), respectively. The area under the curve (AUC) amounted to 0.83. Subsequent ex vivo 1H-nuclear magnetic resonance (1H-NMR) measurements performed on metabolite extracts of resected tumor material (eight specimens) revealed myo-inositol (M-ins) and glycine (Gly) to be the major discriminators of IDH status. We conclude that our approach allows a reliable, non-invasive, fast and cost-effective prediction of IDH status in a standard clinical setting.

Folicular and Diffuse Large B Cell Lymphoma Can Be Distinguished by 1H -Magnetic Resonance Spectroscopy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3584-3584
Author(s):  
Carolina Sanz ◽  
Ignasi Barba ◽  
Gustavo Tapia ◽  
Jose-Luis Mate ◽  
Angels Barbera ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Resonance Spectroscopy ◽  
1H Mrs ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Proton nuclear magnetic resonance spectroscopy (1H MRS) has proven useful in the metabolic characterization of neoplastic tissues both in vitro and in vivo. In vivo 1H MRS can be easily performed in conjunction with conventional MR imaging. Although 1H MRS studies of lymphoma have been performed both in cell lines and animal models, its usefulness as a differential diagnostic tool in lymphoma remains to be explored. T2-filtered high resolution proton magic-angle spinning (HRMAS) MRS of small tissue samples provides sufficient spectral resolution for the identification of chemical cell changes associated with malignancy. HRMAS data from 16 fresh frozen lymph nodes were studied. Histologically, 7 lymph nodes revealed grade I or II follicular lymphoma (FL) and 9 showed diffuse large B cell lymphoma (DLBCL). Each spectrum consisted of the accumulation of 64 scans with a CPMG sequence with an effective T2 delay of 32 ms and an overall experimental time of 6 minutes. Pattern recognition analysis was feasible in all cases except in one FL sample consisting almost exclusively of adipose tissue. Compared with DLBCL, FL cases showed increases in the signal intensity of resonances associted to taurine (3.43 ppm) and decreases in the signal intensity of resonances associated to alanine (1.47 ppm). The mean taurine/alanine ratio was 4.63 (95%SD 1.67) for FL and 1.41 (95%SD 0.69) for DLBCL (P = 0.004). The taurine/alanine ratio proved to be a powerful discriminator between FL and DLBCL at a 2.5 cutpoint, yelding a 90% specificity and an 83% sensitivity to identify DLBCL. Overlapping cases included a case of FL with a diffuse pattern and two cases of DLBCL evolving from indolent lymphomas. The 1H MRS assay proved that FL and DLBCL can be differentiated from a metabolomic standpoint and offers a unique way to explore the underlying biochemistry of malignant transformations. Unlike other techniques, MRS is potentially applicable in vivo and non-invasively in the diagnostic setting. The rapid assessment of nodes or masses before tissue sampling would allow preoperative decisions to be made more efficiently.

Magnetic Resonance Spectroscopy and its Applications in Psychiatry

2002 ◽  
Vol 36 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Gin S. Malhi ◽  
Michael Valenzuela ◽  
Wei Wen ◽  
Perminder Sachdev
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Brain Regions ◽  
Response To Treatment ◽  
Resonance Spectroscopy ◽  
Biochemical Basis ◽  
Non Invasive ◽  
Investigative Technique ◽  
Neurochemical Changes

Objective: This paper briefly describes neuroimaging using magnetic resonance spectroscopy (MRS) and provides a systematic review of its application to psychiatric disorders. Method: A literature review ( Index Medicus/ Medline) was carried out, as well as a review of other relevant papers and data known to the authors. Results: Magnetic resonance spectroscopy is a complex and sophisticated neuroimaging technique that allows reliable and reproducible quantification of brain neurochemistry provided its limitations are respected. In some branches of medicine it is already used clinically, for instance, to diagnose tumours and in psychiatry its applications are gradually extending beyond research. Neurochemical changes have been found in a variety of brain regions in dementia, schizophrenia and affective disorders and promising discoveries have also been made in anxiety disorders. Conclusions: Magnetic resonance spectroscopy is a non-invasive investigative technique that has provided useful insights into the biochemical basis of many neuropsychiatric disorders. It allows direct measurement, in vivo, of medication levels within the brain and has made it possible to track the neurochemical changes that occur as a consequence of disease and ageing or in response to treatment. It is an extremely useful advance in neuroimaging technology and one that will undoubtedly have many clinical uses in the near future.

scholarly journals Arterial spin-labelling and magnetic resonance spectroscopy as imaging biomarkers for detection of epileptogenic zone in non-lesional focal impaired awareness epilepsy

2020 ◽  
Vol 51 (1) ◽  
Author(s):  
Rania Essam-el-dein Mohamed ◽  
Ashraf Ali Aboelsafa ◽  
Rasha Mahmoud Dawoud
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Imaging Biomarkers ◽  
Epileptic Focus ◽  
Resonance Spectroscopy ◽  
Epileptogenic Zone ◽  
1H Mrs ◽  
Combined Use ◽  
Impaired Awareness

Abstract Background The proper identification of an epileptic focus is a pivotal diagnostic issue; particularly in non-lesional focal impaired awareness epilepsy (FIAE). Seizures are usually accompanied by alterations of regional cerebral blood flow (rCBF) and metabolism. Arterial spin labeling-MRI (ASL-MRI) and proton magnetic resonance spectroscopy (1H-MRS) are MRI techniques that can, non-invasively, define the regions of cerebral perfusion and metabolic changes, respectively. The aim of the current study was to recognize the epileptogenic zone in patients with non-lesional FIAE by evaluating the interictal changes in rCBF and cerebral metabolic alterations, using PASL-MRI and 1H-MRS. Results For identification of the epileptogenic zone, increased ASLAI% assessed by PASL-MRI (at a cut-off value ≥ 5.96%) showed 95.78% accuracy, and increased %AF (at a cut-off value ≥ 9.98%) showed 98.14% accuracy, while decreased NAA/(Cho + Cr) ratio estimated by multi-voxels (MV) 1H-MRS (at a cut-off value ≥ 0.59) showed 97.74% accuracy. Moreover, the combined use of PASL-MRI and MV 1H-MRS yielded 100% sensitivity, 98.45% specificity and 98.86% accuracy. Conclusion The combined use of PASL-MRI and MV 1H-MRS can be considered as in-vivo proficient bio-marker for proper identification of epileptogenic zone in patients with non-lesional FIAE.

Sign in / Sign up

Export Citation Format

Share Document