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Early noninvasive metabolic biomarkers of mutant IDH inhibition in glioma

Citation

Radoul, Marina et al. (2021), Early noninvasive metabolic biomarkers of mutant IDH inhibition in glioma, Dryad, Dataset, https://doi.org/10.7272/Q6B856C7

Abstract

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-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.

Methods

MR studies were performed using a vertical 14.1T scanner (Agilent Technologies, Varian Medical Systems, Palo Alto, CA, USA), equipped with a single channel 40 mm 1H coil. 1H MRS spectra were acquired from a single 8 mm3 voxel placed in the center of the tumor region using the PRESS (point-resolved spectroscopy) sequence with: TE = 20 ms, TR = 4000 ms, NA = 512, 10,000 points, spectral width 10,000 Hz.

Usage Notes

See readme.txt file for detailed Usage Notes that offer the best options for accessing the data files:
 
To open the data, please select one of the following options:
 
1. Open with jMRUI
http://www.jmrui.eu/license-and-download/download/
 
Requires: Java 7 or newer (32-bits) (tested with Oracle Java)
Installation note: After downloading jMRUI, uncompress the zip-file in the directory of your choice and read the “readme.txt” file to learn how to install jMRUI properly on 64-bit platforms. In case you want to use the NMRScopeB plug-in, also read the “readme_nmrscopeb.txt” file (for any platform).
Open jMRUI:
File tab > Open as > Choose “Varian Format” > Load > Choose “fid”
 
Hardware requirements: check Java requirements
Tested on Windows 7 and 8 (Desktop).
 
2. Open with Mnova
https://mestrelab.com/download/mnova/
 
Download any data set (01-77) and rename the included files as fid, log, procpar and text (for example, download fid-3, log-3, procpar-3 and text-3 files and rename them as fid, log, procpar and text)
File> Open> fid
 
3. Open with Chenomx
https://www.chenomx.com/free-download-homepage/
 
Download any data set (01-77) and rename the included files as fid, log, procpar and text (for example, download fid-3, log-3, procpar-3 and text-3 files and rename them as fid, log, procpar and text)
Open Chenomx > Processor > File > Open > fid
 
This dataset is for the paper "Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma" that has been already published.

Funding

National Institutes of Health, Award: R01CA197254

National Institutes of Health, Award: R01CA172845

University of California, San Francisco, Award: Loglio collective