DOI: 10.7272/q6b856c7
title: Early noninvasive metabolic biomarkers of mutant IDH inhibition in glioma

description: 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.
description: 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 <sup>1</sup>H coil.<sup>
 1</sup>H MRS spectra were acquired from a single 8
 mm<sup>3</sup> 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.
description: See <b>readme.txt</b> 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:   <b>1. Open with jMRUI</b> 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 &gt; Open as &gt; Choose “Varian Format” &gt; Load &gt; Choose “fid”   Hardware requirements: check Java requirements Tested on Windows 7 and 8 (Desktop).   <b>2. Open with Mnova</b> 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&gt; Open&gt; fid   <b>3. Open with Chenomx</b> 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 &gt; Processor &gt; File &gt; Open &gt; fid   This dataset is for the paper "Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma" that has been already published.