Altered metabolic landscape in IDH-mutant gliomas affects phospholipid, energy, and oxidative stress pathways

Webinar on Oncology by Guillaume Hochart, Study Director
February 6 | 9 am East Coast Time/ 3 pm Paris Time | Online

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Abstract
Altered metabolic landscape in IDH-mutant gliomas affects phospholipid, energy, and oxidative stress pathways based on our publication in partnership LIH (Luxembourg Institute of Health).

Gliomas account for 30% to 40% of all intracranial tumors and have majorly poor prognosis. At the low or secondary grades they are easily subjected to IDH (Isocitrate Deshydrogenase) mutations (mutant IDH1_mIDH1_ and mutant IDH2) leading to an extensive production of 2-hydroxyglutarate and important molecular modifications for which the mechanism is poorly understood, making thus difficult to identify potential therapeutic targets.

Mass Spectrometry Imaging (MSI) is a label-free technique which allows to map hundreds of molecular signals in a single image with the possibility to assign histological features as per complementary techniques (H&E staining, IHC).

In this Webinar in partnership with LIH (Luxembourg Institute of Health), we will present the molecular modifications between patient-derived xenografts (PDX) of IDH1-mutant versus IDH1 wild-type glioma implemented in mouse brains using a 7T-MALDI FTICR instrument (SolariX, Bruker) in order to better understand the mechanistic of these tumors and determine putative novel biomarkers for IDH1-mutant gliomas.

Expression of mIDH model was confirmed by the high levels of 2-HG localized in the tumors. Untargeted approach using differential analysis between IDH and mIDH highlighted more than 100 downregulated or upregulated compounds with strong differences between conditions. Important changes were observed in the tumors for the lipid contents (i.e. phosphatidylethanolamine (PE)) and for the energetic balance. The latter was characterized by reduced glucose turnover and a lower energy potential, correlating with the lower proliferation index of mIDH compared to IDH. Alteration of amino acid and neurotransmitters was pointed out by the NAA and NAAG (neuropeptide) levels defining subclasses of mIDH PDXs and thus different metabolic pathways.
Oxidative stress was evaluated through GSH and GSSG levels from MALDI and LCMS/MS analyses. Similar responses of GSSG/GSH ratios between mIDH and wtIDH were found despite the NADPH reduced levels from mIDH. Balance of the oxidative stress was hypothetically related to the transsulfuration pathway as per the levels of Cystathionine detected for each glioma.

Therefore MSI was able to highlight multiple biological pathways bringing more comprehension to the IDH tumor model providing thus interesting perspectives to evaluate the efficacy of a drug based on its pharmacodynamics.

Keywords: Mass spectrometry imaging, Gliomas, Isocitrate Deshydrogenase.

About Guillaume Hochart
After having obtained his Master degree in Chemical Engineering and his Master of Philosophy (MPhil) in Pure and Applied Chemistry in Glasgow with a thesis in Medicinal Chemistry (Strathclyde University, Glasgow, Scotland), Guillaume Hochart joined a research team as bioanalytical project manager for the method development of a preclinical candidate in Alzheimer disease at the Faculty of Pharmacy of Lille. Guillaume then joined ImaBiotech Service team as a Study Director in 2012 to lead projects in multiple therapeutic areas including oncology, gastroenterology or respiratory diseases to support our sponsor’s requirements.
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About ImaBiotech
ImaBiotech supports pharmaceutical industry with innovative Imaging services that predict more accurately which treatment will work in stratified population.
ImaBiotech is a Contract Research Organization (CRO) with two facilities one in Boston (MA) and one in France. The company offers innovative services to the pharmaceutical research to provide better drug efficacy and toxicity evaluations from preclinical to clinical stages, making better and safer drugs.
Services are based on different imaging techniques combined to Quantitative Mass Spectrometry a technology developed and constantly improved by ImaBiotech. Quantitative Mass Spectrometry (QMSI) has been developed for decades and allows to detect elements and molecules without labelling. ImaBiotech has developed the quantitative aspects through many patents making ImaBiotech the worldwide leader in this field. QMSI is a game changer of the pharmaceutical industry in all therapeutic areas. While actual techniques provide global information, this molecular technique brings deeper information about drug localization and its pharmacology effects to recover disease tissues and damaged cells. This increases the interpretation of drug efficacy and toxicity improving drugs and improving time to market. To interpret datas we’ve developed, thanks to our patents, two softwares called Quantinetix and Multimaging to interpret pharmacology in tissue.
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