Non-invasive measurement of drug and 2-HG signals using 19F and 1H MR spectroscopy in brain tumors treated with the mutant IDH1 inhibitor BAY1436032

  • Simple Summary: Targeted therapies are of growing interest to physicians in cancer treatment. These drugs target specific genes and proteins involved in the growth and survival of cancer cells. Brain tumor therapy is complicated by the fact that not all drugs can penetrate the blood brain barrier and reach their target. We explored the non-invasive method, Magnetic Resonance Spectroscopy, for monitoring drug penetration and its effects in live animals bearing brain tumors. We were able to show the presence of the investigated drug in mouse brains and its on-target activity. Abstract: Background: BAY1436032 is a fluorine-containing inhibitor of the R132X-mutant isocitrate dehydrogenase (mIDH1). It inhibits the mIDH1-mediated production of 2-hydroxyglutarate (2-HG) in glioma cells. We investigated brain penetration of BAY1436032 and its effects using 1H/19F-Magnetic Resonance Spectroscopy (MRS). Methods: 19F-Nuclear Magnetic Resonance (NMR) Spectroscopy was conducted on serum samples from patients treated with BAY1436032 (NCT02746081 trial) in order to analyze 19F spectroscopic signal patterns and concentration-time dynamics of protein-bound inhibitor to facilitate their identification in vivo MRS experiments. Hereafter, 30 mice were implanted with three glioma cell lines (LNT-229, LNT-229 IDH1-R132H, GL261). Mice bearing the IDH-mutated glioma cells received 5 days of treatment with BAY1436032 between baseline and follow-up 1H/19F-MRS scan. All other animals underwent a single scan after BAY1436032 administration. Mouse brains were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Results: Evaluation of 1H-MRS data showed a decrease in 2-HG/total creatinine (tCr) ratios from the baseline to post-treatment scans in the mIDH1 murine model. Whole brain concentration of BAY1436032, as determined by 19F-MRS, was similar to total brain tissue concentration determined by Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), with a signal loss due to protein binding. Intratumoral drug concentration, as determined by LC-MS/MS, was not statistically different in models with or without R132X-mutant IDH1 expression. Conclusions: Non-invasive monitoring of mIDH1 inhibition by BAY1436032 in mIDH1 gliomas is feasible.

Download full text files

Export metadata

Author:Katharina Johanna Wenger-AlakmehORCiDGND, Christian RichterORCiDGND, Michael Christian BurgerORCiDGND, Hans UrbanGND, Stefan Kaulfuß, Patrick Nikolaus HarterORCiDGND, Sridhar SreeramuluORCiDGND, Harald SchwalbeORCiDGND, Joachim Peter SteinbachORCiDGND, Elke HattingenORCiDGND, Roy Oliver Bähr, Ulrich PilatusORCiD
Pubmed Id:
Parent Title (English):Cancers
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/10/29
Date of first Publication:2020/10/29
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/11/12
Tag:19F MR spectroscopy; 1H MR spectroscopy; 2-hydroxyglutarate; IDH mutation; IDH1 inhibitor; glioma; murine model; small molecule inhibitor; targeted therapy
Page Number:11
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0