TY  - JOUR
A1  - Wenger-Alakmeh, Katharina Johanna
A1  - Richter, Christian
A1  - Burger, Michael Christian
A1  - Urban, Hans
A1  - Kaulfuß, Stefan
A1  - Harter, Patrick Nikolaus
A1  - Sreeramulu, Sridhar
A1  - Schwalbe, Harald
A1  - Steinbach, Joachim Peter
A1  - Hattingen, Elke
A1  - Bähr, Oliver
A1  - Pilatus, Ulrich
T1  - 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
T2  - Cancers
N2  - 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.
KW  - glioma
KW  - IDH mutation
KW  - 2-hydroxyglutarate
KW  - murine model
KW  - targeted therapy
KW  - small molecule inhibitor
KW  - IDH1 inhibitor
KW  - 19F MR spectroscopy
KW  - 1H MR spectroscopy
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/56839
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-568399
SN  - 2072-6694
VL  - 12
IS  - 3175
PB  - MDPI
CY  - Basel
ER  -