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Nat Commun. 2018 Apr 16;9(1):1474. doi: 10.1038/s41467-018-03905-6.

Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate.

Author information

1
Department of Radiology, Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Boston, MA, 02129, USA. oandronesi@mgh.harvard.edu.
2
Department of Neurology, Massachusetts General Hospital, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Harvard Medical School, Boston, MA, 02114, USA.
3
Department of Biomedical Imaging and Image-guided Therapy, High Field MR Centre, Medical University of Vienna, Vienna, 1090, Austria.
4
Department of Radiology, Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Boston, MA, 02129, USA.
5
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
6
Department of Pathology, Massachusetts General Hospital, Center for Integrated Diagnostics, Harvard Medical School, Boston, MA, 02114, USA.
7
Brain Tumor Center, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center and School of Medicine, New York, NY, 10016, USA.
8
Dana-Farber Cancer Institute, Boston, MA, 02284, USA.

Abstract

Inhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment. Mutant IDH1 produces high levels of 2-hydroxyglurate (2HG), thought to initiate oncogenesis through epigenetic modifications of gene expression. In this study, we show the initial evidence of the pharmacodynamics of a new mutant IDH1 inhibitor in glioma patients, using non-invasive 3D MR spectroscopic imaging of 2HG. Our results from a Phase 1 clinical trial indicate a rapid decrease of 2HG levels by 70% (CI 13%, P = 0.019) after 1 week of treatment. Importantly, inhibition of mutant IDH1 may lead to the reprogramming of tumor metabolism, suggested by simultaneous changes in glutathione, glutamine, glutamate, and lactate. An inverse correlation between metabolic changes and diffusion MRI indicates an effect on the tumor-cell density. We demonstrate a feasible radiopharmacodynamics approach to support the rapid clinical translation of rationally designed drugs targeting IDH1/2 mutations for personalized and precision medicine of glioma patients.

PMID:
29662077
PMCID:
PMC5902553
DOI:
10.1038/s41467-018-03905-6
[Indexed for MEDLINE]
Free PMC Article

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