Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate
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 evi...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902553/ https://www.ncbi.nlm.nih.gov/pubmed/29662077 http://dx.doi.org/10.1038/s41467-018-03905-6 |
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author | Andronesi, Ovidiu C. Arrillaga-Romany, Isabel C. Ly, K. Ina Bogner, Wolfgang Ratai, Eva M. Reitz, Kara Iafrate, A. John Dietrich, Jorg Gerstner, Elizabeth R. Chi, Andrew S. Rosen, Bruce R. Wen, Patrick Y. Cahill, Daniel P. Batchelor, Tracy T. |
author_facet | Andronesi, Ovidiu C. Arrillaga-Romany, Isabel C. Ly, K. Ina Bogner, Wolfgang Ratai, Eva M. Reitz, Kara Iafrate, A. John Dietrich, Jorg Gerstner, Elizabeth R. Chi, Andrew S. Rosen, Bruce R. Wen, Patrick Y. Cahill, Daniel P. Batchelor, Tracy T. |
author_sort | Andronesi, Ovidiu C. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5902553 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59025532018-04-20 Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate Andronesi, Ovidiu C. Arrillaga-Romany, Isabel C. Ly, K. Ina Bogner, Wolfgang Ratai, Eva M. Reitz, Kara Iafrate, A. John Dietrich, Jorg Gerstner, Elizabeth R. Chi, Andrew S. Rosen, Bruce R. Wen, Patrick Y. Cahill, Daniel P. Batchelor, Tracy T. Nat Commun Article 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. Nature Publishing Group UK 2018-04-16 /pmc/articles/PMC5902553/ /pubmed/29662077 http://dx.doi.org/10.1038/s41467-018-03905-6 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Andronesi, Ovidiu C. Arrillaga-Romany, Isabel C. Ly, K. Ina Bogner, Wolfgang Ratai, Eva M. Reitz, Kara Iafrate, A. John Dietrich, Jorg Gerstner, Elizabeth R. Chi, Andrew S. Rosen, Bruce R. Wen, Patrick Y. Cahill, Daniel P. Batchelor, Tracy T. Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate |
title | Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate |
title_full | Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate |
title_fullStr | Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate |
title_full_unstemmed | Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate |
title_short | Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate |
title_sort | pharmacodynamics of mutant-idh1 inhibitors in glioma patients probed by in vivo 3d mrs imaging of 2-hydroxyglutarate |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902553/ https://www.ncbi.nlm.nih.gov/pubmed/29662077 http://dx.doi.org/10.1038/s41467-018-03905-6 |
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