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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
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.
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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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