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

Ovidiu C. Andronesi (), Isabel C. Arrillaga-Romany, K. Ina Ly, Wolfgang Bogner, Eva M. Ratai, Kara Reitz, A. John Iafrate, Jorg Dietrich, Elizabeth R. Gerstner, Andrew S. Chi, Bruce R. Rosen, Patrick Y. Wen, Daniel P. Cahill and Tracy T. Batchelor
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Ovidiu C. Andronesi: Harvard Medical School
Isabel C. Arrillaga-Romany: Harvard Medical School
K. Ina Ly: Harvard Medical School
Wolfgang Bogner: Medical University of Vienna
Eva M. Ratai: Harvard Medical School
Kara Reitz: Harvard Medical School
A. John Iafrate: Harvard Medical School
Jorg Dietrich: Harvard Medical School
Elizabeth R. Gerstner: Harvard Medical School
Andrew S. Chi: New York University Langone Medical Center and School of Medicine
Bruce R. Rosen: Harvard Medical School
Patrick Y. Wen: Dana-Farber Cancer Institute
Daniel P. Cahill: Harvard Medical School
Tracy T. Batchelor: Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03905-6

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