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

Ovidiu C Andronesi,Eva M Ratai,Daniel P Cahill,Patrick Y Wen,A John Iafrate,Kara Reitz,Jorg Dietrich,Wolfgang Bogner,Tracy T Batchelor,K Ina Ly,Andrew S Chi,Bruce R Rosen,Isabel C Arrillaga-Romany,Elizabeth R Gerstner

doi:10.1038/s41467-018-03905-6

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.

Highlights

Inhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment
The mutant IDH1 glioma are more amenable to gross-total resection[11] and seem to respond better to standard chemoradiation[12,13,14] especially when associated 1p/19q co-deletion, the IDH1 mutations represent a clear opportunity for more targeted treatment either by small-molecule inhibitors of the mutant IDH1 enzyme[15], immunotherapy[16], or by synthetic lethality strategies[17,18]
2HG levels in serum and urine are influenced by other factors, such as the blood–brain barrier (BBB), which is less compromised in mutant IDH1 glioma, and the shedding of tumor material may be reduced

Summary

Introduction

Inhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment. For monitoring the treatment in mutant IDH1 glioma patients the non-invasive MRS detection of 2HG is more feasible[27,28] and has clear advantages, compared to biopsies: (1) there are no associated risks, (2) the technique can be repeated multiple times, (3) the technique can probe multiple tumor regions, and (4) MRS can investigate normal appearing brain as internal control. In this study we used a recently demonstrated 3D MRS imaging (MRSI) method for 2HG detection[27] to assess the pharmacodynamic effects of the new investigational drug IDH305 (Novartis Pharmaceuticals) in mutant IDH1 glioma patients enrolled in an open label first-in-human Phase I clinical trial (ClinicalTrials.gov identifier: NCT02381886). In addition to 2HG, we measured other metabolites that are

Methods

Results

Conclusion