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

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.

Fig. 1

Longitudinal imaging in mutant IDH1 glioma patients treated with IDH305 inhibitor. a Baseline anatomical, structural and metabolic maps before treatment. b Follow-up anatomical, structural, and metabolic maps after 1 week of IDH305 treatment. Metabolic maps are converted to mM by reference to healthy creatine levels. The color bars ranges are 0–3 mM (2HG), 0–20 mM (Glx), 0–1 mM (GSH), 0–16 mM (Lac), 0–3 mM (tCho), 0–20 mM (NAA), and 0–4 μm²/ms (ADC). On the right, examples of 2HG edited spectra (black trace) and the LCModel fits (red trace) are shown

Fig. 2

Histograms of 2HG levels. The distribution of patient 2HG levels within the tumor ROI are shown before (dashed line) and after 1 week (continuous line) of treatment with the mutant IDH1 inhibitor IDH305

Fig. 3

Boxplot of the fractional changes for the mean values averaged over the tumor ROI. Box size represents the first and third quartiles, and horizontal red line indicates the median. Statistical significant changes are indicated by the * symbol (P < 0.05)

Fig. 4

Relation between the treatment induced changes of 2HG and other metabolic and imaging biomarkers. Linear model fitting has been employed to investigate the relationship between the changes: a 2HG and GSH; b 2HG and Glx; c ratio of 2HG/Glx and ADC. A significant inverse correlation was found between changes of 2HG/Glx ratio and changes of ADC after 1 week of treatment with IDH305