A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit

Abstract

Mutations in IDH1 are highly prevalent in human glioma. First line treatment is radiotherapy, which many patients often forego to avoid treatment-associated morbidities. The high prevalence of IDH1 mutations in glioma highlights the need for brain-penetrant IDH1 mutant-selective inhibitors as an alternative therapeutic option. Here, we have explored the utility of such an inhibitor in IDH1 mutant patient-derived models to assess the potential therapeutic benefits associated with intracranial 2-HG inhibition. Treatment of mutant IDH1 cell line models led to a decrease in intracellular 2-HG levels both in vitro and in vivo. Interestingly, inhibition of 2-HG production had no effect on in vitro IDH1 mutant glioma cell proliferation. In contrast, IDH1 mutant-selective inhibitors provided considerable survival benefit in vivo. However, even with near complete inhibition of intratumoral 2-HG production, not all mutant glioma models responded to treatment. The results suggest that disruption of 2-HG production with brain-penetrant inhibitors in IDH1 mutant gliomas may have substantial patient benefit.

Metabolic changes related to the IDH1 mutation in gliomas preserve TCA‐cycle activity: An investigation at the protein level

“…The IDH1 mut induces changes in the concentration of tricarboxylic acid (TCA) cycle intermediates and lipid metabolites . In vitro and in vivo studies demonstrated that the inhibition of IDH1/2‐mutant enzymes decreases intracellular D‐2‐hydroxyglutarate (D‐2HG) levels and reverses epigenetic dysregulation . Gene expression profiles of large cohorts of glioma and acute myeloid leukemia have shown that IDH1/2 mutant tumors display a distinct gene expression profile enriched for genes expressed in progenitor cells .…”

“…4,5 In vitro and in vivo studies demonstrated that the inhibition of IDH1/2-mutant enzymes decreases intracellular D-2-hydroxyglutarate (D-2HG) levels and reverses epigenetic dysregulation. 6,7 Gene expression profiles of large cohorts of glioma and acute myeloid leukemia have shown that IDH1/2 mutant tumors display a distinct gene expression profile enriched for genes expressed in progenitor cells. 8 Metabolic flux analyses have shown that IDH1 mut render tumor cells more dependent on citrate and fatty acids under hypoxia as compared with IDH1 wt cells and this metabolic reprogramming results in decreased cell growth of IDH1 mut cells upon hypoxia.…”

The clinical use of IDH1 and IDH2 mutations in gliomas

“…A reduction of repressive histone trimethylation markers was identified in cells treated with higher doses of the inhibitor [104]. Murine 440 models showed promising results in terms of tumor growth inhibition and increased survival [104,135,136,139]. However, IDH mutant inhibition did not result in mutant cells growth blockade in other studies, despite effective D2HG levels reduction, suggesting that in some lines tumor growth is indepen-445 dent from IDH mutant function [136,140].…”

“…As IDH mutation is an early, truncal and stable alteration 425 leading to the production of a specific oncometabolite, the inhibition of the neomorphic enzymatic activity soon appeared as a logic therapeutic approach. Since the first report of an in vitro effective IDH1 R132H inhibitor [104], several other inhibitors targeting also non-R132H IDH1 and IDH2 430 mutations have been developed [135][136][137][138].…”

“…Preclinical studies showed that IDH mutant inhibition cause a detectable decrease in D2HG levels and the induction of differentiation in IDH mutant glioma cells [104,135,136]. Kopinja et al [136] . reported a decrease in 5-methylcytosine 435 levels in treated tumor sections compared to controls.…”