No abstract

Background Mutations of the isocitrate dehydrogenase (IDH) gene occur in over 80% of low-grade gliomas and secondary glioblastomas. Despite considerable efforts, endogenous in vitro IDH-mutated glioma models remain scarce. Availability of these models is key for the development of new therapeutic interventions. Methods Cell cultures were established from fresh tumor material and expanded in serum-free culture media. D-2-Hydroxyglutarate levels were determined by mass-spectrometry. Genomic and transcriptomic profiling were carried out on the Illumina Novaseq platform, methylation profiling was performed with the Infinium MethylationEpic BeadChip array. Mitochondrial respiration was measured with the Seahorse XF24 Analyzer. Drug screens were performed with an NIH FDA-approved anti-cancer drug set and two IDH-mutant specific inhibitors. Results A set of twelve patient-derived IDHmt cell cultures was established. We confirmed high concordance in driver mutations, copy number and methylation profiles between the tumors and derived cultures. Homozygous deletion of CDKN2A/B was observed in all cultures. IDH-mutant cultures had lower mitochondrial reserve capacity. IDH-mutant specific inhibitors did not affect cell viability or global gene expression. Screening of 107 FDA-approved anti-cancer drugs identified nine compounds with potent activity against IDHmt gliomas, including three compounds with favorable pharmacokinetic characteristics for CNS penetration: teniposide, omacetaxine mepesuccinate, and marizomib. Conclusions Our twelve IDH-mutant cell cultures show high similarity to the parental tissues and offer a unique tool to study the biology and drug sensitivities of high-grade IDHmt gliomas in vitro. Our drug screening studies reveal lack of sensitivity to IDHmt inhibitors, but sensitivity to a set of nine available anti-cancer agents.

Glioblastoma (GBM) remains one of the most difficult tumors to treat. The mean overall survival rate of 15 months and the 5-year survival rate of 5% have not significantly changed for almost 2 decades. Despite progress in understanding the pathophysiology of the disease, no new effective treatments to combine with radiation therapy after surgical tumor debulking have become available since the introduction of temozolomide in 1999. One of the main reasons for this is the scarcity of compounds that cross the blood–brain barrier (BBB) and reach the brain tumor tissue in therapeutically effective concentrations. In this review, we focus on the role of the BBB and its importance in developing brain tumor treatments. Moreover, we discuss drug repurposing, a drug discovery approach to identify potential effective candidates with optimal pharmacokinetic profiles for central nervous system (CNS) penetration and that allows rapid implementation in clinical trials. Additionally, we provide an overview of repurposed candidate drug currently being investigated in GBM at the preclinical and clinical levels. Finally, we highlight the importance of phase 0 trials to confirm tumor drug exposure and we discuss emerging drug delivery technologies as an alternative route to maximize therapeutic efficacy of repurposed candidate drug.