Large-Scale Drug Screening in Patient-Derived IDH mut Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents.

The discovery of the isocitrate dehydrogenase (IDH) mutation in glioma led to a paradigm shift on how we see glioma biology. Difficulties in cultivating IDH mutant glioma stem cells (IDH ^mut GSCs) resulted in a paucity of preclinical models in IDH ^mut glioma, limiting the discovery of new effective chemotherapeutic agents. To fill this gap, we used six recently developed patient-derived IDH ^mut GSC lines and performed a large-scale drug screening with 147 Food and Drug Administration (FDA)-approved anticancer drugs. GSCs were subjected to the test compounds for 72 h in concentrations ranging from 0.0001 to 1 µM. Cell viability was assessed by CellTiterGlo and the induction of apoptosis by flow cytometry with Annexin V/propidium iodide staining. The initial screen was performed with two IDH ^mut GSC lines and identified seven drugs (bortezomib, carfilzomib, daunorubicin, doxorubicin, epirubicin, omacetaxine, plicamycin) with a substantial antiproliferative activity, as reflected by half maximal inhibitory concentrations (IC ₅₀ ) below 1 µM and maximum inhibitory effects (E _max ) below 25%. These findings were validated in an additional four IDH ^mut GSC lines. The candidate drugs, of which plicamycin and omacetaxine are known to cross the blood brain barrier, were used for subsequent cell death analyses. A significant induction of apoptosis was observed at IC ₅₀ values of the respective drugs. In summary, we were able to identify seven FDA-approved drugs that should be further taken into clinical investigations for the treatment of IDH ^mut gliomas.