Automated and personalized glioblastoma tumor organoid drug screening platform exposes sensitivity to proteasome and HDAC inhibitors

Abstract Personalized drug screening aims to improve the survival of glioblastoma (GBM) patients by identifying effective patient-individual drugs. Therefore, we conducted an automated high-throughput drug screening (aHTS) on standardized patient-derived glioblastoma tumor organoids (TOs). Robot-assisted aHTS was performed on TOs from 11 GBM patients. TOs fully compacted after two days, and the size remained stable over 10 days. TOs proliferated over time, and immunofluorescence stainings (GFAP, Tenascin C) confirmed tissue-like architecture. Anti-glioma effects with the lowest drug concentrations were achieved for proteasome inhibitors (carfilzomib, bortezomib, ixazomib), and HDAC inhibitors (panobinostat, romidepsin). Plasma C max -based drug levels ( C max /IC 50 > 1) used as a surrogate were only achieved for the three proteasome inhibitors and the HDACi romidepsin. The impact of their drug targets PSMB5 and HDAC1/2 on the growth of GBM cells was successfully validated by RNAi experiments. We established an aHTS platform for GBM TOs, and identified proteasome and HDAC inhibitors as promising drugs for the treatment of GBMs.