Article
Identification of synergistic drug combinations for therapy of IDH-mutated glioma
Identifikation von synergistischen Medikamentenkombinationen zur Behandlung IDH-mutierter Gliome
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Authors
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Florian Stammler
- Universitätsklinikum Heidelberg, Neurochirurgische Klinik, Experimentelle Neurochirurgie, Heidelberg, Deutschland
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Rolf Warta
- Universitätsklinikum Heidelberg, Neurochirurgische Klinik, Experimentelle Neurochirurgie, Heidelberg, Deutschland
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Christel Herold-Mende
- Universitätsklinikum Heidelberg, Neurochirurgische Klinik, Experimentelle Neurochirurgie, Heidelberg, Deutschland
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Andreas W. Unterberg
- Universitätsklinikum Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
| Published: | May 25, 2022 |
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Outline
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Objective: Isocitrate Dehydrogenase-mutated (IDHmut) and wildtype (IDHwt) gliomas are regarded as separate tumor entities with the need for accordingly adjusted therapies. IDHmut tumors have a better prognosis than the wildtype. Nevertheless they are still not curable since there is no effective drug therapy established. Since a combination of several drugs might help avoiding an unwanted drug resistance, we searched for combinations of FDA-approved drugs to effectively inhibit the growth of IDHmut glioma stem-like cells (GSC) in vitro.
Methods: Drug combinations of 146 antineoplastic FDA-approved drugs were tested on altogether five IDHmut GSC lines. Based on a previous single-agent drugsreen, four drugs showing various drug responses on the individual cell lines were selected (Idarubicin, Ixazumib, Ponatinib, Romidepsin) to be combined with all 146 drugs of the library. Cell viability was assessed by the CellTiterGlo 3D assay (Promega) in 96 well plates, while Caspase-Glo 3/7 3D assay was used to measure induction of apoptosis.
Results: Out of 584 drug combinations tested altogether 45 synergistic drug combinations could be identified. 15 combinations could be validated and were enriched for a combination of HDAC (HDACi) and proteasome inhibitors (Pi). The synergistic HDACi/Pi combination with the highest blood-brain-barrier permeability score (Panobinostat + Ixazomib) was further validated in a 4-point dose-response matrix in all 5 IDHmut GSC lines. Synergistic effect over a wide range of concentrations could be confirmed while drug concentrations to achieve the maximum synergistic effect differed among GSC lines. Finally, quantification of apoptotic cells confirmed the synergistic action of Panobinostat and Ixazomib.
Conclusion: Our combinatorial drug screen of IDH-mut GSCs identified a substantial number of synergistic drug combinations. Enrichment of HDAC/proteamsome inhibitor combinations and their further validation suggest that LGG patients might benefit from a combinatorial treatment of Panobinostat and Ixazomib. These promising findings warrant further preclinical validation.
