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Drug screening on tumor organoids exposes therapeutic vulnerabilities of meningiomas to HDAC1/2i panobinostat

Managing aggressive meningiomas remains challenging because of limited treatment options besides surgical tumor removal and radiotherapy. To increase the repertoire of promising therapies for aggressive meningiomas, we established a multistep drug screening workflow, focusing on targetable genes obt...

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Main Authors: Jungwirth, Gerhard (Author) , Cao, Junguo (Author) , Pan, Yimin (Author) , Warta, Rolf (Author) , Lotsch, Catharina (Author) , Moustafa, Mahmoud (Author) , Knoll, Maximilian (Author) , Yu, Tao (Author) , Braun, Viktor (Author) , Jassowicz, Lena (Author) , Dao Trong, Huy Philip (Author) , Wang, Zhenlin (Author) , Younsi, Alexander (Author) , Scherer, Moritz (Author) , Bendszus, Martin (Author) , Krieg, Sandro (Author) , Deimling, Andreas von (Author) , Debus, Jürgen (Author) , Abdollahi, Amir (Author) , Unterberg, Andreas (Author) , Sahm, Felix (Author) , Herold-Mende, Christel (Author)
Format: Article (Journal)
Language:English
Published: 4 March 2026
In: Science translational medicine
Year: 2026, Volume: 18, Issue: 839, Pages: 1-13
ISSN:1946-6242
DOI:10.1126/scitranslmed.aea3115
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/scitranslmed.aea3115
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Author Notes:Gerhard Jungwirth, Junguo Cao, Yimin Pan, Rolf Warta, Catharina Lotsch, Mahmoud Moustafa, Maximilian Knoll, Tao Yu, Viktor Braun, Lena Jassowicz, Philip Dao Trong, Zhenlin Wang, Alexander Younsi, Moritz Scherer, Martin Bendszus, Sandro M. Krieg, Andreas von Deimling, Juergen Debus, Amir Abdollahi, Andreas Unterberg, Felix Sahm, Christel Herold-Mende
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Summary:Managing aggressive meningiomas remains challenging because of limited treatment options besides surgical tumor removal and radiotherapy. To increase the repertoire of promising therapies for aggressive meningiomas, we established a multistep drug screening workflow, focusing on targetable genes obtained from transcriptome data of highly aggressive grade 3 meningiomas. In vitro screening of 107 targeted drugs identified nine effective inhibitors. To study these drugs in a more natural environment, we established a standardized patient-derived tumor organoid (TO) model preserving accurately the original tissue's genotype and phenotype. Individual drug responses were assessed in TOs from 60 meningioma cases characterized at the molecular level. In particular, the US Food and Drug Administration-approved epigenetic drug panobinostat demonstrated high antimeningioma efficacy in 70% of TOs, mediated through histone deacetylase 1 and 2 (HDAC1/2) inhibition. In addition, treatment in an orthotopic in vivo model revealed improved survival. In search of the molecular mechanism underlying a potentially intrinsic panobinostat resistance, we identified up-regulation of the HDAC8-transforming growth factor-beta (TGF beta)-epithelial-to-mesenchymal transition (EMT) axis in the TO model, whereas subsequent HDAC8 depletion increased the sensitivity to panobinostat. These data highlight the utility of personalized drug screenings on TOs to identify suitable drug targets and inhibitors for more effective treatment of clinically aggressive meningiomas and to help advance our understanding of counteracting resistance mechanisms.
Item Description:Gesehen am 08.05.2026
Physical Description:Online Resource
ISSN:1946-6242
DOI:10.1126/scitranslmed.aea3115

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