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000310296 1001_ $$0P:(DE-He78)896c11d3aed452d93d14aa08e0097c55$$aJungwirth, Gerhard$$b0
000310296 245__ $$aDrug screening on tumor organoids exposes therapeutic vulnerabilities of meningiomas to HDAC1/2i panobinostat.
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000310296 520__ $$aManaging aggressive meningiomas remains challenging because of limited treatment options besides surgical tumor removal and radiotherapy. To increase the repertoire of promising therapies for aggressive meningiomas, we established a multistep drug screening workflow, focusing on targetable genes obtained from transcriptome data of highly aggressive grade 3 meningiomas. In vitro screening of 107 targeted drugs identified nine effective inhibitors. To study these drugs in a more natural environment, we established a standardized patient-derived tumor organoid (TO) model preserving accurately the original tissue's genotype and phenotype. Individual drug responses were assessed in TOs from 60 meningioma cases characterized at the molecular level. In particular, the US Food and Drug Administration-approved epigenetic drug panobinostat demonstrated high antimeningioma efficacy in 70% of TOs, mediated through histone deacetylase 1 and 2 (HDAC1/2) inhibition. In addition, treatment in an orthotopic in vivo model revealed improved survival. In search of the molecular mechanism underlying a potentially intrinsic panobinostat resistance, we identified up-regulation of the HDAC8-transforming growth factor-β (TGFβ)-epithelial-to-mesenchymal transition (EMT) axis in the TO model, whereas subsequent HDAC8 depletion increased the sensitivity to panobinostat. These data highlight the utility of personalized drug screenings on TOs to identify suitable drug targets and inhibitors for more effective treatment of clinically aggressive meningiomas and to help advance our understanding of counteracting resistance mechanisms.
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000310296 7001_ $$00000-0002-2254-8152$$aCao, Junguo$$b1
000310296 7001_ $$aPan, Yimin$$b2
000310296 7001_ $$00000-0003-2821-4361$$aWarta, Rolf$$b3
000310296 7001_ $$0P:(DE-HGF)0$$aLotsch, Catharina$$b4
000310296 7001_ $$0P:(DE-He78)00f2c4d2003902d3abd37481c5268850$$aMoustafa, Mahmoud$$b5$$udkfz
000310296 7001_ $$0P:(DE-He78)34ad9f967b71b1438cf5490a115c02d2$$aKnoll, Maximilian$$b6$$udkfz
000310296 7001_ $$00000-0001-7471-4290$$aYu, Tao$$b7
000310296 7001_ $$00000-0002-2600-3619$$aBraun, Viktor$$b8
000310296 7001_ $$aJassowicz, Lena$$b9
000310296 7001_ $$00000-0001-8063-5425$$aTrong, Philip Dao$$b10
000310296 7001_ $$aWang, Zhenlin$$b11
000310296 7001_ $$00000-0002-8218-9243$$aYounsi, Alexander$$b12
000310296 7001_ $$00000-0003-1203-9351$$aScherer, Moritz$$b13
000310296 7001_ $$00000-0002-9094-6769$$aBendszus, Martin$$b14
000310296 7001_ $$00000-0003-4050-1531$$aKrieg, Sandro M$$b15
000310296 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b16$$udkfz
000310296 7001_ $$00000-0002-6411-4811$$aDebus, Juergen$$b17
000310296 7001_ $$0P:(DE-He78)360c5bc2b71a849e35aca747c041dda7$$aAbdollahi, Amir$$b18$$udkfz
000310296 7001_ $$aUnterberg, Andreas$$b19
000310296 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b20$$udkfz
000310296 7001_ $$aHerold-Mende, Christel$$b21
000310296 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.aea3115$$gVol. 18, no. 839, p. eaea3115$$n839$$peaea3115$$tScience translational medicine$$v18$$x1946-6234$$y2026
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