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000170414 0247_ $$2doi$$a10.1016/j.celrep.2021.109568
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000170414 1001_ $$aCalandrini, Camilla$$b0
000170414 245__ $$aOrganoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors.
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000170414 520__ $$aMalignant rhabdoid tumors (MRTs) represent one of the most aggressive childhood malignancies. No effective treatment options are available, and prognosis is, therefore, dismal. Previous studies have demonstrated that tumor organoids capture the heterogeneity of patient tumors and can be used to predict patient response to therapy. Here, we perform drug screening on patient-derived normal and tumor organoids to identify MRT-specific therapeutic vulnerabilities. We identify neddylation inhibitor MLN4924 as a potential therapeutic agent. Mechanistically, we find increased neddylation in MRT organoids and tissues and show that MLN4924 induces a cytotoxic response via upregulation of the unfolded protein response. Lastly, we demonstrate in vivo efficacy in an MRT PDX mouse model, in which single-agent MLN4924 treatment significantly extends survival. Our study demonstrates that organoids can be used to find drugs selectively targeting tumor cells while leaving healthy cells unharmed and proposes neddylation inhibition as a therapeutic strategy in MRT.
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000170414 650_7 $$2Other$$aMLN4924
000170414 650_7 $$2Other$$adrug screening
000170414 650_7 $$2Other$$amalignant rhabdoid tumors
000170414 650_7 $$2Other$$aneddylation
000170414 650_7 $$2Other$$aorganoids
000170414 650_7 $$2Other$$atargeted therapy
000170414 7001_ $$avan Hooff, Sander R$$b1
000170414 7001_ $$aPaassen, Irene$$b2
000170414 7001_ $$aAyyildiz, Dilara$$b3
000170414 7001_ $$aDerakhshan, Sepide$$b4
000170414 7001_ $$aDolman, M Emmy M$$b5
000170414 7001_ $$aLangenberg, Karin P S$$b6
000170414 7001_ $$avan de Ven, Marieke$$b7
000170414 7001_ $$ade Heus, Cecilia$$b8
000170414 7001_ $$aLiv, Nalan$$b9
000170414 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b10$$udkfz
000170414 7001_ $$ade Krijger, Ronald R$$b11
000170414 7001_ $$aTytgat, Godelieve A M$$b12
000170414 7001_ $$avan den Heuvel-Eibrink, Marry M$$b13
000170414 7001_ $$aMolenaar, Jan J$$b14
000170414 7001_ $$aDrost, Jarno$$b15
000170414 773__ $$0PERI:(DE-600)2649101-1$$a10.1016/j.celrep.2021.109568$$gVol. 36, no. 8, p. 109568 -$$n8$$p109568$$tCell reports$$v36$$x2211-1247$$y2021
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