Journal Article

DKFZ-2021-01917

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors.

Calandrini, C. ; van Hooff, S. R. ; Paassen, I. ; Ayyildiz, D. ; Derakhshan, S. ; Dolman, M. E. M. ; Langenberg, K. P. S. ; van de Ven, M. ; de Heus, C. ; Liv, N. ; Kool, M.DKFZ* ; de Krijger, R. R. ; Tytgat, G. A. M. ; van den Heuvel-Eibrink, M. M. ; Molenaar, J. J. ; Drost, J.

2021
Elsevier [New York, NY]

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Please use a persistent id in citations: doi:10.1016/j.celrep.2021.109568

Abstract: Malignant 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.

Keyword(s): MLN4924 ; drug screening ; malignant rhabdoid tumors ; neddylation ; organoids ; targeted therapy

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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