2. Academic Validation
  3. Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

  • Cell Rep. 2021 Aug 24;36(8):109568. doi: 10.1016/j.celrep.2021.109568.
Camilla Calandrini 1,  Sander R van Hooff 2,  Irene Paassen 1,  Dilara Ayyildiz 1,  Sepide Derakhshan 1,  M Emmy M Dolman 2,  Karin P S Langenberg 2,  Marieke van de Ven 3,  Cecilia de Heus 4,  Nalan Liv 4,  Marcel Kool 5,  Ronald R de Krijger 6,  Godelieve A M Tytgat 2,  Marry M van den Heuvel-Eibrink 2,  Jan J Molenaar 2,  Jarno Drost 7
Affiliations

Affiliations

  • 1 Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands; Oncode Institute, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands.
  • 2 Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands.
  • 3 Preclinical Intervention Unit of the Mouse Clinic for Cancer and Ageing (MCCA), NKI, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
  • 4 Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
  • 5 Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands; Hopp Children's Cancer Center (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center DKFZ and German Cancer Consortium DKTK, 69120 Heidelberg, Germany.
  • 6 Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands; University Medical Center, Department of Pathology, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
  • 7 Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands; Oncode Institute, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands. Electronic address: [email protected].
PMID: 34433038 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.

Keywords

MLN4924; drug screening; malignant rhabdoid tumors; neddylation; organoids; targeted therapy.

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