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  3. High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma

High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma

  • Cancer Lett. 2022 Nov 30;216028. doi: 10.1016/j.canlet.2022.216028.
Sarah Grissenberger 1,  Caterina Sturtzel 2,  Andrea Wenninger-Weinzierl 2,  Branka Radic-Sarikas 3,  Eva Scheuringer 2,  Lisa Bierbaumer 1,  Vesnie Etienne 4,  Fariba Némati 4,  Susana Pascoal 2,  Marcus Tötzl 1,  Eleni Tomazou 1,  Martin Metzelder 5,  Eva M Putz 1,  Didier Decaudin 6,  Olivier Delattre 7,  Didier Surdez 8,  Heinrich Kovar 9,  Florian Halbritter 1,  Martin Distel 10
Affiliations

Affiliations

  • 1 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
  • 2 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria; Zebrafish Platform Austria for Preclinical Drug Screening (ZANDR), Vienna, Austria.
  • 3 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria; Department of Pediatric Surgery, Medical University of Vienna, Vienna, Austria.
  • 4 Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France.
  • 5 Department of Pediatric Surgery, Medical University of Vienna, Vienna, Austria.
  • 6 Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France; Department of Medical Oncology, Institut Curie Research Centre, Paris, France.
  • 7 INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, Paris, France.
  • 8 INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, Paris, France; Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland.
  • 9 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria; Dept. Pediatrics, Medical University Vienna, Vienna, Austria.
  • 10 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria; Zebrafish Platform Austria for Preclinical Drug Screening (ZANDR), Vienna, Austria. Electronic address: [email protected].
PMID: 36462556 DOI: 10.1016/j.canlet.2022.216028
Abstract

Ewing sarcoma is a pediatric bone and soft tissue Cancer with an urgent need for new therapies to improve disease outcome. To identify effective drugs, phenotypic drug screening has proven to be a powerful method, but achievable throughput in mouse xenografts, the preclinical Ewing sarcoma standard model, is limited. Here, we explored the use of xenografts in zebrafish for high-throughput drug screening to discover new combination therapies for Ewing sarcoma. We subjected xenografts in zebrafish larvae to high-content imaging and subsequent automated tumor size analysis to screen single agents and compound combinations. We identified three drug combinations effective against Ewing sarcoma cells: Irinotecan combined with either an Mcl-1 or an BCL-XL inhibitor and in particular dual inhibition of the anti-apoptotic proteins Mcl-1 and BCL-XL, which efficiently eradicated tumor cells in zebrafish xenografts. We confirmed enhanced efficacy of dual Mcl-1/BCL-XL inhibition compared to single agents in a mouse PDX model. In conclusion, high-content screening of small compounds on Ewing sarcoma zebrafish xenografts identified dual Mcl-1/BCL-XL targeting as a specific vulnerability and promising therapeutic strategy for Ewing sarcoma, which warrants further investigation towards clinical application.

Keywords

Anti-apoptotic protein inhibitors; Ewing sarcoma; High-content imaging; Phenotypic drug screening; Zebrafish xenografts.

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