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
  • 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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