PUBLICATION

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

Authors
Grissenberger, S., Sturtzel, C., Wenninger-Weinzierl, A., Radic-Sarikas, B., Scheuringer, E., Bierbaumer, L., Etienne, V., Némati, F., Pascoal, S., Tötzl, M., Tomazou, E., Metzelder, M., Putz, E.M., Decaudin, D., Delattre, O., Surdez, D., Kovar, H., Halbritter, F., Distel, M.
ID
ZDB-PUB-221204-6
Date
2022
Source
Cancer letters   554: 216028 (Journal)
Registered Authors
Distel, Martin, Grissenberger, Sarah, Scheuringer, Eva, Sturtzel, Caterina, Wenninger-Weinzierl, Andrea
Keywords
Anti-apoptotic protein inhibitors, Ewing sarcoma, High-content imaging, Phenotypic drug screening, Zebrafish xenografts
MeSH Terms
  • Apoptosis
  • bcl-X Protein/genetics
  • bcl-X Protein/metabolism
  • Cell Line, Tumor
  • Myeloid Cell Leukemia Sequence 1 Protein/genetics
  • Myeloid Cell Leukemia Sequence 1 Protein/metabolism
  • Sarcoma, Ewing*/drug therapy
  • Sarcoma, Ewing*/genetics
  • Sarcoma, Ewing*/metabolism
  • Animals
  • Drug Evaluation, Preclinical
  • Heterografts
  • Mice
  • Zebrafish/metabolism
  • Humans
(all 15)
PubMed
36462556 Full text @ Cancer Lett.
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.
Genes / Markers
Figures
Figure Gallery (7 images)
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Your Input Welcome
We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
Citation
Grissenberger, S., Sturtzel, C., Wenninger-Weinzierl, A., Radic-Sarikas, B., Scheuringer, E., Bierbaumer, L., Etienne, V., Némati, F., Pascoal, S., Tötzl, M., Tomazou, E., Metzelder, M., Putz, E.M., Decaudin, D., Delattre, O., Surdez, D., Kovar, H., Halbritter, F., Distel, M. (2022) High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma. Cancer letters. 554:216028.