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
-
- Animals
- Apoptosis
- Cell Line, Tumor
- Drug Evaluation, Preclinical
- Heterografts
- Humans
- Mice
- Myeloid Cell Leukemia Sequence 1 Protein/genetics
- Myeloid Cell Leukemia Sequence 1 Protein/metabolism
- Sarcoma, Ewing*/drug therapy
- Sarcoma, Ewing*/genetics
- Sarcoma, Ewing*/metabolism
- Zebrafish/metabolism
- bcl-X Protein/genetics
- bcl-X Protein/metabolism
- PubMed
- 36462556 Full text @ Cancer Lett.
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping