期刊
CANCER LETTERS
卷 554, 期 -, 页码 -出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2022.216028
关键词
Ewing sarcoma; Zebrafish xenografts; Phenotypic drug screening; Anti-apoptotic protein inhibitors; High -content imaging
类别
High-throughput drug screening using zebrafish xenografts identified dual inhibition of anti-apoptotic proteins MCL-1 and BCL-XL as an effective strategy against Ewing sarcoma cells. The combination treatment showed enhanced efficacy compared to single agents in both zebrafish and mouse models, suggesting a promising therapeutic approach for Ewing sarcoma.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据