髓母细胞瘤
音猬因子
癌变
外显率
生物
癌症研究
体内
转录因子
癌症
遗传学
信号转导
表型
基因
作者
Grace H. Hwang,Maria F. Pazyra-Murphy,Hyuk-Soo Seo,Sirano Dhe‐Paganon,Sylwia A. Stopka,Marina DiPiazza,Nizhoni Sutter,Thomas W. Gero,Angela Volkert,Lincoln Ombelets,Georgia Dittemore,Matthew G. Rees,Melissa M. Ronan,Jennifer A. Roth,Nathalie Y.R. Agar,David A. Scott,Rosalind A. Segal
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-01-17
卷期号:84 (6): 872-886
标识
DOI:10.1158/0008-5472.can-22-3784
摘要
Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1-38 functioned as an EYA antagonist and opposed SHH signaling. DS-1-38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising therapies for pediatric SHH-MB.Development of a benzarone derivative that inhibits EYA1 and impedes the growth of SHH medulloblastoma provides an avenue for improving treatment of this malignant pediatric brain cancer.
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