Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.
Cancer Res. 2024 Mar 15;84(6):872-886. doi: 10.1158/0008-5472.CAN-22-3784.
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.
成神经管细胞瘤是儿童中最常见的恶性脑肿瘤之一，其中 30%由 Sonic Hedgehog（SHH）信号通路的功能获得性遗传病变驱动。EYA1 是一种卤酸脱卤酶磷酸酶和转录因子，对于 SHH 成神经管细胞瘤（SHH-MB）的肿瘤发生和增殖至关重要。本扎隆和苯溴马隆已被确定为 EYA 蛋白的别构抑制剂。我们以本扎隆为起点，开发了一组 35 种衍生物，并在 SHH-MB 中进行了测试。在这些化合物中，DS-1-38 作为 EYA 拮抗剂发挥作用，拮抗 SHH 信号。DS-1-38 在体外和体内抑制 SHH-MB 的生长，具有出色的脑穿透性，并延长了易患致命 SHH-MB 的基因工程小鼠的寿命。这些数据表明，EYA 抑制剂代表了治疗小儿 SHH-MB 的有前途的疗法。
开发出一种抑制 EYA1 并阻碍 SHH 成神经管细胞瘤生长的本扎隆衍生物，为改善这种恶性小儿脑癌的治疗提供了一种途径。
