Statins Synergize with Hedgehog Pathway Inhibitors for Treatment of Medulloblastoma.
Statins Synergize with Hedgehog Pathway Inhibitors for Treatment of Medulloblastoma.
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他汀类药物与 Hedgehog 通路抑制剂协同治疗髓母细胞瘤
DOI：
10.1158/1078-0432.ccr-17-2923
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发表时间：
2018-03-15
期刊：
影响因子：
--
通讯作者：
Yang ZJ
中科院分区：
文献类型：
--
作者：
Gordon RE;Zhang L;Peri S;Kuo YM;Du F;Egleston BL;Ng JMY;Andrews AJ;Astsaturov I;Curran T;Yang ZJ
目的：胆固醇生物合成的作用，刺猬途径的活动和刺猬途径髓母细胞瘤（Hh-MB）的进展进行了检查。他汀类药物，常用的降胆固醇剂，用于验证胆固醇生物合成作为Hh-MB的治疗靶点。实验设计：进行生物信息学分析，以评估胆固醇生物合成与刺猬组髓母细胞瘤在人类生物标本之间的关联。在成神经管细胞瘤细胞中评价胆固醇生物合成抑制后hedgehog信号的改变。在肿瘤细胞中胆固醇生物合成的遗传阻断后，检查了小鼠内源性髓母细胞瘤的进展。他汀类药物单独或与维莫德吉（FDA批准的Smoothened拮抗剂）联合用于抑制体内髓母细胞瘤生长。结果：人和小鼠的Hh-MB均能显著促进胆固醇的生物合成。胆固醇生物合成的抑制显着降低Hh通路的活性和髓母细胞瘤细胞的增殖减少。他汀类药物在体内有效抑制髓母细胞瘤生长，并与维莫德吉联合发挥协同作用。结论：胆固醇的生物合成是hedgehog途径中Smoothened活性所必需的，并且它是Hh-MB生长所必需的。靶向胆固醇生物合成代表了治疗Hh-MB的有前景的策略。临床癌症研究; 24（6）; 1375-88。©2018 AACR.
Purpose: The role of cholesterol biosynthesis in hedgehog pathway activity and progression of hedgehog pathway medulloblastoma (Hh-MB) were examined in vivo. Statins, commonly used cholesterol-lowering agents, were utilized to validate cholesterol biosynthesis as a therapeutic target for Hh-MB. Experimental Design: Bioinformatic analysis was performed to evaluate the association between cholesterol biosynthesis with hedgehog group medulloblastoma in human biospecimens. Alterations in hedgehog signaling were evaluated in medulloblastoma cells after inhibition of cholesterol biosynthesis. The progression of endogenous medulloblastoma in mice was examined after genetic blockage of cholesterol biosynthesis in tumor cells. Statins alone, or in combination with vismodegib (an FDA-approved Smoothened antagonist), were utilized to inhibit medulloblastoma growth in vivo. Results: Cholesterol biosynthesis was markedly enhanced in Hh-MB from both humans and mice. Inhibition of cholesterol biosynthesis dramatically decreased Hh pathway activity and reduced proliferation of medulloblastoma cells. Statins effectively inhibited medulloblastoma growth in vivo and functioned synergistically in combination with vismodegib. Conclusions: Cholesterol biosynthesis is required for Smoothened activity in the hedgehog pathway, and it is indispensable for the growth of Hh-MB. Targeting cholesterol biosynthesis represents a promising strategy for treatment of Hh-MB. Clin Cancer Res; 24(6); 1375–88. ©2018 AACR.