塞尔帕卡提尼布与针对线粒体的抗氧化剂MitoQ的组合有效抑制RET突变甲状腺癌
Wenjing Chen1, Sophie Dream2, Pui-Yin Leung1
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
NPJ precision oncology
|February 20, 2024
概括
塞尔珀卡提尼布和MitoQ通过增加线粒体膜潜力 (Δψm) 来协同抑制RET突变的甲状腺癌细胞. 这种组合疗法对不能耐受标准selpercatinib剂量的患者有希望.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 线粒体生物学 线粒体生物学
背景情况:
- 在转移过程中REarranged (RET) 的构成性激活是甲状腺癌的关键驱动因素.
- RET信号影响线粒体功能,但机制尚未完全理解.
- 以前的研究表明,多酶抑制剂增加了RET突变的甲状腺细胞中的线粒体膜潜力 (Δψm).
研究的目的:
- 调查RET选择性抑制剂selpercatinib是否会增加 Δψm.
- 为了确定是否结合selpercatinib与线粒体向 ubiquinone (MitoQ) 诱导RET突变的甲状腺瘤细胞的致命反应.
- 评估selpercatinib和MitoQ组合在临床前模型和患者中的治疗潜力.
主要方法:
- 用selpercatinib和/或MitoQ治疗RET突变的甲状腺瘤细胞.
- 测量线粒体膜潜力 (Δψm).
- 使用RET向的遗传方法对细胞活力产生协同效应的评估.
- 在老鼠的CCDC6-RET融合细胞系异种移植中进行评估.
- 在两个患有RET突变甲状腺癌的患者中临床应用.
主要成果:
- 塞尔珀卡提尼布显著增加了RET突变的甲状腺瘤细胞中的Δψm.
- 塞尔珀卡提尼布和MitoQ的组合协同抑制了这些细胞.
- 组合疗法抑制了小鼠的异种移植瘤,并延长了生存时间.
- 两名患有RET突变甲状腺癌的患者通过降低剂量的selpercatinib和MitoQ显示瘤减少,其中一名患者的生活质量有所改善.
结论:
- 塞尔珀卡提尼布增强了线粒体功能,其与MitoQ的组合为RET突变的甲状腺癌提供了协同治疗策略.
- 这种组合对于不能容忍标准selpercatinib剂量的患者可能特别有益.
- 这些发现支持进一步调查selpercatinib和MitoQ作为RET驱动的甲状腺癌的新疗法.
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