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预测瘤学药物诱导心脏毒性与捐赠者特定的iPSC-CMs-a用多克索鲁比的概念验证研究
Li Pang1, Chengzhong Cai1, Praful Aggarwal2
1Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079, USA.
概括
捐赠者特定的人类诱导的多能干细胞衍生心肌细胞 (iPSC-CMs) 可以预测多克索鲁比诱导心脏毒性 (DIC) 的个体风险. 这种方法有助于个性化癌症治疗,通过识别容易受到化疗心脏损伤的患者.
科学领域:
- 心脏病学 心脏病学
- 基因组学就是基因组学.
- 药物开发 药物开发
背景情况:
- 瘤学药物可能会引起心脏毒性,限制癌症治疗的疗效.
- 心脏毒性的个体间变异性需要个性化风险评估.
- 人类诱导的多能干细胞衍生心肌细胞 (iPSC-CMs) 提供了一个研究患者特异性药物反应的平台.
研究的目的:
- 为了评估药物诱导心脏毒性的iPSC-CM测定中的可变性.
- 建立一个概念验证,用于预测使用捐赠者特定的iPSC-CMs的多克索鲁比诱导心脏毒性 (DIC).
- 为了确定DIC风险的潜在生物标志物.
主要方法:
- 在iPSC-CM阻抗细胞毒性和转录组测试中评估了个体间和个体内变异性.
- 根据表型反应将iPSC-CM分类为耐DOX和敏感DOX的线条.
- 利用特定于捐赠者的iPSC-CM来建模和预测DIC.
- 在耐药性和敏感性iPSC-CMs之间确定了差异表达的基因,包括DND1.
主要成果:
- 捐赠者特定的iPSC-CMs显示出更大的线对线变化,而不是个体内变化.
- 对DOX的iPSC-CM反应模仿了临床心脏毒性模式和机制.
- 供体特异性iPSC-CMs对DOX的敏感性与体内DIC风险相关.
- DND微RNA介导抑制抑制剂1 (DND1) 被确定为一个差异表达的基因.
结论:
- 捐赠者特定的iPSC-CMs对于评估DIC的个人间差异是有价值的.
- 这个模型对未来的DIC风险预测有希望.
- 用更大的iPSC-CM面板进行进一步的研究可能会发现用于预测各种瘤药物心脏毒性的新生物标志物.
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