Merrimack Pharmaceuticals, 1 Kendall Square, Suite B7201, Cambridge, MA 02139, USA.
Toxicol Appl Pharmacol. 2012 Jul 1;262(1):1-10. doi: 10.1016/j.taap.2012.04.008. Epub 2012 Apr 21.
Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers. While documenting the enhanced therapeutic potential of HER2-targeted liposomal doxorubicin can be done with existing models, there has been no validated human cardiac cell-based assay system to rigorously assess the cardiotoxicity of anthracyclines. To understand if HER2-targeting of liposomal doxorubicin is possible with a favorable cardiac safety profile, we applied a human stem cell-derived cardiomyocyte platform to evaluate the doxorubicin exposure of human cardiac cells to HER2-targeted liposomal doxorubicin. To the best of our knowledge, this is the first known application of a stem cell-derived system for evaluating preclinical cardiotoxicity of an investigational agent. We demonstrate that HER2-targeted liposomal doxorubicin has little or no uptake into human cardiomyocytes, does not inhibit HER2-mediated signaling, results in little or no evidence of cardiomyocyte cell death or dysfunction, and retains the low penetration into heart tissue of liposomal doxorubicin. Taken together, this data ultimately led to the clinical decision to advance this drug to Phase I clinical testing, which is now ongoing as a single agent in HER2-expressing cancers.
蒽环类药物方案是早期乳腺癌治疗的基础，但由于心脏毒性，其应用受到限制。在设计和开发包含蒽环类药物和针对 HER2 介导的信号通路的药物（如曲妥珠单抗）的联合治疗方案时，心脏毒性是一个主要考虑因素。在这方面，开发了靶向 HER2 的脂质体多柔比星，通过降低蒽环类药物观察到的心脏毒性并增强目前可用于 HER2 过表达癌症的基于 HER2 的治疗方法的治疗潜力，从而提供临床获益。虽然可以使用现有的模型来证明靶向 HER2 的脂质体多柔比星的增强治疗潜力，但目前还没有经过验证的基于人类心脏细胞的测定系统来严格评估蒽环类药物的心脏毒性。为了了解靶向 HER2 的脂质体多柔比星是否可以具有良好的心脏安全性，我们应用人类干细胞衍生的心肌细胞平台来评估人类心脏细胞对靶向 HER2 的脂质体多柔比星的多柔比星暴露。据我们所知，这是首次应用基于干细胞的系统来评估研究药物的临床前心脏毒性。我们证明，靶向 HER2 的脂质体多柔比星很少或几乎没有进入人类心肌细胞，不会抑制 HER2 介导的信号，很少或没有证据表明心肌细胞死亡或功能障碍，并且保留了脂质体多柔比星进入心脏组织的低通透性。总之，这些数据最终导致了将该药物推进到 I 期临床试验的临床决策，目前正在 HER2 表达的癌症中作为单一药物进行 I 期临床试验。
