Cell Signaling Model Connects Vorinostat Pharmacokinetics and Tumor Growth Response in Multiple Myeloma Xenografts.
Cell Signaling Model Connects Vorinostat Pharmacokinetics and Tumor Growth Response in Multiple Myeloma Xenografts.
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DOI：
10.1002/psp4.12246
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Mager DE
中科院分区：
文献类型：
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作者：
Nanavati C;Ruszaj D;Mager DE
多发性骨髓瘤是一种致命的血液系统恶性肿瘤，具有较高的耐药性和复发率。伏立诺他是一种组蛋白去乙酰化酶抑制剂，与目前的骨髓瘤疗法联合使用时，已显示出增强疗效的前景。在这项研究中，在暴露于伏立诺他的骨髓瘤细胞中测量了关键蛋白质和细胞增殖的时间变化。开发了将生物标志物动力学与细胞增殖联系起来的模型，该模型捕获了伏立诺他对信号转导和细胞活力的影响。固定模型结构和参数以描述体内肿瘤动力学，并估计肿瘤特异性生长和死亡率参数。信号传导模型在一系列剂量水平和方案下捕获鼠异种移植物中的肿瘤生长抑制。该模型可用作将伏立诺他暴露与分子事件和药效学（PD）结果联系起来的机制桥梁。它还可以提供一个翻译平台，以探索伏立诺他作为单一药物和联合方案的活性。
Multiple myeloma is a fatal hematological malignancy with high rates of drug resistance and relapse. Vorinostat, a histone deacetylase inhibitor, has shown promise in enhancing efficacy when combined with current myeloma therapies. In this study, temporal changes of critical proteins and cell proliferation were measured in myeloma cells exposed to vorinostat. A model linking biomarker dynamics to cell proliferation was developed that captured vorinostat effects on signal transduction and cell viability. The model structure and parameters were fixed to describe tumor dynamics in vivo, and tumor‐specific growth and death rate parameters were estimated. The signaling model captured tumor growth inhibition in murine xenografts for a range of dose levels and regimens. This model may be used as a mechanistic bridge to link vorinostat exposure to molecular events and pharmacodynamic (PD) outcomes. It may also provide a translational platform to explore vorinostat activity as a single agent and in combination regimens.