Pharmacodynamic markers of perifosine efficacy
Pharmacodynamic markers of perifosine efficacy
复制标题
DOI：
10.1158/1078-0432.ccr-07-0760
复制
发表时间：
2007-12-15
影响因子：
11.5
通讯作者：
Mills, Gordon B.
中科院分区：
文献类型：
--
作者：
Hennessy, Bryan T.;Lu, Yiling;Mills, Gordon B.
目的：开发方法来量化靶向治疗剂在体内的早期药物动力学作用以提高药物开发并确保生物学上相关的给药是至关重要的。此外，鉴定可能对靶向治疗剂反应的患者的能力会降低临床试验的大小，持续时间和成本，从而更有效地翻译成改进的患者结果。最近的研究表明，periforine抑制磷脂酰肌醇-3'-激酶（PI3K）途径，通过预防Akt pleckstrin同源性域的细胞膜募集，实验性设计：一种新型的功能性蛋白质组学技术，可用于建立和量化药物量的药物： perifosine疗效的标志物：perifosine选择性防止Akt募集到膜上并阻止下游效应子的激活。 perifosine抑制乳房，卵巢癌和前列腺癌模型。生长抑制与凋亡有关。基因组畸变由于基因组畸变的激活预测了perifosine的功效。在细胞系和异种移植物中，不同perifosine剂量的抗肿瘤功效程度与Akt磷酸化的磷酸化及其下游靶标的抗肿瘤功效程度之间存在高度统计学上的显着相关性，尤其是S6.Conclocions。调节PI3K途径生物标志物和量化perifosine疗效，可能会尽早测量具有反相蛋白阵列的这种药效动力学生物标志物，会优化反应的患者的选择并引导粘膜剂量。此外，PI3K途径激活状态可能允许最有可能单独或与其他疗法结合使用perifosine反应的患者基线选择。
Purpose: It is critical to develop methods to quantify the early pharmacodynamic effects of targeted therapeutics in vivo to make drug development more efficient and ensure biologically relevant dosing. Furthermore, an ability to identify patients likely to respond to targeted therapeutics would decrease the size, duration, and cost of clinical trials, resulting in more efficient translation to improved patient outcomes. Recent studies suggest that perifosine inhibits the phosphatidylinositol-3'-kinase (PI3K) pathway by preventing cell membrane recruitment of the AKT pleckstrin homology domain.Experimental Design: A novel functional proteomics technology, reverse phase protein array, was used to establish and quantify pharmacodynamic markers of perifosine efficacy.Results: Perifosine selectively prevents AKT recruitment to the membrane and blocks activation of downstream effectors. Perifosine inhibited breast, ovarian, and prostate cancer models. Growth inhibition was associated with apoptosis. Activation of AKT as a consequence of genomic aberrations predicted perifosine efficacy. In cell lines and xenografts, there was a highly statistically significant correlation between the degree of antitumor efficacy of different perifosine doses and quantified down-regulation of phosphorylation of AKT and of its downstream targets, particularly S6.Conclusions: Because of a strong correlation between proportional modulation of PI3K pathway biomarkers and quantified perifosine efficacy, it is likely that early measurement of such pharmacodynamic biomarkers with reverse phase protein array will optimize selection of responding patients and guide perifosine dosing. Furthermore, PI3K pathway activation status may allow baseline selection of patients most likely to respond to perifosine alone or in combination with other therapies.