Hennessy Bryan T, Lu Yiling, Poradosu Enrique, Yu Qianghua, Yu Shuangxing, Hall Hassan, Carey Mark S, Ravoori Murali, Gonzalez-Angulo Ana Maria, Birch Robert, Henderson I Craig, Kundra Vikas, Mills Gordon B
Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Clin Cancer Res. 2007 Dec 15;13(24):7421-31. doi: 10.1158/1078-0432.CCR-07-0760.
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.
A novel functional proteomics technology, reverse phase protein array, was used to establish and quantify pharmacodynamic markers of perifosine efficacy.
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.
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.
开发体内定量靶向治疗药物早期药效学效应的方法至关重要，这有助于提高药物研发效率并确保给药具有生物学相关性。此外，能够识别可能对靶向治疗有反应的患者，将减小临床试验的规模、缩短其持续时间并降低成本，从而更有效地转化为改善患者预后。近期研究表明，哌立福新通过阻止细胞膜招募AKT普列克底物蛋白同源结构域来抑制磷脂酰肌醇-3'-激酶（PI3K）通路。
一种新型功能蛋白质组学技术——反相蛋白质阵列，被用于建立和定量哌立福新疗效的药效学标志物。
哌立福新选择性地阻止AKT募集到细胞膜并阻断下游效应器的激活。哌立福新抑制乳腺癌、卵巢癌和前列腺癌模型。生长抑制与细胞凋亡相关。基因组畸变导致的AKT激活可预测哌立福新疗效。在细胞系和异种移植模型中，不同剂量哌立福新的抗肿瘤疗效程度与AKT及其下游靶点（尤其是S6）磷酸化的定量下调之间存在高度统计学显著相关性。
由于PI3K通路生物标志物的比例调节与哌立福新疗效定量之间存在强相关性，使用反相蛋白质阵列早期测量此类药效学生物标志物可能会优化对有反应患者的选择并指导哌立福新给药。此外，PI3K通路激活状态可能有助于从基线选择最有可能对哌立福新单药治疗或与其他疗法联合治疗有反应的患者。
