The enhanced in vivo activity of the combination of a MEK and a PI3K inhibitor correlates with [18F]-FLT PET in human colorectal cancer xenograft tumour-bearing mice.
The enhanced in vivo activity of the combination of a MEK and a PI3K inhibitor correlates with [18F]-FLT PET in human colorectal cancer xenograft tumour-bearing mice.
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DOI：
10.1371/journal.pone.0081763
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Newell DR
中科院分区：
文献类型：
--
作者：
Haagensen EJ;Thomas HD;Wilson I;Harnor SJ;Payne SL;Rennison T;Smith KM;Maxwell RJ;Newell DR
联合靶向癌症中的MAPK和PI 3 K信号通路可能是最佳治疗活性所必需的。为了支持联合治疗的临床研究，在临床前模型中评价了通过正电子发射断层扫描（PET）测量的3′-脱氧-3 ′-[18 F]-氟胸苷（[18 F]-FLT）摄取作为非侵入性替代缓解生物标志物。在携带HCT 116和HT 29人结肠直肠癌异种移植物肿瘤的小鼠中评价了MEK抑制剂PD 0325901和PI 3 K抑制剂GDC-0941单独和组合的体内抗肿瘤功效和PK-PD特性，并在携带HCT 116异种移植物的小鼠中研究了[18 F]-FLT PET。PI 3 K和MEK的双重靶向在体内诱导显著的肿瘤生长抑制，并且在治疗2天后通过[18 F]-FLT PET扫描预测增强的抗肿瘤活性。使用PI 3 K抑制剂GDC-0941和MEK抑制剂PD 0325901的组合的药效学分析揭示，与用任一单一药剂观察到的相比，增加的功效与增强的ERK 1/2、S6和4 EBP 1的磷酸化抑制相关，并且维持对AKT磷酸化的抑制。药代动力学研究表明，两种药物之间没有明显的PK相互作用。这些结果共同表明，PI 3 K和MEK抑制剂的组合可以产生显著的功效，并且首次证明[18 F]-FLT PET可以与PI 3 K和MEK抑制剂组合治疗的改善的功效相关。
Combined targeting of the MAPK and PI3K signalling pathways in cancer may be necessary for optimal therapeutic activity. To support clinical studies of combination therapy, 3′-deoxy-3′-[18F]-fluorothymidine ([18F]-FLT) uptake measured by Positron Emission Tomography (PET) was evaluated as a non-invasive surrogate response biomarker in pre-clinical models. The in vivo anti-tumour efficacy and PK-PD properties of the MEK inhibitor PD 0325901 and the PI3K inhibitor GDC-0941, alone and in combination, were evaluated in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice, and [18F]-FLT PET investigated in mice bearing HCT116 xenografts. Dual targeting of PI3K and MEK induced marked tumour growth inhibition in vivo, and enhanced anti-tumour activity was predicted by [18F]-FLT PET scanning after 2 days of treatment. Pharmacodynamic analyses using the combination of the PI3K inhibitor GDC-0941 and the MEK inhibitor PD 0325901 revealed that increased efficacy is associated with an enhanced inhibition of the phosphorylation of ERK1/2, S6 and 4EBP1, compared to that observed with either single agent, and maintained inhibition of AKT phosphorylation. Pharmacokinetic studies indicated that there was no marked PK interaction between the two drugs. Together these results indicate that the combination of PI3K and MEK inhibitors can result in significant efficacy, and demonstrate for the first time that [18F]-FLT PET can be correlated to the improved efficacy of combined PI3K and MEK inhibitor treatment.
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影响因子：
9.3
作者：
Hoeben, Bianca A. W.;Troost, Esther G. C.;Kaanders, Johannes H. A. M.
通讯作者：
Kaanders, Johannes H. A. M.
影响因子：
4.2
作者：
Duong HQ;Kim HJ;Kang HJ;Seong YS;Bae I
通讯作者：
Bae I
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.2
作者：
Edgar, Kyle A.;Wallin, Jeffrey J.;Belvin, Marcia
通讯作者：
Belvin, Marcia
影响因子：
11.2
作者：
Hoeflich, Klaus P.;Merchant, Mark;Belvin, Marcia
通讯作者：
Belvin, Marcia