Personalised Healthcare and Biomarkers, AstraZeneca, Cheshire, SK10 4TG, UK.
Mol Imaging Biol. 2013 Aug;15(4):476-85. doi: 10.1007/s11307-013-0613-3.
The phosphatidyl inositol 3 kinase, AKT and mammalian target of rapamycin are frequently deregulated in human cancer and are among one of the most promising targets for cancer therapy. AZD5363 (AstraZeneca) is an AKT inhibitor in phase 1 clinical trials. Given its utility in assessing glucose metabolism, we investigated the role of 2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG) positron emission tomography (PET) as a biomarker to demonstrate target inhibition and its potential to predict and demonstrate the anti-tumour activity of AZD5363.
18F-FDG PETscans were performed in nude mice in a number of xenograft models (U87-MG glioblastoma, BT474C breast carcinoma and Calu-6 lung). Mice were fasted prior to imaging, and either static or dynamic 18F-FDG PET imaging was performed.
We have shown that 18F-FDG uptake in tumour xenografts was reduced by 39% reduction compared to vehicle after a single dose of AZD5363, demonstrating activation of the AKT pathway after only 4 h of dosing. Multiple doses of AZD5363 showed an anti-tumour volume effect and a reduction in 18F-FDG uptake (28% reduction compared to vehicle), highlighting the potential of 18F-FDG PET as an efficacy biomarker. Furthermore, the degree of inhibition of 18F-FDG uptake corresponded with the sensitivity of the tumour model to AZD5363. The use of dynamic 18F-FDG PET and a two-compartmental analysis identified the mechanism of this change to be due to a change in cellular uptake of 18F-FDG following administration of AZD5363.
We conclude that 18F-FDG PET is a promising pharmacodynamic biomarker of AKT pathway inhibition, with potential to predict and demonstrate anti-tumour activity. It is a biomarker that may stop ineffective drug schedules, helping to make early stop decisions and identify responding subsets of patients, resulting in improved clinical decision making both during drug development and patient management.
磷脂酰肌醇 3 激酶、AKT 和哺乳动物雷帕霉素靶蛋白在人类癌症中经常失调，是癌症治疗最有前途的靶点之一。AZD5363（阿斯利康）是正在进行临床试验的 AKT 抑制剂。鉴于其在评估葡萄糖代谢方面的应用，我们研究了 2-脱氧-2-[18F]氟-D-葡萄糖（18F-FDG）正电子发射断层扫描（PET）作为生物标志物的作用，以证明靶抑制作用及其预测和证明 AZD5363 的抗肿瘤活性的潜力。
在许多异种移植模型（U87-MG 神经胶质瘤、BT474C 乳腺癌和 Calu-6 肺癌）中，对裸鼠进行了 18F-FDG PET 扫描。在成像前对小鼠进行禁食，并进行静态或动态 18F-FDG PET 成像。
我们已经表明，与载体相比，AZD5363 单次给药后肿瘤异种移植中的 18F-FDG 摄取减少了 39%，表明仅在给药 4 小时后 AKT 途径就被激活。AZD5363 的多次给药显示出抗肿瘤体积效应，并减少 18F-FDG 摄取（与载体相比减少 28%），突出了 18F-FDG PET 作为疗效生物标志物的潜力。此外，18F-FDG 摄取抑制的程度与肿瘤模型对 AZD5363 的敏感性相对应。使用动态 18F-FDG PET 和双室分析确定，这种变化的机制是由于 AZD5363 给药后 18F-FDG 的细胞摄取发生变化。
我们得出结论，18F-FDG PET 是 AKT 途径抑制的有前途的药效学生物标志物，具有预测和证明抗肿瘤活性的潜力。它是一种生物标志物，可阻止无效的药物方案，有助于做出早期停止决策并识别有反应的患者亚组，从而在药物开发和患者管理过程中改善临床决策。
