A clinical protocol to inhibit the HGF/c-Met pathway for malignant mesothelioma with an intrapleural injection of adenoviruses expressing the NK4 gene.
A clinical protocol to inhibit the HGF/c-Met pathway for malignant mesothelioma with an intrapleural injection of adenoviruses expressing the NK4 gene.
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DOI：
10.1186/s40064-015-1123-3
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Tagawa M
中科院分区：
文献类型：
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作者：
Tada Y;Hiroshima K;Shimada H;Morishita N;Shirakawa T;Matsumoto K;Shingyoji M;Sekine I;Tatsumi K;Tagawa M
肝细胞生长因子(HGF)/c-Met信号通路在人间皮瘤中上调，在临床前研究中，与HGF结构同源的竞争性抑制剂NK4抑制HGF/c-Met信号通路，对间皮瘤产生抗肿瘤作用。间皮瘤对许多化疗药物具有高度耐药性，但远端转移到胸外器官相对罕见，直到晚期才发生。我们计划利用表达NK4基因的腺病毒（Ad-NK4）进行基因治疗以控制局部肿瘤生长的临床研究。该研究旨在将Ad-NK4以剂量递增的方式注入胸膜腔内，从每位患者1010到1012个病毒颗粒，并检查安全性和可能的临床益处。该临床研究是首次使用NK4基因并通过基因药物阻断HGF/c-Met通路的人体试验。作为临床前研究之一，我们进行了动物体内实验来检验安全性水平，结果表明，在胸膜腔中给药的Ad DNA在许多实质器官中都被检测到。生化和病理分析表明，肝损害是主要的不良反应，对其他器官的毒性很小。这些研究首次在动物实验中证实了Ad载体胸膜内注射后的生物分布和转基因表达，与静脉注射相比，Ad- nk4的清除速度相对较快。临床研究还可以通过检测间皮瘤细胞中c-Met的去磷酸化，提供有关NK4蛋白和抗NK4抗体的产生以及HGF/c-Met通路抑制水平的信息。这些数据对于判断局部生产NK4分子是否可以作为一种抗癌策略至关重要。试验注册：日本UMIN临床试验注册中心。注册ID: UMIN15771
The hepatocyte growth factor (HGF)/c-Met signal pathway is up-regulated in human mesothelioma and suppression of the HGF/c-Met signaling with a competitive inhibitor, NK4 homologous to HGF in the structure, produced anti-tumor effects to mesothelioma in a preclinical study. Mesothelioma is highly resistant to a number of chemotherapeutic agents but distant metastasis to extra-thoracic organs is relatively infrequent until the late stage. We planned to conduct a clinical study of gene therapy with adenoviruses expressing the NK4 gene (Ad-NK4) to control the local tumor growth. The study is designed to inject Ad-NK4 into the intrapleural cavity with a dose escalation manner from 1010 to 1012 virus particles per patient and to examine safety and possible clinical benefits. The clinical investigation is a first-in-human trial to use the NK4 gene and to block the HGF/c-Met pathway with gene medicine. We conducted in vivo animal experiments to examine the safety level as one of the preclinical studies, and showed that Ad DNA administered in the pleural cavity was detected in many parenchymal organs. Biochemical and pathological analyses showed that liver damages were the major adverse effects with little toxicity to other organs. These studies firstly demonstrated biodistribution and transgene expression after an intrapleural injection of Ad vectors in an animal study, which contrasts with an intravenous injection showing relatively rapid clearance of Ad-NK4. The clinical study can also provide information regarding production of NK4 protein and antibody against NK4, and inhibition levels of the HGF/c-Met pathway by detecting dephosphorylation of c-Met in mesothelioma cells. These data will be crucial to judge whether local production of NK4 molecules can be an anti-cancer strategy. Trial registration: UMIN clinical trials registry, Japan. Register ID: UMIN15771