Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression
Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression
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DOI：
10.1158/0008-5472.can-08-2428
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发表时间：
2008-12-01
期刊：
影响因子：
11.2
通讯作者：
Kaufmann, Joerg
中科院分区：
文献类型：
--
作者：
Aleku, Manuela;Schulz, Petra;Kaufmann, Joerg
我们之前已经描述了一种用于小鼠血管中RNA干扰（RNAi）的小干扰RNA （siRNA）递送系统（AtuPLEX）。在这里，我们报告了Atu027的临床前数据，Atu027是一种针对蛋白激酶N3 （PKN3）的sirna脂质体，目前正在开发中，用于治疗晚期实体癌。体外研究表明，atu027介导的PKN3功能在原代内皮细胞中的抑制会损害细胞外基质上的管状形成和细胞迁移，但对增殖不是必需的。在小鼠、大鼠和非人灵长类动物中，通过反复给药或输注Atu027可导致rnai介导的PKN3表达特异性沉默。我们发现Atu027在前列腺癌和胰腺癌原位小鼠模型中具有显著抑制肿瘤生长和淋巴结转移形成的功效。atu027治疗动物的肿瘤血管显示淋巴血管密度特异性降低，但微血管密度无显著变化。[癌症研究2008；68 (23): 9788 - 98)
We have previously described a small interfering RNA (siRNA) delivery system (AtuPLEX) for RNA interference (RNAi) in the vasculature of mice. Here we report preclinical data for Atu027, a siRNA-lipoplex directed against protein kinase N3 (PKN3), currently under development for the treatment of advanced solid cancer. In vitro studies revealed that Atu027-mediated inhibition of PKN3 function in primary endothelial cells impaired tube formation on extracellular matrix and cell migration, but is not essential for proliferation. Systemic administration of Atu027 by repeated bolus injections or infusions in mice, rats, and nonhuman primates results in specific, RNAi-mediated silencing of PKN3 expression. We show the efficacy of Atu027 in orthotopic mouse models for prostate and pancreatic cancers with significant inhibition of tumor growth and lymph node metastasis formation. The tumor vasculature of Atu027-treated animals showed a specific reduction in lymph vessel density but no significant changes in microvascular density. [Cancer Res 2008;68(23):9788-98]