Multimodal Microvascular Imaging Reveals that Selective Inhibition of Class I PI3K Is Sufficient to Induce an Antivascular Response
Multimodal Microvascular Imaging Reveals that Selective Inhibition of Class I PI3K Is Sufficient to Induce an Antivascular Response
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DOI：
10.1593/neo.13470
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发表时间：
2013-07-01
期刊：
影响因子：
4.8
通讯作者：
Carano, Richard A. D.
中科院分区：
文献类型：
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作者：
Sampath, Deepak;Oeh, Jason;Carano, Richard A. D.
磷脂酰肌醇3-激酶（PI 3 K）通路是血管内皮生长因子（VEGF）驱动的血管生成的中心介质。选择性靶向PI 3 K或PI 3 K和哺乳动物雷帕霉素靶标（mTOR）的小分子抑制剂的发现提供了一个机会，以确定这些关键信号传导节点在VEGF-A驱动的体内肿瘤血管生成中的贡献。本研究使用一系列微血管成像技术监测选择性I类PI 3 K、mTOR或双重PI 3 K/mTOR抑制剂在结直肠癌和前列腺癌异种移植模型中的抗血管作用。采用微计算机断层扫描（micro-CT）血管造影、动态对比增强磁共振成像（DCE-MRI）、血管尺寸指数（VSI）MRI和DCE超声（DCE-U/S）定量评价血管（结构和生理）对这些抑制剂的反应。发现GDC-0980（一种双重PI 3 K/mTOR抑制剂）可降低微CT血管造影血管密度，而VSI MRI显示血管密度显著降低，平均血管尺寸增加，与小功能血管丢失和显著抗血管反应一致。DCE-MRI显示，GDC-0980通过降低血管通透性/灌注相关参数K-trans. Interestingly，观察到GDC-980和GNE-490（选择性I类PI 3 K抑制剂）具有相当的抗血管作用。此外，mTOR选择性抑制剂不影响血管密度，表明PI 3 K抑制足以产生结构变化，这是稳健抗血管反应的特征。本研究支持使用无创微血管成像技术（DCE-MRI、VSI MRI、DCE-U/S）作为药效学试验，以定量测量体内PI 3 K和双重PI 3 K/mTOR抑制剂的活性。
The phosphatidylinositol 3-kinase (PI3K) pathway is a central mediator of vascular endothelial growth factor (VEGF)-driven angiogenesis. The discovery of small molecule inhibitors that selectively target PI3K or PI3K and mammalian target of rapamycin (mTOR) provides an opportunity to pharmacologically determine the contribution of these key signaling nodes in VEGF-A-driven tumor angiogenesis in vivo. This study used an array of microvascular imaging techniques to monitor the antivascular effects of selective class I PI3K, mTOR, or dual PI3K/mTOR inhibitors in colorectal and prostate cancer xenograft models. Micro-computed tomography (micro-CT) angiography, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), vessel size index (VSI) MRI, and DCE ultrasound (DCE-U/S) were employed to quantitatively evaluate the vascular (structural and physiological) response to these inhibitors. GDC-0980, a dual PI3K/mTOR inhibitor, was found to reduce micro-CT angiography vascular density, while VSI MRI demonstrated a significant reduction in vessel density and an increase in mean vessel size, consistent with a loss of small functional vessels and a substantial antivascular response. DCE-MRI showed that GDC-0980 produces a strong functional response by decreasing the vascular permeability/perfusion-related parameter, K-trans. Interestingly, comparable antivascular effects were observed for both GDC-980 and GNE-490 (a selective class I PI3K inhibitor). In addition, mTOR-selective inhibitors did not affect vascular density, suggesting that PI3K inhibition is sufficient to generate structural changes, characteristic of a robust antivascular response. This study supports the use of noninvasive microvascular imaging techniques (DCE-MRI, VSI MRI, DCE-U/S) as pharmacodynamic assays to quantitatively measure the activity of PI3K and dual PI3K/mTOR inhibitors in vivo.