Bcl-xl选择性抑制剂脱靶问题对其在肺癌实体瘤疗效的影响及小分子NA-2a的干预机制研究

在与化疗药物联合用于肺癌实体瘤治疗中，Bcl-xl选择性抑制剂在耐受性和疗效方面均优于Bcl-2选择性抑制剂，展示出很好的应用前景，但仍没有获批上市，制约Bcl-xl选择性抑制剂临床应用的具体原因尚不清楚。我们的细胞实验显示，Bcl-xl选择性抑制剂因不能有效到达线粒体而失去对靶标的调控能力，具有线粒体靶向效应的小分子NA-2a能够干预其脱靶问题并提高其凋亡诱导能力，故假设Bcl-xl抑制剂的脱靶问题是影响其在实体瘤疗效的重要原因，NA-2a通过改善Bcl-xl抑制剂进入线粒体与靶标结合产生on-target效应，最终提高其抑癌活性。但是，脱靶问题的影响以及NA-2a在改善Bcl-xl抑制剂疗效的作用和潜在机理尚不明确。因此，本课题拟系统研究Bcl-xl抑制剂在肺癌实体瘤中的脱靶问题以及NA-2a的干预作用和潜在分子机制，为Bcl-xl选择性抑制剂在实体瘤中开展临床应用提供理论依据。

Bcl-xl-selective inhibitor is better than Bcl-2-selective inhibitor both in efficacy and toleration, when combined with chemotherapeutic agents for the treatment of lung cancer. The Bcl-xl–selective inhibitor exhibits potential clinical application, however, it is still not approved for marketing, and the mechanism responsible for restricting the clinical application of Bcl-xl-selective inhibitor is not clear. Our preliminary experiments in cultured cells suggest that Bcl-xl-selective inhibitor loses the ability to regulate the target due to the inability to reach mitochondria effectively; Na-2a, a small molecule with mitochondrial targeting effect, could intervene its off-target problem and improve its ability to induce apoptosis. Therefore we hypothesize that the off-target of Bcl-xl inhibitor is an important reason for its efficacy in solid tumor, Na-2a can increase the anti-cancer activity of Bcl-xl inhibitor by improving the entrance of Bcl-xl inhibitor to mitochondria to produce on-target effect. However, the effect of the off-target of Bcl-xl inhibitor for therapy and the potential mechanism of NA-2a in improving the efficacy of Bcl-xl inhibitor are still unclear. It is therefore important to study the off-target problem of Bcl-xl inhibitor in solid tumor of lung cancer and the intervention and potential molecular mechanism of NA-2a. After this project is completed, the effect of off-target of Bcl-xl selective inhibitor on its efficacy in solid tumor of lung cancer and the intervention mechanism of NA-2a will be supplied, which could provide a theoretical basis for the clinical application of Bcl-xl-selective inhibitors in solid tumors.