目前普遍认为肝癌缺氧微环境所致的化疗失败是临床肝癌治疗面临的瓶颈问题，亟需寻找在缺氧微环境中有效的抗肝癌药物。我们前期发现国内自主研发的新型FAK抑制剂CT707（I期临床）在正常氧压和缺氧下均可发挥显著的抗肝癌作用，并显示更强的缺氧抗肿瘤活性，其机制不依赖于自身靶点FAK，可能与抑制IGF1R激酶活性和YAP通路相关。基于此，本课题将进一步研究CT707缺氧抗肝癌作用的特点，探索缺氧差异性激活的IGF1R在其中的作用，明确IGF1R是CT707发挥缺氧抗肝癌作用的关键靶点，阐明缺氧下IGF1R通过Trio-Rho GTPase级联调控YAP的分子机制。通过本课题的研究，不仅将拓展CT707的临床应用，还将以CT707为小分子探针发现IGF1R介导缺氧肝癌恶性进展的新信号通路，为以IGF1R为靶点设计和发现基于缺氧微环境调控的全新抗肿瘤药物提供理论依据。

Hypoxia-caused the failure of chemotherapy is the major problem in clinic hepatocellular carcinoma treatment. It is urgent to exploit the unique efficacy anticancer strategy targeting hypoxic microenvironment in hepatocellular carcinoma. Our study found that independent innovation of chinese novel FAK inhibitor CT707 (Phase I clinical trail) could obviously inhibit hepatocellular carcinoma cell growth both in normoxia and hypoxia, especially shown much higher anticancer activity in hypoxia. This effect of CT707 was not rely on its own target FAK, but may be related to block the kinase activity of IGF1R and YAP pathway. We wish to further clarify the characteristics of anticancer activity in hepatocellular carcinoma of CT707 under hypoxia, then explore how selectively activated IGF1R by hypoxia influences the activity of CT707, reveal the important role of IGF1R in this effect, in addition elucidate the molecular mechanism that IGF1R activated YAP pathway through stimulating Trio-Rho GTPase. Our study not only will expand the clinical application of CT707, but also figure out the new signaling pathway which involved in the hypoxia-envoked malignant progression of hepatocellular carcinoma, thus providing theoretical basis for the design and discovery of novel hypoxia-target drugs via inhibiting IGF1R.