NEDD9小分子抑制剂的筛选及机理研究

Metastasis, an important biological characteristics of malignant tumor, is the major cause for poor survival of lung cancer. When clinically diagnosed as lung cancer , most patients have associated with metastasis. The curative effect of surgery or adjuvant chemotherapy/ radiotherapy is limited, which seriously reduces life quality of the patients. Fortunately, gene therapy with the superiority of high specificity and safety brings new hope to the despairing patients, and it has been proved to be an effective treatment in clinic. Therefore, looking for more important genes contributed to lung cancer metastasis and screening the related inhibitors have been becoming an urgent problem of great significance nowadays. Our recent studies have demonstrated that high NEDD9 expression is clinically associated with malignancy progression and metastasis of human lung cancers, as well as NEDD9 plays a critical downstream mediator in lung cancer metastasis evoked by LKB1 loss, which hints that NEDD9 is pro-metastatic gene related to lung cancer metastasis and can be identified as a candidate target for gene therapy of lung cancer metastasis. Thus, this proposal intends to screen small molecular inhibitors targeting NEDD9. We are able to verify the efficacy of these candidate compounds and discuss the possible mechanism by combined lung cancer cell lines in vitro and mouse models in vivo. We hope our results could provide strong evidence of promising gene therapy for metastatic lung cancer treatment.

浸润转移是恶性肿瘤的重要生物学特征，也是影响肺癌患者疗效的主要因素。多数肺癌患者在确诊时已伴有转移，手术或辅助放化疗的疗效有限，患者生活质量严重降低。分子靶向治疗已被临床证实是一种有效手段，其在特异性和安全性方面的优势给肺癌患者带来了新希望。因此，寻找重要的肺癌转移分子并筛选其抑制剂是当下亟待解决的问题，具有重大的现实意义。我们的前期研究显示促肿瘤转移相关基因 NEDD9 的高表达与临床肺癌的恶性进展和转移呈显著正相关，NEDD9作为关键的下游分子介导了LKB1 缺失引起的肺癌转移，提示 NEDD9 是重要的促肺癌转移分子，可以作为治疗肺癌转移的候选靶点。基于此，本课题拟从小分子化合物库中筛选NEDD9的小分子抑制剂，并结合肺癌细胞株和动物模型对这些化合物进行药效验证及机制探讨, 以期为临床上肺癌患者的靶向治疗提供理论基础和新策略。

浸润转移是恶性肿瘤最重要的生物学特征之一，也是影响肺癌疗效的主要因素。NEDD9是一个重要的促肿瘤转移基因，且其敲除的纯合型小鼠并无明显的发育障碍，提示NEDD9抑制剂在临床应用上有较好的安全性。此外，高频突变的LKB1（30%）和EGFR（10-30%）存在“排它性”，这导致LKB1突变的肺癌患者不能收益于EGFR抑制剂。我们的前期研究显示NEDD9作为关键下游分子介导了LKB1 缺失引起的肺癌恶性进展，提示研发NEDD9小分子抑制剂有望在“EGFR抑制剂受益不佳的肺癌患者”研究领域获得新线索。基于此，我们构建了NEDD9小分子抑制剂的筛选系统，并在此基础上从上千种化合物中筛选到了三种候选抑制剂；同时我们已构建了四种体内动物模型，将用于这些候选抑制剂的体内疗效评估，此外，我们还将对其进行分子机理探讨。最终，我们期望能在进一步的转化医学研究中迈出一步，切实为肺癌患者的临床诊治提供理论基础和开拓新策略。