靶向蛋白Neddylation修饰通路诱导非小细胞肺癌放射增敏及其机制研究

项目名称： 靶向蛋白Neddylation修饰通路诱导非小细胞肺癌放射增敏及其机制研究

项目编号： No.81472793

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 韦栋平

作者单位： 南京医科大学

项目金额： 72万元

中文摘要： 泛素-蛋白酶体系统已被证实是非小细胞肺癌的放射增敏靶标，其增敏机制与Cullin-RING E3 泛素连接酶（CRLs）底物积聚密切相关。基于CRLs活化高度依赖Neddylation修饰这一生物学特征，我们设想Neddylation修饰通路可以作为非小细胞肺癌放射增敏的直接靶标。本研究首先利用RNA干扰技术和药理学干预方法，从体外细胞水平评价靶向Neddylation修饰通路诱导非小细胞肺癌放射增敏的效果；然后利用RNA干扰文库筛选肺癌放射增敏相关的CRLs底物并阐明其在肺癌放射增敏中的作用，以揭示放射增敏的分子机制。为了模拟肿瘤在正常肿瘤微环境下对放射治疗的反应，我们拟用小鼠原发性肺腺癌作为临床前治疗模型，深度研究靶向Neddylation修饰通路诱导肺癌放射增敏的效果及机制。本项目的完成将为今后临床通过靶向Neddylation修饰通路提高非小细胞肺癌的放射治疗效果提供科学依据。

中文关键词： C05_气管；支气管；肺肿瘤；放射治疗；放射增敏；蛋白Neddylation通路；放射敏感性

英文摘要： Despite optimal radiation therapy (RT), chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer fail treatment. Proteasome inhibition has demonstrated radiosensitizing properties in non-small cell lung cancer model and in association with accumulation of cullin-RING E3 ligases (CRLs) substrate (e.g. IκBα) involved in DNA damage and repair. These suggest that CRLs may serve as a direct radiosensitizing target in this human cancer. Given that CRLs activation is exclusively dependent on cullin neddylation, we reasoned that inhibition of the neddylation pathway may improve radiotherapy in non-small lung cancer. To test this hypothesis, we will first determine the effect of the neddylation pathway inhibition by genetic (RNAi) and pharmacological (MLN4924, an investigational small molecule inhibitor of neddylation entering Phase I/II clinical trials) approaches on radiosensitization of non-small cell lung cancer using cell culture model.For better understanding of the mechenisms for radiosensitization by targeting the neddyhlation pathway, we use RNAi library to identify CRLs substrates and investigate their roles in regulating this biological phenotype. To predict human clinical efficacy of targeting the neddylation pathway by MLN4924, we will further adapt primary mouse lung cancer triggered by mutation in K-ras (K-rasG12D ) in combination with p53 null deletion. Tumor response of mice to radiation therapy will be assessed with micro-CT and FLT-PET and the mechanistic study is to be carried out in-dept. Collectively，we proposed thatthe neddylayion pathway may be a promising target for the improvement of local therapy in non-small cell lung cancer.

英文关键词： Lung cancer;Radiotherapy;radiosensitization;neddylation pathway;radiosensitivity