胰腺癌是最具侵袭性的消化道恶性肿瘤，阐明胰腺癌转移的分子机理并探索有效治疗靶点对于改善胰腺癌患者的预后具有重要意义。研究表明，NF-κB信号通路在乳腺癌、黑色素瘤等恶性肿瘤的侵袭转移过程中发挥了重要作用。TBK1可以激活NF-kB，然而TBK1-NF-kB信号通路在胰腺癌中的作用目前并不清楚。本课题组研究结果显示，TBK1在胰腺癌中的表达水平显著高于正常胰腺及癌前病变组织，Amlexanox可显著抑制胰腺癌细胞系的迁移。由此我们提出假设，Amlexanox可通过调节TBK1-NF-kB信号通路来抑制胰腺癌的恶性转化。本项目拟通过体外实验阐明TBK1-NF-kB信号通路与胰腺癌细胞恶性生物学行为的相关性；并通过裸鼠胰腺癌PDX移植瘤模型研究Amlexanox对胰腺癌的抑制作用。预期研究成果将为针对TBK1-NF-κB信号通路的新药研发以及Amlexanox在胰腺癌治疗中的应用奠定理论基础。

Pancreatic cancer is the most aggressive malignancies among digestive system neoplasms. Elucidating molecular mechanisms and identifying effective therapeutic target is of crucial importance for the prognoses of patients with pancreatic cancer. Activation of NF-κB signaling pathway is involved in metastases and chemotherapeutic resistance in breast cancer and melanoma. TBK1 is a potential activator of NF-κB, however, the correlation between pancreatic cancer and TBK1-NF-κB pathway is still not yet been well clarified. Here we show that, TBK1 is over expressed in pancreatic cancer compared with normal or adenoma controls. Moreover, Amlexanox, a drug for oral ulceration, could repress the migration of pancreatic cancer cell lines. Therefore, we hypothesize that Amlexanox could inhibit pancreatic cancer progression by targeting TBK1-NF-κB signaling pathway. In this study, we will demonstrate the correlation between pancreatic cancer progression and TBK1-NF-κB pathway activation through in vitro molecular experiments. We will also testify the efficacy of Amlexanox on pancreatic cancer in vivo by utilizing Patient-derived xenograft models. This study will provide theoretical and experimental evidence for the development of novel drugs against TBK1 and also the application of Amlexanox towards the effective management of patient with pancreatic cancer.