新型小分子化合物Ibr-7调控TRIM32增敏吉西他滨抗胰腺癌的作用及机制研究

胰腺癌是死亡率最高的恶性肿瘤之一。吉西他滨是目前胰腺癌治疗的一线药物，但其临床有效率不到20%。因此，寻找可提升吉西他滨药效的治疗策略迫在眉睫。我们在前期工作中发现全新结构的依鲁替尼衍生物Ibr-7的抗胰腺癌活性明显强于依鲁替尼，且具有增敏吉西他滨的效果。该协同作用可能与Ibr-7抑制mTOR-S6K通路、显著下调E3泛素连接酶TRIM32的表达有关，但具体的分子过程有待阐明。基于此，本项目将首先明确Ibr-7单用及联合吉西他滨的体内外抗胰腺癌活性，确证TRIM32在胰腺癌恶性进展中扮演的角色，阐释mTOR-S6K通路与TRIM32之间的调控方式，进而深入探究TRIM32作为Ibr-7增敏吉西他滨抗胰腺癌的分子靶标。本项目研究结果不仅为解决胰腺癌缺乏靶向药物的问题提供研究思路，同时也将丰富TRIM32在胰腺癌中的调控网络，为临床新药开发和联合用药方案设计提供新的治疗靶点和科学依据。

Pancreatic cancer is one of the most malignant cancers worldwide. Although treatment strategies have been improved for the last decades, gemcitabine remains as the first-line therapeutic medicine in clinical applications. Unfortunately, the clinical response rate of gemcitabine is far from satisfactory. Therefore, novel targeted drugs that specifically inhibit pancreatic cancer are urgently needed. In our previous work, we identified a novel kinase inhibitor Ibr-7, which have shown potent inhibitory effect in pancreatic cancer cells by suppressing mTOR-S6K pathway. Moreover, Ibr-7 was found to reverse the up-regulation of TRIM32 caused by the treatment of gemcitabine in pancreatic cancer cells, and thereby exerting a synergistic effect when used in combination with gemcitabine both in vitro and in vivo. In this project, we aim to corroborate the combinatorial benefits of Ibr-7 and gemcitabine; then explore the role of TRIM32 in the progression and resistance features of pancreatic cancer; finally illustrate the regulatory relationship between mTOR-S6K pathway and TRIM32. Our result will not only provide novel therapeutic regimes in treating pancreatic cancer, but also shed light on the exploration of potential therapeutic targets in combinatorial treatments for pancreatic cancer chemotherapy.