应用多模态影像技术监控由药靶活性改变和代谢重编程介导的肿瘤对c-Met靶向治疗耐药的研究

Targeted therapy provides the foundation of precision medicine, but the responsive rate and drug efficacy are very limited mainly because of the resistance to targeted therapy in cancer patients. Our preliminary data indicated that the key molecular events during the progression of resistance to c-Met (a tyrosine kinase) targeted therapy are loss of the kinase activity of c-Met and the reprogramming of metabolism from glucose to glutamine in tumors. We propose to 1) develop a novel fluorescent “off-on” probe responsive to c-Met kinase activity; 2) utilize the 18F-FDG for glucose metabolism and 18F-FGln for glutamine metabolism. Using the multiple imaging modalities, including fluorescence, positron emission tomography (PET) and computed tomography (CT) imaging, the progression of drug resistance to c-Met target therapy will be visualized in the cell and living animal models of gastric cancer and lung cancer, respectively. The correlations among quantitative imaging information, sequential drug resistance to c-Met inhibitors, and progression of key molecular events promoting drug resistance will be established, in order to guide the prospective adjustment of targeted therapy regimen of cancer patients. The imaging modalities using in this proposal have been widely in clinical practices, as well as the proposed visualization system for resistance to c-Met targeted therapy is easily to be adjusted for other tyrosine kinase inhibitors, which are with great translational potentials and make a significant contribution to the National Key Research Program of China.

肿瘤靶向治疗为精准医疗带来新契机，但其响应率和有效率十分有限，与肿瘤对靶向治疗耐药紧密相关。我们的初步数据显示肿瘤对酪氨酸蛋白激酶c-Met靶向治疗耐药的关键事件是药靶活性降低和从葡萄糖过渡到谷氨酰胺代谢的重编程。我们计划：1）开发全新的c-Met激酶活性调控的荧光关开型探针；2）利用针对葡萄糖代谢的18F-FDG和谷氨酰胺代谢的18F-FGln探针，在胃癌、肺癌等对c-Met靶向治疗耐药的肿瘤细胞和小鼠模型中，开展荧光和正电子发射扫描/计算机断层扫描（PET/CT）成像，对耐药演进过程进行可视化监控，以期建立影像信号-肿瘤耐药现象-关键机制事件之间的准确关联，前瞻性地决定序贯治疗方案，从而延缓或规避耐药。本申请采用的成像技术已在临床广泛应用，易于实现成果向临床诊疗转化；而且该方法学的建立，可推广至更多的激酶抑制剂靶向治疗耐药研究中，为实现重大研究计划的总体目标做出贡献。

肿瘤靶向治疗为精准医疗带来新契机，但其响应率和有效率十分有限，与肿瘤对靶向治疗耐药紧密相关。为此，本项目以c-Met为主要研究对象，寻找肿瘤在酪氨酸蛋白激酶靶向治疗耐药演进过程中关键分子与生物学过程，并进行可视化评估：拟构建对c-Met靶向治疗耐药的肿瘤模型，并明确药物靶标c-Met激酶活性降低和肿瘤代谢的转变为c-Met靶向治疗耐药的关键分子事件；拟开发c-Met激酶活性特异性调控的关开型荧光探针，实现用荧光成像可视化评估药物靶标c-Met激酶活性；拟基于18F-FDG和18F-FGln探针，实现用PET成像可视化评估肿瘤中葡萄糖代谢与谷氨酰胺代谢；计划在对c-Met靶向治疗耐药的肿瘤模型中，建立影像信号-肿瘤耐药关键分子机制事件之间的准确关联。.本项目已完成：1、获得了由c-Met激酶活性特异性调控的关开型荧光探针，并在对c-Met治疗靶向治疗天然敏感、原发耐药及获得性耐药的肿瘤细胞中证明了该探针荧光信号关开效应与药物靶点c-Met活性的相关性。2、建立了基于18F-FDG和18F-FGln探针的PET成像技术，对神经母细胞肿瘤的葡萄糖代谢与谷氨酰胺代谢水平进行了可视化评估。3、发现了c-Met治疗靶向治疗获得性耐药的肿瘤细胞中发生了代谢重编程，在对异种移植瘤荷瘤小鼠进行c-Met抑制剂治疗过程中，证明18F-FDG PET/CT成像能够动态监测其疗效。4、发现了与膀胱肿瘤进程至不良预后相关的糖代谢关键标志物ST3GAL6和脂代谢关键分子ox-LDL。.总之，我们已按照研究计划顺利完成各项研究目标，相关的研究成果已发表SCI论文11篇（包括Cancer Research、Theranostics等期刊），获得计算机软件著作权1项。新开发的c-Met活性调控的关开型荧光探针为肿瘤病人的精准分子分型提供了新工具；基于最广泛应用的18F-FDG PET/CT成像对c-Met靶向治疗耐药演进过程中药物靶点活性变化的可视化监控，极易转化至临床实践中。