高分辨分子成像在肿瘤代谢重编程机制及精准靶点定位的基础研究

Precisely evaluating biological molecular and metabolic characteristics has become the important opportunities in personalized and big data medicine in cancer. Warburg effect is one of most valuable targets in precision medicine of cancer. 18F-FDG PET molecular imaging technology based on Warburg effect is the effective method can be used in precision medicine of cancer. On the basis of work about 18F-FDG PET/CT quantitative analysis and metabolic flux assay, we are going to set up the high resolution molecular imaging platform via combined 18F-FDG PET/CT with DNP MRS, which would be a feasible technical scheme for precision medicine of cancer. On the basis of work about Sirtuin family, PKM2, LDHA and others studies, we hypothesizes that PKM2/LDHA-SIRTs regulatory loop would be a pivotal mechanism in Warburg effect and tumorigenesis, which might provide key rationale for precision medicine of cancer. Through these studies, we would elaborate the underlying mechanisms of Warburg effect and set up a high resolution molecular imaging platform, which would provide key rationale for translational and clinical application of Warburg effect.

精准评价生物分子与代谢特征已成为肿瘤个体化诊疗和大数据医疗的重要机遇，而Warburg效应是肿瘤精准医疗最有价值的靶标之一，以18F-FDG PET为基础的分子影像技术则是切实有效的研究路径。课题组在18F-FDG PET/CT定量分析和细胞代谢流量分析技术的基础上，拟建立18F-FDG PET/CT联合应用动态核极化（DNP）MRS的高分辨多模态分子影像定量分析技术平台并评价其准确性，以期为肿瘤精准医疗提供客观可行的技术方案。课题组在Sirtuin家族、PKM2和LDHA等理论研究的基础上，提出PKM2/LDHA-SIRTs交互调节Warburg效应促进肿瘤发生发展的研究假说及潜在的干预靶点，以期为肿瘤精准医疗提供关键的理论依据。通过上述研究，阐述Warburg效应关键调控机制及建立高分辨多模态分子影像定量分析技术平台，为精准靶向肿瘤Warburg效应的临床转化奠定科学依据。

精准评价生物分子与代谢特征已成为肿瘤个体化诊疗和大数据医疗的发展方向。以Warburg 效应为基础的18F-FDG PET/CT 分子影像技术，结合代谢影像、代谢酶和基因的表达显像，成为了高分辨影像精准靶向定位诊疗的有效手段。课题组在本项目的资助下，建立了18F-FDG PET/CT、SPECT/CT、光声成像与离体细胞代谢动态流量监测等相融合的多模态高分辨分子影像技术，通过该技术开发了一系列肿瘤特异性蛋白（如MET、TIGAR、PFKFB3等）和非编码RNA（如LINC01123、circ_0001944等）靶点，揭示了SIRT1、SIRT5、SIRT6等Sirtuin去乙酰化酶家族成员在肿瘤发生发展中对代谢酶PKM2、LDHB等翻译后调控和分子机制。同时利用该多模态分子影像技术，开发了免疫PET技术和多个代谢示踪探针，在临床实践中利用PET/CT精准分析了在体肿瘤代谢重编程表型，并指导了肿瘤化疗、靶向HER2、PD1/PD-L1治疗及新型纳米药物治疗及效果，实现对肿瘤精准治疗的评价。因此，课题组完善了Warburg 效应关键调控的理论体系，建立了高分辨多模态分子影像定量分析技术平台，为精准靶向肿瘤Warburg 效应的临床转化奠定了科学依据。