基于靶向细胞周期依赖性激酶CDK4/6的多模态分子影像技术监测乳腺癌抗肿瘤药物疗效的研究

基于18F-FDG的PET/CT分子影像技术，与RECIST标准相比，治疗后1周内就可以判断疗效，显著地缩短了评价时间、可及时调整用药，但是该技术不能监测药物靶点、特异性较差。鉴于此，基于可视化药物靶点的多模态分子影像技术能够特异性地监测靶点，还可以尽早、精准地评估抗肿瘤疗效。细胞周期异常是肿瘤的重要特征，其依赖性激酶CDK4/6的活性增强促进乳腺癌细胞的增殖。CDK4/6抑制剂Palbociclib是治疗乳腺癌的新型靶向药物，已在国内外获批上市。本项目在应用细胞周期报告基因监测CDKs和抗肿瘤疗效系列研究的基础上，拟构建靶向CDK4/6活性的多模态分子探针，通过在乳腺癌细胞和小动物反复验证，实现CDK4/6活性及细胞周期的可视化。本项目将进一步监测细胞周期药物的抗乳腺癌疗效，优化治疗方案，旨在建立多模态分子影像技术监测靶点活性和评价抗肿瘤药物疗效的体系。

Compared with RECIST criteria, 18F-FDG PET/CT imaging can assess the therapeutic response within one week after anti-tumor treatment, significantly shorten the cycle of the evaluation, and timely adjust the regimens. However, 18F-FDG PET/CT cannot directly monitor the target of drug, and has a relative low specificity. Therefore, a new approach is needed to specifically monitor the target of drug based on multimodal molecular imaging, which could visualize the target and assess the efficacy as early and accurately as possible. The dysregulation of cell cycle is a characteristic manifestation of tumor. Abnormal activation of the cell cycle-dependent kinase CDK4/6 promotes the proliferation of breast cancer. Palbociclib, a CDK4/6 inhibitor, has been approved as a novel drug using in the treatment of breast cancer. Based on a series of our previous studies using luciferase reporters for monitoring CDKs activity and cell cycle to evaluate therapeutic response of anti-tumor drugs, a set of multimodal molecular probes targeting CDK4/6 activity will be constructed in this project. The reflection and visualization of the CDK4/6 activity and cell cycle by those molecular probes will be tested and verified repeated in vitro and in vivo. Importantly, we will pursuit the study on multimodal molecular imaging for monitoring the anti-breast cancer efficacy of CDK4/6 inhibitors, optimizing the treatment options. This study aims to establish a system of multimodal molecular imaging to monitor the activity of target and evaluate the efficacy of anti-tumor drug.