新型p38MAPK抑制剂治疗癌症相关恶病质中白色脂肪棕色化的多模态MR评估

Cancer-associated cachexia is a disorder characterized by loss of adipose tissue and skeletal muscle. Half of all cancer deaths worldwide are attributed to the cancers most frequently associated with cachexia. There is a lack of effective treatment and accurate evaluation of cancer related cachexia clinically. Activation of the p38 mitogen-activated protein kinases (MAPKs) pathway by tumor related inflammatory cytokines promotes browning of white adipose tissue and stimulates angiogenesis, lead to accelerated heat production and catabolism. This project is to use the new type of p38MAPK inhibitor (RWJ67657 and VCP) to treat pre-cachexia though down-regulation of inflammation and to observe the key point of browned white adipose tissue in cell and animal level. We develop a one-stop multi-modality MR evaluation system with which to noninvasively monitor the browning of white adipose tissue in the structural, functional and molecular level in three animal models of cancer-associated cachexia at 7.0T micro-MR scanner. To dynamically demonstrate the pathophysiology and efficacy assessment of p38MAPK inhibitor and potential mechanisms, this project is not to measure the lipid content and oxygenation in vivo, also to design and synthesize the novel thermosensitive molecular probes to display the temperature changes in browning of white adipose tissue, which to provide data guiding potential studies in human.

癌症相关恶病质的显著特征是白色脂肪减少及骨骼肌质量下降。超过一半的癌症死亡率与其密切相关。目前临床缺乏对癌症相关恶病质的有效治疗及精确评价。肿瘤相关炎症因子激活细胞信号通路p38MAPK，促进白色脂肪棕色化及间质血管新生，加速产热及分解代谢。本项目从细胞和动物层面利用新型p38MAPK抑制剂RWJ67657及VCP下调炎症反应来干预治疗癌症相关恶病质前期，研究逆转白色脂肪棕色化过程这一恶病质前期的关键点。活体动物实验拟采用7.0T磁共振仪，建立三种癌症相关恶病质小鼠模型，从脂肪组织结构、功能及分子水平建立一站式多模态MR评估方法，检测白色脂肪脂质含量及血氧变化，构建温度敏感型分子探针并活体探测局部温度变化，对白色脂肪棕色化过程进行全方位监测，活体评价癌症相关恶病质病理过程的在体变化，揭示下调炎症反应对癌症相关恶病质前期干预的疗效、作用机制及转归，为进一步临床应用提供科学参考。

癌症相关恶病质（Cancer-associated cachexia，CAC）的显著特征是白色脂肪减少及骨骼肌质量下降，超过一半的癌症死亡率与其密切相关。CAC一旦从恶病质前期发展到恶病质，缺乏有效的干预措施及相关药物治疗。因此，早期诊断、早期治疗CAC至关重要。肿瘤相关炎症因子激活细胞信号通路p38MAPK，促进白色脂肪棕色化及间质血管新生，加速产热及分解代谢。本项目从细胞和动物层面均显示CAC激活p38通路导致白色脂肪棕色化，p38 MAPK抑制剂SB203580、VCP979均能有效降低白色脂肪棕色化，有效治疗CAC并改善预后，其中新型p38 MAPK 抑制剂VCP979疗效更佳，这是由于VCP979通过特异性抑制p38α亚基，达到高效抑制炎症反应、逆转白色脂肪棕色化，同时应用多参数磁共振脂质定量成像动态显示VCP979治疗组的皮下、内脏及附睾周围白色脂肪组织脂质含量均逐步增高，表明白色脂肪组织棕色化发生逆转，证实多参数MR能动态准确定量检测脂肪类型转变及脂质含量变化来诊断并监测CAC的治疗反应及治疗效果。为了尽早诊断癌症相关恶病质并预测预后，本项目开展大量临床研究，构建CAC患者多模态影像及临床数据库，建立并验证非小细胞肺癌、肝细胞癌等癌症相关恶病质的诊断及预测预后研究。CAC患者常规18F-FDG PET/CT检查图像发现肝脏FDG摄取值更低，内脏与皮下脂肪的FDG摄取值更高，这将成为诊断CAC的影像学标志物，具有非常大的临床应用前景。通过提取非小细胞肺癌患者腹部CT图像白色脂肪组织及骨骼肌影像组学特征，建立并验证基于影像组学模型能有效诊断及预测CAC的发生及预后；提取首诊肝细胞癌MR影像特征预测疾病后期发生CAC及预后，上述诊断及预测模型均具有很大的临床转化的可行性，为进一步早期诊断、早期治疗CAC提供准确评估方法，为后续肿瘤患者治疗方案的制定提供科学参考。