PET/MR功能成像预测宫颈癌新辅助化疗敏感性及p53信号通路参与耐药机制的研究

Neoadjuvant chemotherapy (NACT) can improve operability and operative resective rate for locally advanced cervical cancer. However, drug resistance will delay effective therapy, which makes NACT a dilemma in clinics. Thus, to predict therapy sensitivity calls for a safe, effective and strongly feasible imaging method, and drug-resistance mechanisms for NACT are still under debate. In our previous laboratory study, p53 signaling pathway was identified to participate in NACT mechanisms, but evidence for their participation in regulating drug resistance needs further clarification. This study combines multi-modality functional imaging methods by hybrid PET/MR, including fluodeoxyglucose (FDG) metabolizing imaging, diffusion weighted imaging (DWI), perfusion weighted imaging (PWI) and blood oxygen level dependent (BOLD) imaging, as well as pathology indexes, to clarify the differences in pathophysiology between NACT drug sensitivity and drug resistance. Then we investigate the value of hybrid PET/MR functional imaging to predict response to NACT in cervical cancer and get according quantification indexes for functional imaging. Finally, we aim to find evidence for p53 signaling pathway to regulate NACT drug resistance, so as to provide some evidence in future molecular targeting therapy of cervical cancer by overcoming drug resistance.

新辅助化疗（NACT）可提高局部晚期宫颈癌可手术率及手术切除率，但NACT耐药会延误此类患者治疗时机。目前临床缺乏安全有效、可行性强的NACT疗效敏感性预测的影像学方法，而且对其耐药机制无统一定论。我们在前期基础研究中发现p53信号通路参与NACT起效机制，但是否参与耐药调控需要进一步研究。本研究综合运用一体机PET/MR多模态功能成像方法，包括葡萄糖（FDG）代谢显像、扩散加权成像（DWI）、灌注成像（PWI）及血氧水平依赖（BOLD）成像，同时获得宫颈癌NACT治疗前、后肿瘤在体状态下的多重功能成像信息指标，结合病理学指标，揭示宫颈癌NACT治疗敏感与耐药间病理生理差异机制；评价PET/MR功能成像预测宫颈癌NACT疗效敏感性的价值，获得相应的功能影像学定量指标；研究p53信号通路参与NACT耐药调控的证据和机制，为临床上宫颈癌克服药物抵抗治疗提供分子靶点和治疗依据。

目的：我们的研究目的是评价PET/MR多模态功能成像预测局部晚期宫颈癌（IB2-IIA期）新辅助化疗（NACT）疗效敏感性的价值，寻求受p53调控的相关蛋白参与NACT耐药调控的证据，揭示可能的耐药机制。方法：研究共前瞻性收集局部晚期宫颈癌患者88例，化疗前后2周分别行PET/MR检查，增加IVIM扫描序列，后处理得到D图、D*图、f图，化疗前后在PET与MR图像上分别测量肿瘤体积，在PET图像上测量肿瘤SUVpeak，T2WI图像上测量化疗前后肿瘤最大径，在D、D*、f图上勾画感兴趣区得到扩散系数D、灌注系数D*及灌注分数f，根据PERCIST、RECIST标准分别进行疗效评价，进一步选择不同治疗方案，根治性手术切除者测量病理大体标本肿瘤的最大径，未进行根治手术者1周后行PET/MR-IVIM检查，测量肿瘤最大径及D、D*、f值。在进行化疗前后进行PET/MR检查的两个时间点，分别进行两次阴道镜取病理，进行免疫组化染色，比较前后TIGAR、GLUT-1、VEGF、HIF-1α及AQP-1的表达差异。结果：NACT前后肿瘤体积有显著统计学差异（PET体积t=5.80，P<0.001,T2WI体积t=5.45，P<0.001）;SUVpeak（t=-2.11，P<0.001）、D（t=3.10；P＜0.001）、f值（t=2.63；P＜0.001）在放疗前后有显著统计学差异。D*（r=0.22，P＞0.05）在在化疗前后无差异。免疫组化结果方面，SUVpeak与VEGF及AQP-1的表达水平相关性最高（r=0.529，P=0.000；r=0.356，P=0.007），TIGAR及GLUT-1是预测NACT疗效的较好指标，而IVIM中的纯扩散系数D可以用于预测NACT疗效，TIGAR及GLUT-1表达水平与D之间存在相关性（r=0.525，p=0.028）。结论：PET/MR多模态功能成像中的SUVpeak、D值、f值是预测局部晚期宫颈癌NACT疗效敏感性的较好指标，可以用于术前预测宫颈癌NACT疗效。p53信号通路相关蛋白（TIGAR、GLUT-1）表达水平在NACT前后表达有差异，可能在宫颈癌的耐药调控中发挥作用。