人源性淋巴瘤异种移植耐药模型的构建及新型PET/CT探针早期检测在其中的应用

Lots of advances about drug resistance of lymphoma have been made so far. The application of animal models has contributed to these studies. However, the use of cell lines to grow tumors will result in a lack of appropriate tumor growth environment, which is difficult for clinical transformation. The application of patient derived tumor xenograft (PDX) model has become the trend. Meanwhile, the specificity and efficiency of 18F-FDG PET/CT are also unsatisfactory. The new probe 18F-C-SNAT which is combined by Stanford University can detect apoptosis by targeting caspase 3/7, and its application in lymphoma has not been reported worldwide. Our previous study found that most types of lymphomas showed caspase 3/7 apoptosis after doxorubicin treatment. Therefore, we hypothesize that 18F-C-SNAT is able to assess the therapeutic effect on PDX model with drug resistance (PDX-R) and give it back to the clinic as a medication guide. We will use PDX to culture lymphoma cells with drug resistance, reverse the drug resistance after the construction of PDX-R and use 18F-C-SNAT for PET/CT, the results will be a clinical guideline. This study will not only establish a new PDX-R model for the first time, but also lay the theoretical foundation for the future application of 18F-C-SNAT probe and provide ideas for the precision medicine of lymphoma.

淋巴瘤耐药研究目前已取得一定进展，动物模型的应用功不可没。但是，利用细胞株成瘤会使得肿瘤缺乏相应的生长环境，研究结果很难实现临床转化，人源性肿瘤异种移植模型（PDX）的应用已为大势所趋。另外，18F-FDG PET/CT的特异性和时效性也差强人意。斯坦福大学合成的新型探针18F-C-SNAT能够以caspase3/7为靶点，检测细胞凋亡，其在淋巴瘤中的应用国内外未见报道。我们前期研究发现大部分类型淋巴瘤经阿霉素治疗后产生以caspase3/7为主的凋亡，因此提出假设：18F-C-SNAT能够评估淋巴瘤PDX耐药模型（PDX-R）的治疗效果并反馈于临床，作为用药指导。我们将利用PDX培养淋巴瘤耐药细胞，构建PDX-R后逆转耐药，用18F-C-SNAT检测，其结果用于临床指导。这项研究不仅首次构建出PDX-R模型，还为18F-C-SNAT今后的应用提供依据，也为淋巴瘤的精准化治疗提供思路。

淋巴瘤耐药研究目前已取得一定进展，动物模型的应用功不可没。但是，利用细胞株成瘤会使得肿瘤缺乏相应的生长环境，研究结果很难实现临床转化，人源性肿瘤异种移植模型的应用已为大势所趋。另外，在新药时代，淋巴瘤的预后评估却止步于以其临床特征和生化指标为基础的评分系统，因此急切地需要进一步探索淋巴瘤的分子机制，为早期诊断及精准治疗做准备。本研究利用人源性肿瘤组织构建耐药动物模型，通过大数据筛选构建能够预测患者预后的分子积分系统，研究结果显示，人源性肿瘤异种移植模型的生物特异性与人体肿瘤组织具有高度相似性，能够很好的在体外复刻肿瘤生长过程，在体外对肿瘤生长进行干预的研究结果反馈于临床治疗后能够有较好的疗效，其结果与预后预测系统评估相似，提示具有一定的临床适用性。这项研究不仅首次构建出淋巴瘤人源性肿瘤异种移植耐药模型，并成功进行体外药物筛选，还为淋巴瘤分子预后模型的建立及今后的应用提供依据，也为淋巴瘤的精准化治疗提供思路。