PARP抑制剂联合TRAIL靶向治疗子宫内膜癌的作用及其分子机制研究

PARP inhibitors have entered clinical trials for the targeted therapy of endometrial cancer (EC). How to improve the efficacy of PARP inhibitors is currently one of the key scientific issues needed to be resolved. Tumor-associated macrophage (TAM) is a critical component of tumor microenvironments, which affect tumor growth, tumor angiogenesis, immune suppression, metastasis and chemoresistance. Our previous work revealed that TAM confers resistance to PARP inhibitor in the treatment of EC cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) re-educates TAM to an antitumor phenotype (Mol Biol Cell. 2015). Herein we propose to treat the endometrial cancer with PARP inhibitor and TRAIL. Our recently preliminary data showed that the combination of PARP inhibitor and TRAIL significantly inhibited the growth of EC cells and promoted their apoptosis. However, the molecular mechanisms underlying are not clear. Using in vitro coculture assay and genetic mouse model, we will investigate whether TRAIL promote the curative effect of PARP inhibitor in EC by re-educates TAM to an antitumor phenotype. We will also test the effects of PARP inhibitor on TRAIL receptor DR4/5 and signaling pathways. Finally, we will verify our data using clinical samples. The long-term goal of this project is to ultimately enhance the curative effect of PARP inhibitors in endometrial cancer.

PARP抑制剂是靶向治疗子宫内膜癌的临床试验药物，如何提高其疗效是亟待解决的关键科学问题。肿瘤相关巨噬细胞（TAM）在肿瘤发生发展中起重要作用，申请人前期研究发现，TAM能够降低子宫内膜癌对PARP抑制剂的敏感性；而肿瘤坏死因子相关的凋亡诱导配体（TRAIL）除直接杀伤肿瘤细胞外，还诱导TAM向抑制肿瘤的M1型转变（Mol Biol Cell．2015）。基于此，本研究拟将PARP抑制剂和TRAIL联合治疗子宫内膜癌。预实验结果显示，两药联用显著抑制子宫内膜癌细胞生长，但其分子机制尚不完全清楚。申请人通过体外共培养模型和基因工程小鼠模型，研究TRAIL通过增强TAM的M1型功能，进而增加PARP抑制剂在子宫内膜癌中的敏感性；同时检测PARP抑制剂对TRAIL受体通路的调节。最后用临床标本验证，深入探讨两药相互增敏的分子机制。本研究将为提高PARP抑制剂在治疗子宫内膜癌中的敏感性提供新思路。

PTEN功能缺失是子宫内膜癌中最常见的突变，然而已有研究表明PTEN缺失型子宫内膜癌细胞对PARP抑制剂单药并不敏感。因此，探究影响PARP抑制剂疗效的关键因子，探寻基于PARP抑制剂的联合用药方案，对于拓展PARP抑制剂的临床应用范围意义重大。TRAIL是肿瘤坏死因子家族成员，能够选择性地诱导肿瘤细胞凋亡。本项目对PARP抑制剂联合TRAIL治疗PTEN缺失性子宫内膜癌的有效性及多重分子机制进行研究。通过体外PTEN缺失型子宫内膜癌细胞系和临床子宫内膜肿瘤活组织切片短期离体培养模型，阐明了PARP抑制剂联合TRAIL有效抗PTEN缺失型子宫内膜癌的治疗效果，并深入探讨了两药协同作用的多重分子机制，发现PARP抑制剂可以增加TRAIL受体的表达，进而增强子宫内膜癌细胞对TRAIL的敏感性；而TRAIL可造成细胞同源重组修复能力下降，DNA损伤加剧，与PARP抑制剂形成“合成致死”效应。此外，我们还发现PI3K抑制剂联合PARP抑制剂也能够有效治疗PTEN缺失型子宫内膜癌，而对PTEN功能完整性子宫内膜癌治疗效果并不明显，并利用PTEN缺失型子宫内膜癌遗传工程小鼠进行体内实验验证。本项目为探寻基于PARP抑制剂的联药方案治疗PTEN缺失型子宫内膜癌患者的临床应用提供理论依据。