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胰腺癌是死亡率最高的肿瘤，其被发现时多数已为晚期。由于早期手术的机会较少，且部分患者即使能够手术切除，但常常由于术后复发或转移而导致治疗失败，其5年生存率低于9%。目前应用的标准化疗方案效果均不满意，而在其他肿瘤中获得较好效果的免疫关卡抑制剂，在胰腺癌中也疗效不佳，其主要原因是胰腺癌组织中大量的结缔组织、低氧状态和免疫抑制导致的各种治疗策略的失败。因此需要拓展新的思路，针对胰腺癌的组织结构及分子调控网络开拓新的治疗路径。“协同致死”治疗策略的应用已经改善了部分患者的预后，但由于出现了PARP抑制剂耐药的现象，促使人们深入挖掘DNA损伤修复通路的调控网络。随着对非同源末端连接修复替代机制的认识，靶向DNA聚合酶θ的治疗为“协同致死”策略提供了更有效的手段，也为胰腺癌患者带来了新的希望。另外，针对肿瘤微环境，特别是各种免疫治疗策略也在进行深度挖掘，结合合成生物学手段改良或重组免疫细胞基因组中的各种调控元件，也为胰腺癌患者带来更多的希望。溶瘤病毒治疗胰腺癌也获得了一定程度的进展，该方法不仅可以特意性杀伤肿瘤细胞，同时还可激活微环境中的免疫细胞，从而达到杀伤肿瘤细胞和激活免疫细胞双重抗癌效果。
Abstract：Pancreatic cancer is the most malignant tumor, with the 5-year overall survival rate below 9%. A multidrug regimen of 5-fluorouracil(5-FU), leucovorin, irinotecan, and oxaliplatin(FOLFIRINOX) or gemcitabine/nab-paclitaxel therapeutics becomes standard treatment for late stage of patients, only applying for patients with good performance status. However, the treatment was mostly failed because of recurrence or metastasis. Immunotherapeutics have been reported to increase the overall survival time of other kinds of cancer, but no obvious improvement was observed in pancreatic cancer. Pancreatic cancer can be featured with low mutational burden, fibrosis, hypoxia and immunosuppression. By deep understanding the character of microenvironment and the phenotype of gene regulation network of pancreatic cancer, it is hopeful to develop novel effective therapeutic strategies by discovering new pathways and innovating the composition of regimen. Targeting BRCA1/2 deficiency pancreatic cancer by PARP inhibitors has improved patients′ survival time. However, about 40% of patients appeared PARP inhibitor resistance. The efficiency of ″synthetic lethality″ in cancer therapy attracted more interests for DNA damage repair(DDR) research. By deep understanding the DDR regulation network, it was recognized that a new DDR pathway, alternative end-joining pathway, plays an important role. It has been tested by targeting DNA polymerase θ and more clinical trials are ongoing. Oncolytic virus therapy is a promising candidate to overcome the challenges of the microenvironment of pancreatic cancer. It exerts cancer-specific cytopathic effect and activates immune response.
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基本信息:
DOI：
中图分类号:R735.9
引用信息:
[1]苏小茉,郭明洲.突破胰腺癌治疗挑战的新路径[J].胃肠病学和肝病学杂志,2025,34(09):1249-1251.
基金信息:
国家重点研发计划(2018YFA0208902,2020YFC2002705); 国家自然科学基金委员会资助项目(82272632,81672138); 解放军总医院青年自主创新科学基金项目(22QNCZ027)