IRF8通过Fas/FasL信号通路调控前列腺癌化疗敏感性的分子机制研究

Advanced CRPC resistance (AR antagonist resistance and chemotherapy resistance) is the main cause of death in PCa patients, and the major problem in clinical treatment. How to delay the occurrence of drug resistant CRPC is the mainstream of the current research, among which early intervention of chemotherapy has become a hot topic. 2016 NCCN and EAU guidelines have recommend that ADT combined with docetaxel for treatments of PCa patients newly diagnosed with metastasis or high risk with localized PCa, to prolong overall survival in castration sensitive PCa. Whereas there are significant individual differences in PCa patients, different patients and patients with different stages have different response to chemotherapy. Early intervention of chemotherapy is an enormous challenge due to the absence corresponding predictive markers guiding the combination of ADT and chemotherapy. Previously we have discovered that IRF8, as a transcription factor regulating immunity, can regulate PCa cell response to death signals; there exists an IRF8-positive and IRF8-negative state among a wide variety of primary prostate cancer tissues and targeting IRF8 can influence resistance to chemotherapy. However, the definite mechanisms are not well understood. We hypothesis that IRF8 could regulate chemo-sensitivity by Fas/FasL pathway. In this renewing project, we will 1) At cellular and overall level, illustrate that IRF8 can influence resistance to chemotherapy, combining chemotherapy regiments with adjuvant therapy targeting IRF8 can promote the efficacy of chemotherapeutic drug. 2) At the molecular, illustrate the regulation mechanisms of IRF8 in the Fas/FasL death signaling pathway. 3) illustrate that the IRF8 state is associated with chemo-sensitivity across different chemotherapy drug in PCa and a clinical classifier for IRF8 status and targeting IRF8 is a therapy predictive markers for the individualization of cancer management.

晚期CRPC耐药是PCa患者的主要死因，如何延缓耐药CRPC发生是目前研究的主要方向，其中化疗的早期介入成为热点。最新指南推荐去势联合多西他赛可用于初诊转移性和高危局限性PCa患者的治疗，以延长去势敏感性患者的总生存期。但不同PCa患者以及不同病程阶段对化疗反应性差异大，缺乏预测标志物以指导去势联合化疗的早期介入。前期研究发现，IRF8可调节PCa细胞对死亡信号的应答；PCa患者IRF8表达具有个体差异，其表达高低与化疗敏感性密切相关，但机制未明。本项目拟进一步研究: 1)从细胞和整体水平系统研究IRF8增强PCa对化疗药物的敏感性，多种模型验证联合用药增强IRF8表达可增强化疗敏感性。2)验证IRF8通过Fas/FasL信号通路影响化疗敏感性。3)通过前瞻性及回顾性分析临床IRF8异常表达与化疗敏感性密切相关，靶向IRF8联合化疗则可增强化疗敏感性，阐明IRF8可作为化疗疗效预测标志物。

去势抵抗性前列腺癌（CRPC）是前列腺癌患者死亡的主要原因，也是目前治疗的难点。我们前期研究发现IRF8 在前列腺癌中主要发挥抗肿瘤活性并调节前列腺癌对雄激素受体（AR）拮抗剂恩杂鲁胺（Enz）的敏感性。在此基础上，本项目探索 IRF8 表达对化疗药物敏感性的影响及确切的调控机制：（1）从细胞、动物模型和前列腺癌患者不同阶段的组织标本进行比对分析，发现IRF8在原位前列腺癌中表达上调，与AR表达正相关；CRPC中表达下调，与AR表达负相关。（2）IRF8通过泛素化蛋白酶体途径调控AR蛋白稳定性进而影响前列腺癌细胞增殖及恩杂鲁胺敏感性；(3)基于转化医学的研究思路，以IRF8作为靶点，IFNα能够诱导IRF8高表达，增强AR拮抗剂恩杂鲁胺对CRPC的杀伤能力，并在此基础开展小样本临床研究，证实IRF8激动剂IFNa联合内分泌治疗高危前列腺癌患者的疗效更佳，为临床治疗学提供理论和实验依据。