组蛋白去乙酰化酶抑制剂西达苯胺影响胰腺癌缺氧微环境血管新生的作用机制

Pancreatic cancer (PC) patients suffer from unapparent symptoms and poor prognosis. Studies have shown a correlation of the development and progression of pancreatic cancer with epigenetic unbalance mediated by histone deacetylase (HDAC). As a new epigenetic drug developed by our country, Chidamide specifically targets class Ⅰ and class Ⅱ HDAC family members and has obtained favorable treatment indications and low toxicity reactions in PhaseⅡ/Ⅲ clinical trials in T-cell lymphoma patients. In previous studies, we have found that Chidamide could mediate interaction between tumor cells and vascular endothelial cells and also mediate angiogenesis under tumor hypoxia microenvironment through in vivo and in vitro experiments in pancreatic cancer. In the present study, we will further elucidate whether Chidamide affects tumor and angiogenesis microenvironment via HDAC family and HDAC/HIF-1α signaling pathway in epigenetic modulation by using chromatin immunoprecipitation, cytokine microarray, fluorescence footbed test, in situ PC bearing mice, siRNA of HDAC1 delivered by nano-particles and etc. We aim to reveal the epigenetic modulation mechanism of Chidamide in pancreatic cancer microenvironment, thus providing experimental and theoretical basis for broader clinical indications of Chidamide in pancreatic cancer patients.

胰腺癌患者发病隐匿，预后较差。研究表明，组蛋白去乙酰化酶（HDAC）介导的表观失衡与胰腺癌的发生发展密切相关。西达苯胺作为国内自主研发的新型表观药物，特异性靶向I类和IIb类HDAC家族成员，已在T细胞淋巴瘤的临床II/III期实验中获得了良好的治疗适应证和低毒反应。前期研究中我们通过一系列体内外研究，发现西达苯胺可以介导胰腺癌肿瘤细胞和血管内皮细胞的相互作用和肿瘤缺氧微环境介导下的血管新生，本研究中我们拟通过染色质免疫共沉淀、细胞因子芯片、荧光足蹼实验、原位胰腺癌荷瘤鼠、纳米基因递送干扰核酸siHDAC1等技术平台，进一步阐释西达苯胺在表观调控中是否通过HDAC家族和HDAC/HIF-1α信号通路影响肿瘤和血管新生微环境，揭示西达苯胺在胰腺癌微环境中的表观调控机制，为扩大西达苯胺在胰腺癌临床适应证中的应用提供实验基础和理论依据。

胰腺癌患者发病隐匿，预后较差。研究表明，组蛋白去乙酰化酶（HDAC）介导的表观失衡与胰腺癌的发生发展密切相关。西达苯胺作为国内自主研发的新型表观药物，特异性靶向I类和IIb类HDAC家族成员，已在T细胞淋巴瘤的临床II/III期实验中获得了良好的治疗适应证和低毒反应。前期研究中我们开展了西达苯胺对胰腺癌的体内外研究，发现西达苯胺可以介导肿瘤细胞和血管内皮细胞的相互作用和肿瘤缺氧微环境介导下的血管新生，本研究中我们通过体内外功能和机制研究，结合代谢组学数据和生信分析，表明西达苯胺可通过介导HDAC1/HIF-1a信号通路影响肿瘤和血管新生微环境，为其在胰腺癌中的单一或者联合应用提供参考，希望改善胰腺癌患者的临床治疗效果，最终改善患者的生存。