组蛋白去甲基化酶KDM3B突变体促进肉瘤血管拟态形成并预测培唑帕尼疗效的作用和机制

培唑帕尼是批准用于化疗失败的晚期软组织肉瘤患者的首个抗血管生成靶向药物，但对中国肉瘤患者临床数据和抗血管生成药物有效的疗效预测靶标依然缺乏。我们前期通过全外显子组测序结合培唑帕尼治疗肉瘤的疗效分析，初步建立了疗效预测基因集，发现KDM3B基因突变肿瘤对培唑帕尼较敏感, KDM3B突变可诱导肉瘤细胞血管拟态形成并提高相关因子表达。在此基础上拟研究KDM3B突变激活血管拟态形成相关因子的作用及机制；探讨KDM3B突变对SMRT相关共抑制复合体在相关基因启动子区域募集和对其相关信号通路调控血管拟态的影响；探索KDM3B野生型和突变型蛋白的差异性靶基因和及其相关信号传导，进一步明确KDM3B突变调控肉瘤细胞对培唑帕尼或抗血管生成药物敏感性的具体机制及信号通路，并在动物模型体内验证培唑帕尼对KDM3B突变肉瘤的作用及机制。从而为晚期肉瘤患者精准选择药物、提高抗血管生成药物疗效提供理论依据和实验依据。

Pazopanib is the first multi-targeted drug approved by FDA for patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy but failed. However, there is still a lack of data for the efficacy and toxicity of pazopanib in Chinese sarcoma patients, and validated genetic factors for response prediction to pazopanib therapy are still limited. In the preliminary work we have distinguished gene panels to predict the response to pazopanib treatment by comparative analysis based on results of whole exome sequencing (WES). We identified that patients with KDM3B mutations were sensitive to pazopanib therapy. And we demonstrated that KDM3B mutations could induce the formation of vasculogenic mimicry (VM) and enhance the expression of VM related factors. On this basis, we aimed to investigate the role and mechanism of KDM3B mutation in activating VM-related factors; to explore whether KDM3B mutation impact on the recruitment of SMRT co-suppressor complexes on gene promoters or regulate the downstream signal pathways; to differentiate the target genes of wild-type and mutated KDM3B proteins as well as the relevant signal transductions, to further clarify the underlying mechanism that KDM3B mutation regulates the sensitivity of sarcoma to pazopanib or other anti-angiogenic drugs, and study the role and mechanism of mutated KDN3B sarcoma treated by pazopanib in animal model. Together, our findings implicate that KDM3B may be predictive of response to pazopanib treatment in sarcoma, which provide theoretical and experimental basis for patients with advanced sarcoma on precise drug selection and efficacy improvement of anti-angiogenic drugs.