高级别浆液性卵巢癌（HGSOC）的死亡率占恶性卵巢癌的70-80%，其关键原因之一是治疗耐药，亟需发展新的治疗策略。本团队前期结果表明MYC异常活化能驱动HGSOC的发生：输卵管上皮细胞FTEC在同时失活TP53和过表达MYC时可转变为具有肿瘤干细胞特性的HGSOC细胞，其形成的肿瘤与HGSOC患者来源的肿瘤具有相似的分子特征，均富集MYC靶基因的表达；联合抑制MYC靶基因EZH2和AURKA的活性可协同抑制MYC驱动的肿瘤干细胞的生长并诱导其凋亡。本项目拟进一步明确患者HGSOC组织中EZH2及AURKA与MYC表达的临床相关性，同时在小鼠移植瘤和PDX模型中验证该联合用药策略对MYC驱动的HGSOC的治疗作用，并采用多组学手段探究其分子机理。本项目的完成将阐明EZH2和AURKA可能是MYC高拷贝驱动HGSOC发生的潜在靶点及其具体分子机理，为HGSOC的综合治疗提供新的策略。

High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths due to treatment resistance, and novel therapeutic strategies are needed to improve patient survival rate. Our pilot studies indicated that MYC hyperactivity drives HGSOC initiation and progression. Simply combining MYC overexpression and TP53 inactivation is sufficient to transform human fallopian tube epithelial cells (FTEC) into HGSOC with cancer stem cell (CSC) properties. Gene expression profiling analysis demonstrated that MYC-transformed FTEC and patient derived HGSOC shared similar gene signatures, which enriched MYC target genes. Our further studies indicated that EZH2 and AURKA antagonists synergistically inhibit CSC proliferation and induce apoptosis. Here, to confirm our in vitro findings, we will further assess the clinical relevance of EZH2 and AURKA in MYC-driven HGSOC tumor tissues and evaluate the therapeutic efficacy of combination treatment in vivo with ovarian cancer cell-derived and patient-derived xenograft models (CDX/PDX models). Moreover, multi-omics profiling strategies will be performed to uncover molecular mechanisms underlying this combination treatment for MYC-driven HGSOC. Therefore, we believe this project would define EZH2 and AURKA as potential therapeutic targets in MYC-driven HGSOC and shed light on the molecular mechanisms underlying combined treatment, and more importantly, this study may provide a novel therapeutic strategy to treat HGSOC.