Background. High-grade serous ovarian cancer is a lethal gynecologic disease. Conventional therapies, such as platinum-based chemotherapy, are rendered inadequate for disease management as most advanced disease patients develop resistance to this therapy and soon relapse, leading to poor prognosis. Novel immunotherapy and targeted therapy are currently under investigation as treatment options for ovarian cancer, but so far with little success. Epigenetic changes, such as aberrant DNA methylation, have been reported in resistance to platinum-based therapy. Decitabine is a hypomethylating agent which is effective against platinum-resistant disease and also exhibits several anti-tumor immune functions. Selinexor is a selective inhibitor of nuclear protein export. It restored platinum sensitivity in patient-derived ovarian cancer cell lines and is currently in clinical trials for the treatment of platinum-resistant ovarian cancer. We hypothesized that these two agents used in combination could elicit more potent anti-tumor immune responses in vivo than either agent used alone. Methods. These studies were designed to investigate the efficacy of these two agents used in combination to treat ovarian cancer by assessing murine models for changes in disease pathology and in anti-tumor responses. Results. Decitabine priming followed by selinexor treatment significantly limited ascites formation and tumor size. This combination of agents also promoted T cell effector function as measured by granzyme B secretion. Treatment of mice with decitabine and selinexor led to the significant release of a broader range of macrophage and T cell cytokines and chemokines above control PBS and vehicle and above decitabine or selinexor treatment alone. Conclusions. These results reveal crucial information for the design of clinical trials which may advance therapy outcomes in ovarian cancer.
背景：高级别浆液性卵巢癌是一种致命的妇科疾病。以铂类药物为基础的化疗等常规疗法在疾病管理中效果有限，因为大多数晚期患者会对该疗法产生耐药性并很快复发，导致预后不良。目前正在研究新型免疫疗法和靶向疗法作为卵巢癌的治疗选择，但迄今为止收效甚微。已有报道指出，表观遗传变化（如异常的DNA甲基化）与铂类疗法耐药性相关。地西他滨是一种去甲基化药物，对铂类耐药疾病有效，并具有多种抗肿瘤免疫功能。塞利尼索是一种核蛋白输出选择性抑制剂，它能在患者来源的卵巢癌细胞系中恢复铂类敏感性，目前正处于治疗铂类耐药卵巢癌的临床试验阶段。我们假设，这两种药物联合使用比单独使用任何一种药物都能在体内引发更强的抗肿瘤免疫反应。方法：本研究旨在通过评估小鼠模型的疾病病理变化和抗肿瘤反应，探讨这两种药物联合治疗卵巢癌的疗效。结果：地西他滨预处理后给予塞利尼索治疗，显著限制了腹水形成和肿瘤大小。通过颗粒酶B分泌测定，该药物组合还促进了T细胞效应功能。与对照组PBS、溶剂组以及单独使用地西他滨或塞利尼索相比，地西他滨和塞利尼索联合治疗的小鼠释放了更广泛的巨噬细胞和T细胞因子及趋化因子，且释放量显著增加。结论：这些结果为临床试验设计提供了关键信息，可能有助于改善卵巢癌的治疗效果。
Selinexor in Combination with Decitabine Attenuates Ovarian Cancer in Mice
肿瘤(癌症)患者之家