Stiff Patrick J, Mehrotra Swati, Potkul Ronald K, Banerjee Swarnali, Walker Christopher, Drakes Maureen L
Cardinal Bernardin Cancer Center, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Edward Hines Junior VA Hospital, Hines, IL 60141, USA.
Cancers (Basel). 2023 Sep 13;15(18):4541. doi: 10.3390/cancers15184541.
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.
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.
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.
These results reveal crucial information for the design of clinical trials which may advance therapy outcomes in ovarian cancer.
高级别浆液性卵巢癌是一种致命的妇科疾病。传统疗法，如铂类化疗，在疾病管理方面已显不足，因为大多数晚期疾病患者会对这种疗法产生耐药性并很快复发，导致预后不良。新型免疫疗法和靶向疗法目前正在作为卵巢癌的治疗选择进行研究，但迄今为止收效甚微。已有报道称，表观遗传变化，如异常的DNA甲基化，与铂类疗法的耐药性有关。地西他滨是一种去甲基化剂，对铂耐药疾病有效，并且还具有多种抗肿瘤免疫功能。塞利尼索是一种核蛋白输出的选择性抑制剂。它恢复了患者来源的卵巢癌细胞系对铂的敏感性，目前正处于治疗铂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在体内能比单独使用任何一种药物引发更强效的抗肿瘤免疫反应。
这些研究旨在通过评估小鼠模型的疾病病理学变化和抗肿瘤反应，来研究这两种药物联合使用治疗卵巢癌的疗效。
先用低剂量阿糖胞苷预处理，再用塞利尼索治疗，可显著限制腹水形成和肿瘤大小。通过颗粒酶B分泌来衡量，这种联合用药还促进了T细胞效应功能。用低剂量阿糖胞苷和塞利尼索治疗小鼠，导致巨噬细胞和T细胞细胞因子及趋化因子的释放范围比对照PBS和赋形剂以及单独使用低剂量阿糖胞苷或塞利尼索治疗时显著更广。
这些结果为设计可能改善卵巢癌治疗结果的临床试验揭示了关键信息。
