Selinexor in Combination with Decitabine Attenuates Ovarian Cancer in Mice

SIMPLE SUMMARY: Ovarian cancer is frequently discovered in the later stages. Current treatment for advanced disease ovarian cancer is inadequate and survival is poor. Our goal was to investigate how treatment with targeted therapy decitabine and/or selinexor could improve ovarian cancer in mice, when compared with experimental controls. Mice were administered ovarian cancer cells. About one week later, they were administered experimental treatment decitabine followed by selinexor. Disease outcome or improvement with single or combination treatment was studied by analyzing pathology changes in several organs to determine tumor spread and in biological experiments conducted on cells obtained from mice to investigate how treated mice developed anti-tumor immune responses to fight ovarian cancer. This study is of great significance as it may lead to new clinical trials with combination decitabine and selinexor and potentially to future therapies with these agents, which may prolong the life of women diagnosed with ovarian cancer. ABSTRACT: 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.