Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden.

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

A pilot randomized control trial of topical capsaicin as adjunctive therapy for nausea and vomiting of pregnancy.

BACKGROUND: Nausea and vomiting is one of the most common complications of pregnancy, affecting 50% to 80% of pregnant persons. Moreover, despite its prevalence, it remains a challenging condition to treat. Treatment often involves oral and intravenous medications with potential side effects, particularly when taken in combination. Capsaicin cream is proven to decrease nausea and vomiting in cyclic vomiting syndrome; however, its use has not been well studied among pregnant patients. OBJECTIVE: This study aimed to test the feasibility of the off-label use of capsaicin for the treatment of nausea and vomiting in pregnancy. STUDY DESIGN: This was a double-blinded randomized controlled trial of pregnant individuals in their first trimester of pregnancy seeking care at a tertiary care hospital for nausea and vomiting. Consenting participants were randomized to abdominal application of topical capsaicin vs placebo. All participants received intravenous hydration and metoclopramide. The primary outcome, total treatment time, was recorded for all participants. In addition, symptom severity was assessed every 30 minutes using a visual analog scale. Data were analyzed using the Wilcoxon rank-sum test for continuous variables and the Fisher exact test for binary variables. RESULTS: Of the 38 eligible individuals approached, 30 were randomized. There was a trend toward decreased mean treatment time in the capsaicin group compared with the placebo group (79.9 vs 97.3 minutes; P=.1). There was no significant difference in visual analog scale scores at any time point between groups. Furthermore, capsaicin was well tolerated, with only 1 individual requesting the medication be removed. CONCLUSION: This study demonstrated that capsaicin is an acceptable treatment of nausea and vomiting in pregnancy and additional explorations of its use as treatment are feasible. A larger randomized controlled trial is needed to determine the efficacy of capsaicin in this population.