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Selinexor in Combination with Decitabine Attenuates Ovarian Cancer in Mice
Patrick J Stiff1, Swati Mehrotra2, Ronald K Potkul3
1Cardinal Bernardin Cancer Center, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
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.
Insights
Combining decitabine (a hypomethylating agent) and selinexor (a nuclear export inhibitor) shows promise for treating platinum-resistant ovarian cancer by enhancing anti-tumor immune responses and reducing tumor growth.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- High-grade serous ovarian cancer (HGSOC) is a lethal disease with poor prognosis due to platinum resistance.
- Conventional therapies are inadequate; novel immunotherapies and targeted therapies show limited success.
- Aberrant DNA methylation is linked to platinum resistance, and decitabine (hypomethylating agent) and selinexor (nuclear export inhibitor) are potential treatments.
Purpose of the Study:
- To investigate the combined efficacy of decitabine and selinexor in treating ovarian cancer.
- To assess the in vivo anti-tumor immune responses elicited by the combination therapy.
Main Methods:
- Murine models of ovarian cancer were used to evaluate the combination therapy.
- Changes in disease pathology and anti-tumor immune responses were assessed.
Main Results:
- Decitabine followed by selinexor significantly reduced ascites formation and tumor size.
- The combination therapy enhanced T cell effector function, indicated by increased granzyme B secretion.
- Combined treatment led to a broader release of macrophage and T cell cytokines and chemokines compared to single agents or controls.
Conclusions:
- The combination of decitabine and selinexor demonstrates potent anti-tumor activity and immune modulation in ovarian cancer models.
- These findings provide crucial information for designing future clinical trials for ovarian cancer therapy.
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