{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:29:10Z","timestamp":1760149750197,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T00:00:00Z","timestamp":1694563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cronk Foundation"},{"name":"Perritt Charitable Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers15184541","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T10:00:23Z","timestamp":1694685623000},"page":"4541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Selinexor in Combination with Decitabine Attenuates Ovarian Cancer in Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Patrick J.","family":"Stiff","sequence":"first","affiliation":[{"name":"Cardinal Bernardin Cancer Center, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swati","family":"Mehrotra","sequence":"additional","affiliation":[{"name":"Edward Hines Junior VA Hospital, Hines, IL 60141, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald K.","family":"Potkul","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Loyola University Chicago, Maywood, IL 60153, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swarnali","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, Loyola University Chicago, Chicago, IL 60660, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Walker","sequence":"additional","affiliation":[{"name":"Karyopharm Therapeutics, Newton, MA 02459, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maureen L.","family":"Drakes","sequence":"additional","affiliation":[{"name":"Cardinal Bernardin Cancer Center, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"280","DOI":"10.3322\/caac.21559","article-title":"Epithelial ovarian cancer: Evolution of management in the era of precision medicine","volume":"69","author":"Lheureux","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e26849","DOI":"10.1097\/MD.0000000000026849","article-title":"Effect of molecular targeted agents in chemotherapy for treating platinum-resistant recurrent ovarian cancer: A systematic review and meta-analysis","volume":"100","author":"Liu","year":"2021","journal-title":"Medicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s12032-017-0960-z","article-title":"A brief review of the management of platinum-resistant-platinum-refractory ovarian cancer","volume":"34","author":"Oronsky","year":"2017","journal-title":"Med. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1080\/14656566.2017.1328055","article-title":"Overcoming platinum resistance in ovarian cancer treatment: From clinical practice to emerging chemical therapies","volume":"18","author":"Tomao","year":"2017","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ygyno.2020.07.008","article-title":"Incidence and mortality of ovarian cancer at the global, regional, and national levels, 1990\u20132017","volume":"159","author":"Zheng","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100629","DOI":"10.1016\/j.ctarc.2022.100629","article-title":"Epithelial ovarian cancer: Review article","volume":"33","author":"Sambasivan","year":"2022","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40425-015-0051-7","article-title":"Immunotherapeutic approaches to ovarian cancer treatment","volume":"3","author":"Chester","year":"2015","journal-title":"J. Immunother. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1001\/jamaoncol.2018.6258","article-title":"Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer: Phase 1b Results From the JAVELIN Solid Tumor Trial","volume":"5","author":"Disis","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1093\/intimm\/dxw020","article-title":"Immune checkpoint inhibition in ovarian cancer","volume":"28","author":"Hamanishi","year":"2016","journal-title":"Int. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3987","DOI":"10.1200\/JCO.2015.63.7785","article-title":"Targeting Programmed Cell Death 1 in Ovarian Cancer","volume":"33","author":"Homicsko","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.3389\/fonc.2020.01290","article-title":"Mechanisms of Cancer Resistance to Immunotherapy","volume":"10","author":"Bai","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev-immunol-070621-030155","article-title":"Resistance Mechanisms to Anti-PD Cancer Immunotherapy","volume":"40","author":"Vesely","year":"2022","journal-title":"Annu. Rev. Immunol."},{"key":"ref_15","first-page":"271","article-title":"Resistance to cis- and carboplatin initiated by epigenetic changes in ovarian cancer patients","volume":"2","author":"Schwarzenbach","year":"2019","journal-title":"Cancer Drug Resist."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1158\/0008-5472.CAN-11-3909","article-title":"Epigenetic resensitization to platinum in ovarian cancer","volume":"72","author":"Matei","year":"2012","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13148-018-0602-0","article-title":"Epigenetic therapy for ovarian cancer: Promise and progress","volume":"11","author":"Moufarrij","year":"2019","journal-title":"Clin. Epigenet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.gore.2017.03.007","article-title":"Epigenetic therapy for the treatment of epithelial ovarian cancer: A clinical review","volume":"20","author":"Smith","year":"2017","journal-title":"Gynecol. Oncol. Rep."},{"key":"ref_19","first-page":"214","article-title":"Therapeatic Efficacy of Decitabine on Low and Moderate-Risk MDS Patients and the Prognostic Factors","volume":"28","author":"Shu","year":"2020","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5792","DOI":"10.18632\/aging.102973","article-title":"Decitabine in combination with low-dose cytarabine, aclarubicin and G-CSF tends to improve prognosis in elderly patients with high-risk AML","volume":"12","author":"Hong","year":"2020","journal-title":"Aging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40164-020-00160-8","article-title":"Indirect comparison of azacitidine and decitabine for the therapy of elderly patients with acute myeloid leukemia: A systematic review and network meta-analysis","volume":"9","author":"Wen","year":"2020","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1182\/asheducation-2016.1.348","article-title":"Mutations in AML: Prognostic and therapeutic implications","volume":"2016","author":"DiNardo","year":"2016","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program Book"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1158\/0008-5472.CAN-19-3837","article-title":"Epigenetic Attire in Ovarian Cancer: The Emperor\u2019s New Clothes","volume":"80","author":"Matei","year":"2020","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e1323619","DOI":"10.1080\/2162402X.2017.1323619","article-title":"The safety, efficacy, and treatment outcomes of a combination of low-dose decitabine treatment in patients with recurrent ovarian cancer","volume":"6","author":"Zhang","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1158\/2326-6066.CIR-15-0073","article-title":"Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model","volume":"3","author":"Wang","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.molcel.2021.01.038","article-title":"DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells","volume":"81","author":"Bell","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, L.X., Mei, Z.Y., Zhou, J.H., Yao, Y.S., Li, Y.H., Xu, Y.H., Li, J.X., Gao, X.N., Zhou, M.H., and Jiang, M.M. (2013). Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062924"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41571-019-0266-5","article-title":"The emerging role of epigenetic therapeutics in immuno-oncology","volume":"17","author":"Topper","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nrc1274","article-title":"Nuclear transport and cancer: From mechanism to intervention","volume":"4","author":"Kau","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nrc2149","article-title":"Nuclear microenvironments in biological control and cancer","volume":"7","author":"Zaidi","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41571-020-00442-4","article-title":"The nuclear export protein XPO1\u2014From biology to targeted therapy","volume":"18","author":"Azmi","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1158\/1078-0432.CCR-16-1333","article-title":"Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer","volume":"23","author":"Chen","year":"2017","journal-title":"Clin. CancerRes. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41698-022-00315-2","article-title":"Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14)","volume":"6","author":"Nguyen","year":"2022","journal-title":"npj Precis. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e511","DOI":"10.1016\/S2352-3026(20)30120-4","article-title":"Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): A single-arm, multinational, multicentre, open-label, phase 2 trial","volume":"7","author":"Kalakonda","year":"2020","journal-title":"Lancet Haematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ygyno.2020.10.019","article-title":"A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers","volume":"160","author":"Rubinstein","year":"2021","journal-title":"Gynecol. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s40164-021-00251-0","article-title":"Selinexor in combination with standard chemotherapy in patients with advanced or metastatic solid tumors","volume":"10","author":"Thein","year":"2021","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.ygyno.2019.11.012","article-title":"Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies","volume":"156","author":"Vergote","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ygyno.2022.11.004","article-title":"Selinexor in combination with weekly paclitaxel in patients with metastatic solid tumors: Results of an open label, single-center, multi-arm phase 1b study with expansion phase in ovarian cancer","volume":"168","author":"Westin","year":"2023","journal-title":"Gynecol. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13119","DOI":"10.18632\/oncotarget.3761","article-title":"Anti-tumor activity of selective inhibitors of XPO1\/CRM1-mediated nuclear export in diffuse malignant peritoneal mesothelioma: The role of survivin","volume":"6","author":"Cominetti","year":"2015","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/leu.2015.194","article-title":"Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice","volume":"30","author":"Etchin","year":"2016","journal-title":"Leukemia"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hay, Z.L.Z., and Slansky, J.E. (2022). Granzymes: The Molecular Executors of Immune-Mediated Cytotoxicity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031833"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1158\/2159-8290.CD-13-1005","article-title":"Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy","volume":"4","author":"Tan","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1091\/mbc.e12-01-0045","article-title":"NESdb: A database of NES-containing CRM1 cargoes","volume":"23","author":"Xu","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10418","DOI":"10.1073\/pnas.190318397","article-title":"Nucleocytoplasmic translocation of Stat1 is regulated by a leucine-rich export signal in the coiled-coil domain","volume":"97","author":"Begitt","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1172\/JCI15372","article-title":"Regulation of Stat3 nuclear export","volume":"111","author":"Bhattacharya","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6031","DOI":"10.1158\/1078-0432.CCR-17-1201","article-title":"Increased IFNgamma+ T Cells Are Responsible for the Clinical Responses of Low-Dose DNA-Demethylating Agent Decitabine Antitumor Therapy","volume":"23","author":"Li","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e36967","DOI":"10.7554\/eLife.36967","article-title":"Topography of cancer-associated immune cells in human solid tumors","volume":"7","author":"Kather","year":"2018","journal-title":"eLife"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1758835920967241","DOI":"10.1177\/1758835920967241","article-title":"Prognostic impact of tumor-infiltrating lymphocytes in high grade serous ovarian cancer: A systematic review and meta-analysis","volume":"12","author":"Hao","year":"2020","journal-title":"Ther. Adv. Med. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/18\/4541\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:50:11Z","timestamp":1760129411000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/18\/4541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,13]]},"references-count":48,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["cancers15184541"],"URL":"https:\/\/doi.org\/10.3390\/cancers15184541","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2023,9,13]]}}}