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STAT3, a promising molecular target for cancer therapies, is a member of the STAT family of transcription factors that mediate cellular responses to cytokines and growth factors. Therefore, there is a critical need to develop novel strategies to treat advanced and drug resistant ovarian cancer. Despite efforts to overcome resistance using alternate chemotherapy agents, mortality remains high in platinum-resistant patients. However, there is no effective treatment for recurrent drug-resistant ovarian cancer. Most patients eventually experience recurrence and require further treatment. Treatment for ovarian cancer remains challenging despite a high initial response rate to first line platinum-taxane treatment. Taken together, our findings provide a foundation for clinical trials with ruxolitinib, either as a single agent or in combination with paclitaxel, for the treatment of recurrent and advanced ovarian cancer. Finally, our results demonstrate that combination of ruxolitinib and paclitaxel leads to a greater reduction of tumor growth compared to single treatment of either agent in a tumor mouse model that represents late stage ovarian cancer with peritoneal metastasis and ascites formation. Evaluation of the combination index (CI) shows that ruxolitinib synergistically interacts with paclitaxel in all three human ovarian cancer cells.
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In addition, ruxolitinib significantly increases the anti-tumor activity of chemotherapy agents, including paclitaxel, cisplatin, carboplatin, doxorubicin and topotecan in ovarian cancer cells. We show that ruxolitinib inhibits STAT3 activation and ovarian tumor growth both in ovarian cancer cells and in an ovarian cancer mouse model. We investigated the therapeutic potential of ruxolitinib, a JAK1/JAK2 inhibitor that has been FDA-approved for the treatment of myelofibrosis, to treat ovarian cancer either alone or in combination with conventional chemotherapy agents. Targeting JAK/STAT3, therefore, could be a potential novel therapeutic approach for treating advanced and chemoresistant ovarian cancer. Persistent activation of STAT3 is associated with cancer growth and progression and is also involved in cell resistance to platinum and taxane treatment. Received: OctoAccepted: JanuEpub: JanuPublished: May 11, 2018 Yim, email: ruxolitinib ovarian paclitaxel combination synergy
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Yim 1ġDepartment of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USAĢDepartment of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USAģDepartment of Comparative Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USAĤCurrent/Present address: Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL 33314, USA