Momelotinib decreased cancer stem cell associated tumor burden and prolonged disease-free remission period in a mouse model of human ovarian cancer
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Emily Chan1, Rodney Luwor2, Christopher Burns3, George Kannourakis4,5, Jock K. Findlay1,6 and Nuzhat Ahmed1,4,5,6
1Department of Obstetrics and Gynaecology, University of Melbourne, Victoria 3052, Melbourne, Australia
2Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Victoria 3052, Melbourne, Australia
3Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Parkville, Australia
4Fiona Elsey Cancer Research Institute, Victoria 3353, Ballarat, Australia
5Federation University Australia, Victoria 3010, Ballarat, Australia
6The Hudson Institute of Medical Research, Victoria 3168, Clayton, Australia
Nuzhat Ahmed, email: email@example.com
Keywords: ovarian carcinoma; tumor cells; ascites; chemoresistance; chemotherapy
Received: October 27, 2017 Accepted: February 27, 2018 Published: March 30, 2018
Despite a good initial response to front-line chemotherapy, majority of the ovarian cancer patients relapse with consecutive phases of recurrences; and nearly 60% die within 5 years due to the development of a chemoresistant disease. This study investigated whether inhibition of the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway by momelotinib is sufficient in suppressing tumor burden and prolonging the disease-free survival period in a mouse model of ovarian cancer. We demonstrate that paclitaxel treatment enhanced JAK2/STAT3 activation which resulted in the enrichment of cancer stem cell (CSC)-like phenotype in the surviving ovarian cancer cells in vitro and in in vivo mouse xenografts. Combined treatment with paclitaxel and momelotinib inhibited paclitaxel-induced JAK2/STAT3 activation and CSC-like development in mice xenografts, and consequently reduced the tumor burden significantly greater than that achieved by paclitaxel-treatment alone. However, robust recurrent tumor growth with enhanced JAK2/STAT3 activation and CSC-like phenotype was observed in all mice groups after termination of treatments, but was delayed significantly in the paclitaxel and momelotinib treated group compared to other treatment groups. Daily oral gavage of momelotinib after termination of paclitaxel treatment showed sustained inhibition of tumor growth and a prolonged disease-free survival period in 50% of the mice. The other 50% of mice that developed tumors with ongoing momelotinib treatment also showed significantly increased survival benefit and a smaller tumor burden. These preliminary findings may have a profound clinical impact in developing an effective momelotinib-based ‘maintenance-therapy’ in ovarian cancer patients’ post-chemotherapy treatment.
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