Abstract
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.
Highlights
Despite improvements in the treatment for epithelial ovarian cancer over the last three decades, the mortality rate remains largely unchanged
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
Summary
Despite improvements in the treatment for epithelial ovarian cancer over the last three decades, the mortality rate remains largely unchanged. Current chemotherapy treatments lead to substantial tumor regression in the majority of the ovarian cancer cases but they do not eliminate subpopulations of residual cancer stem cells (CSCs) which have been demonstrated to be responsible for the regrowth of tumors in the recurrent scenario [2,3,4,5,6]. The JAK2/ STAT3 and CSC associated pathways are potential targets for the development of novel drugs aimed at suppressing their constitutive as well as ligand induced activation. Several anti-STAT3 compounds have been identified to inhibit cancer-associated proliferation, inflammation and chemotherapy resistance [9, 10]. None of these compounds have shown effects on CSCs, which theoretically have been suggested to drive chemoresistance
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