Momelotinib decreased cancer stem cell associated tumor burden and prolonged disease-free remission period in a mouse model of human ovarian cancer

Emily Chan, Rodney Luwor, Christopher Burns, George Kannourakis, Jock K. Findlay, Nuzhat Ahmed

Research output: Contribution to journalArticleResearchpeer-review

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 paclitaxelinduced 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' postchemotherapy treatment.

Original languageEnglish
Pages (from-to)16599-16618
Number of pages20
JournalOncotarget
Volume9
Issue number24
DOIs
Publication statusPublished - 30 Mar 2018
Externally publishedYes

Keywords

  • Ascites
  • Chemoresistance
  • Chemotherapy
  • Ovarian carcinoma
  • Tumor cells

Cite this

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title = "Momelotinib decreased cancer stem cell associated tumor burden and prolonged disease-free remission period in a mouse model of human ovarian cancer",
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 paclitaxelinduced 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' postchemotherapy treatment.",
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Momelotinib decreased cancer stem cell associated tumor burden and prolonged disease-free remission period in a mouse model of human ovarian cancer. / Chan, Emily; Luwor, Rodney; Burns, Christopher; Kannourakis, George; Findlay, Jock K.; Ahmed, Nuzhat.

In: Oncotarget, Vol. 9, No. 24, 30.03.2018, p. 16599-16618.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Momelotinib decreased cancer stem cell associated tumor burden and prolonged disease-free remission period in a mouse model of human ovarian cancer

AU - Chan, Emily

AU - Luwor, Rodney

AU - Burns, Christopher

AU - Kannourakis, George

AU - Findlay, Jock K.

AU - Ahmed, Nuzhat

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Y1 - 2018/3/30

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KW - Ascites

KW - Chemoresistance

KW - Chemotherapy

KW - Ovarian carcinoma

KW - Tumor cells

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U2 - 10.18632/oncotarget.24615

DO - 10.18632/oncotarget.24615

M3 - Article

VL - 9

SP - 16599

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JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

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