Ruxolitinib sensitizes ovarian cancer to reduced dose Taxol, limits tumor growth and improves survival in immune competent mice

• Type of Material: Article
• Authors: Patrick M. Reeves, Massachusetts General Hospital; Mojgan A. Abbaslou, Massachusetts General Hospital; Farah R.W. Kools, Massachusetts General Hospital; Kritchai Vutipongsatorn, Massachusetts General Hospital; Xiaoyun Tong, Massachusetts General Hospital; Christina Gavegnano, Emory University; Raymond F Schinazi, Emory University; Mark C. Poznansky, Massachusetts General Hospital
• Language: English
• Date: 2017-11-07
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Reeves et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.21541
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 8
• Issue: 55
• Start Page: 94040
• End Page: 94053
• Grant/Funding Information: PR and MCP funded by the VIC Innovation Fund.; MP DOD/Congressionally Directed Medical Research Program W81XWH-13-PRCRP-IA.; PR funded by the Prof. Ray Schinazi Research Fellowship Fund.; This project was supported by the Schinazi Fellowship (to PMR) and the Vaccine and Immunotherapy Center Innovation Fund. RFS is funded by NIH grant 2P30AI050409 and 1RO1MH100999.
• Keywords: PACLITAXEL; Oncology; immunocompetent; Science & Technology; Life Sciences & Biomedicine; COLONY-STIMULATING FACTOR; COMBINATION; combination; INHIBITION; Taxol; DOUBLE-BLIND; CELLS; RESISTANCE; Ruxolitinib; ovarian; Cell Biology; CHECKPOINT BLOCKADE; MYELOFIBROSIS; IN-VITRO
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology; Health Sciences, Obstetrics and Gynecology

Abstract

Background: Chemotherapy initially reduces the tumor burden in patients with ovarian cancer. However, tumors recur in over 70% of patients, creating the need for novel therapeutic approaches. Methods: We evaluated Ruxolitinib, an FDA-approved JAK 1/2 kinase inhibitor, as a potential adjunctive therapy for use with low-dose Taxol (Paclitaxel) by assessing the impact on in vitro proliferation and colony formation of ID8 cells or human TOV- 112D ovarian cancer cells, as well as flow cytometric measurement of surface markers associated with cellular stress and stemness by ID8 cells. The syngeneic ID8 murine model of ovarian cancer was used to assess the impact of Ruxolitinib and Taxol, individually and in combination, on tumor initiation and growth, as well as capacity to extend survival. Results: Ruxolitinib (≤10 μM) sensitized both ID8 and TOV-112D cells to low concentrations of Taxol (≤5 nM), limiting cell proliferation and colony formation in vitro. Mechanistically, we demonstrated that Taxol induced expression of stress and stemness markers including GRP78 and CD133 was significantly reduced by addition of Ruxolitinib. Finally, we demonstrated that a single administration of a low-dose of Taxol (10 mg/Kg) together with daily Ruxolitinib (30 mg/Kg; which is equivalent to plasma concentrations of ~ 0.01 μM steady-state) limited ID8 tumor growth in vivo and significantly extended median survival up to 53.5% (median 70 v 107.5 days) as compared to control mice. Conclusion: Together, these data support the use of Ruxolitinib in combination with low-dose Taxol as a therapeutic approach with the potential for improved efficacy and reduced side effects for patients with recurrent ovarian cancer.