Abstract
BackgroundChemotherapy 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.MethodsWe 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.ResultsRuxolitinib (≤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.ConclusionTogether, 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.
Highlights
Many patients with ovarian cancer are diagnosed late in disease progression, resulting in a 5-year survival rate of less than 30% [1, 2]
We demonstrated that Taxol induced expression of stress and stemness markers including GRP78 and CD133 was significantly reduced by addition of Ruxolitinib
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% as compared to control mice
Summary
Many patients with ovarian cancer are diagnosed late in disease progression (stage III and IV), resulting in a 5-year survival rate of less than 30% [1, 2]. Numerous approaches using targeted therapies to limit tumor growth and neovascularization remain under evaluation including Bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, and Erlotinib, a small molecule inhibitor of epidermal growth factor receptor (EGFR) [4,5,6]. Another approach seeks to enhance the sensitivity of cancer cells to chemotherapy through the use of small molecules targeting essential signal transducing molecules such as AKT and Aurora kinases [7, 8]. Tumors recur in over 70% of patients, creating the need for novel therapeutic approaches
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