In ovarian cancer chemotherapy initially reduces tumor burden; however, >70% of patients experience tumor recurrence, creating a need for additional therapies. We evaluated the ability of Ruxolitinib, a FDA approved JAK 1/2 kinase inhibitor, as a potential adjunctive therapy for paclitaxel treatment of ovarian cancer. Using murine ID8 and human TOV-112D ovarian cancer cells we tested the ability of Ruxolitinib alone and in combination with low-dose paclitaxel to limit cell proliferation and colony formation in vitro. Additionally, using flow cytometry we assessed the capacity of paclitaxel to induce the expression of cell surface markers associated with stemness and the cellular stress response. We next determined if Ruxolitinib could reduce paclitaxel-induced expression of stemness and stress markers. Finally daily administration of Ruxolitinib, both alone and in combination with a single low-dose administration of paclitaxel, was tested for the capacity to reduce tumor growth and extend survival using the syngeneic ID8 luciferase-expressing model of ovarian cancer in C57Bl/6 mice.
Our in vitro data demonstrate that Ruxolitinib can sensitize both murine ID8 and human TOV-112D cells to low concentrations of paclitaxel, as evidenced by a significant reduction of cell proliferation and colony formation. We find that pre-incubation with Ruxolitinib is sufficient to sensitize cells to subsequent incubation with paclitaxel. Paclitaxel-induced expression of stemness and stress markers (SCA-1, GRP78 and CD133) is reduced by co-incubation with Ruxolitinib. In vivo, Ruxolitinib plus administration of a single low-dose paclitaxel treatment is sufficient to limit tumor growth and significantly extend median survival from in mice bearing ID8 ovarian cancer tumors (Control 59days vs Ruxolitinib-paclitaxel 77 days).
Together, these data indicate that Ruxolitinib can increase the susceptibility of both murine and human ovarian cancer cells to reduced concentrations paclitaxel chemotherapy in vitro and that combination therapy with Ruxolitinib and a single low-dose paclitaxel administration extends survival in mice. Our data provide important pre-clinical data to support the use of Ruxolitinib to enhance the efficacy of paclitaxel therapy for patients with ovarian cancer.
Citation Format: Patrick Reeves PhD, Mojgan Abbaslou MD, Mark C. Poznansky MD PHD. RUXOLITINIB SENSITIZES OVARIAN CANCER CELLS TO LOW–DOSE PACLITAXEL THERAPY [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-105.