The effect of selective JAK2 inhibitor SAR302503 on tumorigenic STAT3 signaling in human prostate cancer in vivo.

Abstract

192 Background: STAT3 transcription factor is a critical mediator of signaling by IL-6, a cytokine promoting aggressive, castration-resistant prostate cancers (CPRCs). Importantly, STAT3 activation propagates from cancer cells to the tumor-associated immune cells, thereby generating immunosuppressive and proangiogenic tumor microenvironment. Janus kinase inhibitors provide an attractive method for disrupting IL-6/Jak/STAT3 signaling in both cancer and immune cells to amplify therapeutic effects. Methods: We tested the effect of selective Jak2 inhibitor, SAR302503, in xenotransplanted DU145 CPRCs and the tumor-associated myeloid immune cells in NSG mice. Results: Our initial results confirmed verified that oral gavage of 75 to 100 mg/kg SAR302503 results in dose-dependent inhibition of Jak2 phosphorylation in lysates from whole s.c. growing DU145 tumors within 18 h after treatment. Repeated daily treatment using SAR302503 (75 mg/kg) reduced phosphorylation of both Jak2 and STAT3, induced cancer cell death and significantly reduced growth of aggressive DU145 tumors. More detailed flow cytometric analysis revealed confirmed STAT3 inhibition in cancer cells and even greater extent in tumor-associated myeloid cells. SAR302503 did not reduce the total percentage of tumor-infiltrating myeloid cells. However, it promoted maturation of myeloid-derived suppressor cells. Conclusions: Our findings indicate that SAR302503 can potentially induce both direct and immune-mediated effects on castration-resistant prostate tumors. These preliminary results merit further studies in syngeneic tumor models that will assess whether Jak2/STAT3 inhibition can disrupt immunosuppressive and/or angiogenic functions of prostate cancer-associated myeloid cells. Further, these results may support clinical examination of SAR302503 either alone or in combination with other immunomodulatory therapies for metastatic CPRC.