Abstract 1113: Targeting the JAK2/STAT3 pathway in ovarian cancer

Abstract

Abstract Ovarian cancer is the fifth leading cause of death and the most lethal gynecological cancer among women in the United States. Persistent activation of signal transducer and activator of transcription 3 (STAT3), a cytoplasmic transcription factor, is frequently detected in EOC. STAT3 transduces signals from cytokines such as interleukin 6 (IL-6) via interactions with the IL-6 receptor and Janus kinases (JAK). JAK2 activates STAT3 by phosphorylation, leading to dimerization and translocation of STAT3 to the nucleus where it activates transcription of target genes regulating proliferation, survival and motility. Importantly, in addition to tumor cells, STAT3 signaling is also critical for immune cell activity and, in particular, inflammatory response. The inflammatory tumor microenvironment is important for ovarian cancer progression; therefore, we hypothesized that disruption of the STAT3 pathway would block ovarian tumor progression by: 1) directly inhibiting the growth of tumor cells; and 2) reducing a pro-tumorigenic inflammatory microenvironment. To target JAK2-mediated activation of STAT3 we used AZD1480, a JAK2-selective small molecule inhibitor. The effects of AZD1480 treatment on cell proliferation, apoptosis, adhesion and motility were evaluated in cultured human ovarian carcinoma cells. To study the effects of AZD1480 in vivo, we used MISIIR-TAg mice, a transgenic mouse model of ovarian carcinoma. Tumor growth in MISIIR-TAg mice was monitored and quantified in mice by weekly magnetic resonance imaging (MRI). Drug treatment-mediated alterations in gene expression were evaluated by microarray analysis and changes in the inflammatory response were evaluated by flow cytometry analysis of cells extracted from ovarian tumors, spleens and peritoneal washes. AZD1480 treatment significantly reduced primary ovarian tumor growth in transgenic mice. Microarray analysis showed changes in expression of genes involved in the acute immune response, such as Gbp6, Ifi44, Irgm, Igtp, Gzmb and Cd69. Analysis of immune cell populations by flow cytometry showed a significant decrease in the number and percent of T helper and T regulatory cells present in the peritoneal cavity of drug-treated mice compared to controls. As T regulatory cells are associated with a poor prognosis in ovarian cancer patients, the decrease of this subpopulation in drug-treated mice suggests a change in the tumor microenvironment that may contribute to reduced tumor growth. Taken together, these results indicate that targeting JAK2/STAT3 impedes ovarian tumor growth through complex mechanisms, including the reduction of primary tumor growth and inflammation in the tumor microenvironment. These findings highlight the potential utility of targeting the JAK2/STAT3 pathway for the treatment of ovarian cancer patients. Citation Format: Galina Gritsina, Fang Xiao, Shane W. O'Brien, Marisa A. Maglaty, Ren-Huan Xu, Luis J. Sigal, Samuel Litwin, Denise C. Connolly. Targeting the JAK2/STAT3 pathway in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1113. doi:10.1158/1538-7445.AM2014-1113