Abstract
High grade serous ovarian cancer remains deadly for countless women; therefore, better treatment options are necessary. To identify new targeted therapies for this disease, it is necessary to delineate critical signaling pathways that are driving the pathogenesis of ovarian cancer. Since ovarian cancer in patients grows as three dimensional clusters, particularly within the peritoneum, we examined signaling pathways that were activated with 3D culture in vitro. Comparing the growth of ovarian cancer cell lines in 2D and 3D, we found that the transcription factor STAT3 consistently becomes activated in 3D culture systems. Ovarian cancer cells that lack STAT3 activation when grown in 2D acquire STAT3 activation when grown in 3D. Additionally, ovarian cancer cell lines that have constitutively active STAT3 when grown in 2D display enhanced STAT3 activation when these cells are grown in 3D. STAT3 is often activated through autocrine or paracrine mechanisms via cytokine receptors interacting with the transmembrane signal transducing molecule GP130 and intracellular Jak kinases. Once activated, these kinases tyrosine phosphorylate STAT3, which then translocates to the nucleus, binds to cognate DNA binding sites, and regulates genes that are involved in migration, invasion, and survival. We have found that not only is STAT3 tyrosine phosphorylated in cells grown in 3D, but that STAT3 is functionally active such that STAT3 DNA binding and target gene expression is enhanced in ovarian cancer cells grown in 3D versus 2D. We next determined if STAT3 signaling was necessary for ovarian cancer cell growth in 3D. Using RNA interference directed to STAT3 or GP130, we found that both proteins are necessary for the 3D growth of ovarian cancer cells. In addition, we have found that cells grown in 3D are more resistant to cytotoxic drugs; therefore, we wanted to determine if inhibiting STAT3 would enhance the response to conventional chemotherapy. Using both chemical biology and computational approaches, we have identified small molecule inhibitors of STAT3 that target a number of distinct points in the STAT3 activation pathway. We have found that a subset of these compounds disrupt the morphology of ovarian cancer spheroids. Furthermore, combination of these inhibitors with paclitaxel leads to enhanced loss of viability of cells grown in 3D, raising the possibility of using STAT3 inhibitors alone or in combination with chemotherapeutic drugs for the treatment of ovarian cancer.
Citation Format: Sarah R. Walker, Yixi Zhang, Suhu Liu, Zachary T. Giaccone, and David A. Frank. TARGETING COMPONENTS OF THE STAT3 SIGNALING PATHWAY FOR OVARIAN CANCER THERAPY: IMPLICATIONS FROM 3D CULTURE SYSTEMS [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-111.
