Abstract 3587: Developing targeted therapy for the treatment of drug-resistant ovarian cancer

Abstract

Abstract Despite therapeutic approaches that combine surgical cytoreduction with chemotherapy, ovarian cancer remains the principal cause of death among women with gynecological malignancies. Virtually all patients relapse with drug-resistant disease. To elucidate the biological mechanisms that contribute to this resistance, we established a repository of patient-derived xenograft (PDX) models of ovarian cancer in mice. We used RNA-seq and Ingenuity Canonical Pathway software to analyze chemotherapy induced changes in expression patterns of six of these models. We found that the sphingosine-1-phosphate (S1P) signaling pathway is one of the pathways most affected by paclitaxel and cisplatin treatment, with altered expression in seven genes associated with the S1P pathway (p<0.05). The biologically active lipid S1P contributes to cell growth, survival/apoptosis, angiogenesis, migration and metastasis in normal and tumor tissue. The S1P pathway has also been reported to be involved in chemoresistance in several types of solid tumors. The S1P pathway depends predominately on three core lipids: ceramide, sphingosine, and S1P. These molecules are termed the ceramide-sphingosine-S1P rheostat, and their expression is tightly regulated both intra- and extra-cellularly. Recent studies suggest a correlation between aberrations in the S1P pathway and poor prognosis, advanced stage, and resistance to chemotherapy and radiation. Preliminary data using the sphingosine analog FTY-720 is consistent with the hypothesis that the S1P pathway regulates cell survival by effecting changes in the relative levels of ceramide, sphingosine, and S1P, as a cytoprotective autophagic mechanism to evade chemotherapy-induced cytotoxic effects. Cell proliferation assays, immunoblots, and fluorescence microscopy results of ovarian cancer cells exposed to FTY-720 in combination with carboplatin or paclitaxel treatment provide evidence that the S1P pathway may evade cell death through the induction of cytoprotective autophagy. Our data suggest that the S1P pathway contributes to the chemoresistance of ovarian cancer cells to conventional chemotherapeutic agents. Citation Format: Kelly M. Kreitzburg, Zacchary Dobbins, Ashwini Katre, Tooba Anwer, Ronald Alvarez, Charles N. Landen, Karina J. Yoon. Developing targeted therapy for the treatment of drug-resistant ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3587. doi:10.1158/1538-7445.AM2015-3587