All ETDs from UAB

Advisory Committee Chair

Karina J Yoon

Advisory Committee Members

Stephen G Aller

Ronald D Alvarez

Susan Bellis

Douglas Hurst

Charles N Landen

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Despite satisfactory initial responses to frontline therapies that combine tumor debulking with platinum and taxane-based chemotherapies, ovarian cancer remains the principle cause of gynecological malignancies. Drug resistance at relapse contributes to poor outcomes for women diagnosed with advanced disease and underscores the need for novel therapeutic strategies. Compelling data have implicated bioactive sphingolipids and their metabolism in the development and progression of ovarian cancer. Aberrations in sphingolipid metabolism that limit levels of the tumor suppressor lipid ceramide contribute to chemotherapy resistance. This dissertation presents work investigating the anticancer efficacy of the immunomodulatory drug FTY720. The sphingosine analog FTY720 has shown antitumor activity as a single-agent and combination therapy in several cancers by promoting apoptosis and increasing intracellular ceramide levels. Thus, we proposed that FTY720 would provide an effective means inhibit tumor cell proliferation and circumvent drug resistance in ovarian cancer cells and preclinical tumor models by increasing intracellular levels of ceramide. We firstly assessed the efficacy of FTY720 alone and in combination with carboplatin and paclitaxel chemotherapies. Our in vitro data demonstrate FTY720 sensitized drug-resistant and high-grade serous (HGS) ovarian cancer cell lines to carboplatin and paclitaxel. In vivo data show FTY270 + carboplatin induced tumor regressions of patient-derived xenograft (PDX) ovarian tumors. Tumor regressions and increases in intracellular levels of ceramide and the apoptosis marker cleaved caspase 3 occurred simultaneously. Secondly, we evaluated the efficacy of FTY720 with the ER-alpha modulator tamoxifen. In vitro data demonstrate FTY720 + tamoxifen was synergistic and sensitized drug-resistant and HGS cell lines to tamoxifen irrespective of ER-alpha expression. Further, FTY720 + tamoxifen arrested PDX tumor growth, increased levels of ceramide, cleaved caspase 3, and the cell cycle inhibitor p21 more effectively than each single agent in vivo. Lastly, we investigated combinations of FTY720 with epigenetic agents in vitro. Data show FTY720 + the histone deacetylase inhibitor vorinostat was synergistic in drug-resistant and HGS cell lines and FTY720 + the bromodomain inhibitors JQ1 or iBET-762 was synergistic in OVCAR3 and CAOV3 HGS cell lines. Our data suggest FTY720 warrants further investigation as a potential treatment strategy for ovarian cancer.

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