Abstract 801: Comparison of cisplatin induced changes in serous ovarian cancer and normal fallopian tube cells

Abstract

Abstract Platinum drugs are the most active agents for treatment of ovarian cancer. While most patients initially respond to this treatment, the majority eventually become resistant and ultimately succumb to the disease. Despite much investigation, in vitro elucidated mechanisms of platinum resistance have not correlated with those involved in clinical chemoresistance. Traditionally, in vitro models have consisted of established ovarian cancer cell lines that have been propagated in culture for decades. Chemoresistance is then modeled by growing cells in the presence of increasing concentrations of platinum or other cytotoxic drugs. As an alternative approach, we developed primary cell lines from normal human fallopian tube epithelial cells (n=5) and serous ovarian cancers (n=15). The latter group included tumors isolated from chemo-naïve (n=9) and chemo-exposed (n=6) patients. Each primary cell line was treated with vehicle and cisplatin (50uM) for 24hrs and expression profiling was performed using Affymetrix arrays. Differentially expressed genes were identified using BRB ArrayTools (P<0.001 considered significant). The expression profiles of chemo-naïve and chemo-exposed samples were similar regardless of vehicle or cisplatin treatment. However, comparison of cisplatin and vehicle treated cells revealed robust differences between cell types with 3312 differentially expressed genes in the chemo-naiive, 6160 genes in the chemo-exposed, and 5277 genes in normal FT cells lines (all at P<0.001 cutoff). More than 1200 genes (1274) were differentially regulated in all three types of cells however; large number of genes were also uniquely altered in each cell type: normal FTs (2269), chemo-exposed (2772), and chemo-naïve (1016). After cisplatin treatment, 1975 genes showed altered expression in both chemo-naïve and chemo-exposed cells. Seven genes were selected for further investigation based on their expression pattern and known biological function. Microarray data was validated using real time RT-PCR in an independent set of cisplatin treated ovarian cancer cell lines. Expression of select targeted genes was also evaluated in the ES2 and SKOV3 ovarian cancer cells treated with increasing doses of cisplatin. All of the selected genes showed a change in expression pattern after cisplatin treatment consistent with array data. To further investigate the role of these target genes, we are testing dose response to platinum following modulating their expression using siRNA mediated knockdown and overexpression. Our investigation will provide a better understanding of genes involved in response to cisplatin in normal and ovarian cancer cells. By exploiting common and unique features of this response we hope to develop novel strategies for overcoming drug resistance and hence increased efficacy of the adjuvant chemotherapy for treatment of ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 801. doi:1538-7445.AM2012-801