Abstract 1714: Chemoresistance in patients with papillary serous carcinoma of the ovary

Abstract

Abstract The majority of patients with ovarian carcinoma present at an advanced stage, with metastatic disease throughout the peritoneal cavity. Therefore, patients commonly undergo platinum-based chemotherapy. Even though the initial response rates can be high, the majority of patients will have recurrent disease and the 5-year survival rate is only 10-20%. The human lung resistance protein (LRP) is a multidrug resistance protein that has been shown to be overexpressed in models of chemotherapy resistance, but has not been adequately explored in platinum-resistant epithelial ovarian cancer (EOC). The primary aim of this study was to compare LRP expression in the tumor cells from ascitic fluid with tumor cells from omental metastasis in chemotherapy-naïve patients with advanced EOC. The secondary aim was to explore possible mechanisms in which LRP might cause drug resistance. After IRB approval, patient ascites and metastatic implants were collected and evaluated for platinum sensitivity and expression of LRP, phospho-ERK, and AKT using western blots and immunohistochemistry (IHC). Both ascites and omental metastatic implants were treated with 50 uM carboplatin for 48 hours and cell viability was analyzed. LRP, phospho-ERK, and AKT were analyzed using IHC on samples treated with 50 uM carboplatin or phosphate buffered saline. Of 20 patients who had matched ascites and omental metastatic implants adequate for analysis, 4 were platinum resistant, 3 were platinum sensitive, and 13 displayed intermediate platinum sensitivity. Overall, the malignant cells in ascites were more resistant to carboplatin than the metastatic implants (p=0.001) and the malignant cells in ascites showed higher expression of LRP than the omental metastatic implants by IHC and western blotting. IHC and western blotting also demonstrated that the malignant cells in ascites had lower expression of phospho-ERK and higher expression of AKT than the metastatic implants. After treatment with 50 uM carboplatin, the platinum resistant patients had decrease in phospho-ERK and an increase in AKT versus the platinum sensitive patients who had an increase in phopho-ERK and a decrease in AKT and LRP. High expression of LRP in the tumor cells in ascitic fluid may indicate platinum resistance prior to initiation of platinum-based chemotherapy. Also, changes in phospho-ERK and AKT following platinum based therapy may indicate the extent of response of EOC to this therapy. Supported in part by the Kaleidoscope of Hope ovarian cancer foundation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1714. doi:10.1158/1538-7445.AM2011-1714