Abstract 2999: Interleukin-8 mediates resistance to anti-VEGF therapy in ovarian cancer

Purpose: Vascular endothelial growth factor (VEGF) families of ligands and receptors are primary signaling pathways in tumor angiogenesis and have been extensively targeted by cancer therapeutics. Ovarian tumors are highly vascularized and high degrees of tumor angiogenesis and VEGF expression in ovarian carcinomas correlate with poorer survival. Encouraging results have been obtained with trials in ovarian cancer that target the VEGF and its receptor. However, the clinical benefits are short-lived, followed by a restoration of tumor progression. Understanding the mechanisms of tumor escape from anti-VEGF therapy is critical to find strategies to overcome the resistance. The purpose of this study was to investigate the potential targets of ovarian cancer resistance to anti-VEGF treatments using experimental phenotypic resistance models. Methods: We generated SKOV3 ovarian cancer xenograft in athymic nude mice and treated with sorafenib (10 mg/kg daily, PO) or bevacizumab (10 mg/kg BIW, IP) over an 8-week period. Treatment-resistance tumors were defined by a long-term trend toward continued tumor progression (> 50% increase from the initial volume) under bevacizumab or sorafenib treatment after an initial response whereas treatment-sensitive tumors were defined by a long-term trend toward stable disease or regression. We performed mouse and human angiogenesis multiplex assay to identify the soluble factor differences in the plasma of resistant and sensitive mice. To examine the role of IL-8 mediated resistance, we disrupted IL-8 function of SKOV3 and HUVEC using pharmacological inhibitors (e.g., anti-IL-8 antibody or IL-8 receptor CXCR2 inhibitor) for in vitro assays of cell growth inhibition, spheroid formation, and cell migration. Further, we evaluated the effectiveness of sorafenib and SB 225002 combination in vivo in SKOV3 xenograft mice. CXCR2 expression was evaluated in human ovarian cancer tissue micro array (TMA). Results: In both sorafenib and bevacizumab resistant mice, IL-8 levels were elevated by 2 to 4 folds compared to their respective sensitive treatment groups in a time-dependent manner. Growth inhibition was significantly higher in SKOV3 (32%, P = 0.002) and HUVEC (25%, P = 0.015) cells when treated with a CXCR2 inhibitor SB 225002 (2 µM) and sorafenib (4 µM) compared to sorafenib alone. SB 225002 (2 µM) disrupted the spheroid formation in SKOV3 cells. SB 225002 and sorafenib combination treatment resulted in 40% less migration of SKOV3 cells when compared to treatment with sorafenib alone. Conclusion: Our results suggest that IL-8 may serve as an important target for sorafenib and bevacizumab resistance in ovarian cancer and disruption of IL-8 activity via CXCR2 inhibition could improve outcomes of anti-VEGF therapy. Citation Format: Bharat Kumar Devapatla, Ankur Sharma, Sukyung Woo. Interleukin-8 mediates resistance to anti-VEGF therapy in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2999. doi:10.1158/1538-7445.AM2014-2999