Abstract B70: Akt-activated endothelium constitute a niche for residual disease and resistance to bevacizumab in ovarian cancer
Authors: Bella S. Guerrouahen, Jennifer Pasquier, Nadine Abu Kaoud, Marie-Claude Beauchamp, Pegah Ghiabi, Mahtab Maleki, Raphael Lis, Ahmed Saleh, Walter H. Gotlieb, Shahin Rafii, Arash Rafii
Journal: Clinical Cancer Research (2013)

Abstract Background. Ovarian cancer is the second leading cause of cancer-related death in women worldwide. Despite optimal cytoreduction and adequate adjuvant therapy, initial tumor response is often followed by relapse. Targeted therapies have been evaluated in ovarian cancer to overcome resistant disease. Among them anti-angiogenic therapies inhibit new blood vessel growth, induce endothelial cell apoptosis, and block the incorporation of haematopoietic and endothelial progenitor cells into new blood vessels. Despite in-vitro and in vivo successes anti-vascular therapy with bevacizumab targeting VEGF has limited efficacy in ovarian cancer. Anti-angiogenic treatment increases hypoxia, and might lead to tumor rebound and drug resistance. The precise molecular mechanisms underlying clinical resistance to anti-VEGF therapies are not well understood. Hypothesis. We hypothesized that abnormalities in the tumor endothelium may contribute to treatment resistance and produce and promote a residual microscopic disease and resistance to bevacizumab. Methods. We showed that Akt pathway is activated in vitro and in vivo in ovarian cancer endothelium. We used Akt-activated endothelial cells (EC) that replicate tumor endothelium biology, and their control, HUVEC to investigate the anti-angiogenic activity of bevacizumab by angiogenesis and migration assays. We conducted XTT assay to examine the effect of bevacizumab on proliferation of VEGF producing human ovarian cancer cell lines. Expression of FGF-2, phospho-AKT was assessed by western blotting and flow cytometry. Finally, using a feeder-free matrigel and spheroid models of ovarian cancer we examined the effect of bevacizumab on residual disease. Results. We demonstrated that ovarian cancer cells (OCC) activate the endothelium, which displays resistance to bevacizumab. Bevacizumab had no effect on the proliferation of Akt-activated EC, but significantly inhibited angiogenesis and delayed wound healing in HUVEC. We showed the existence of an autocrine loop based on FGF-2 secretion. We demonstrate the role of Akt-activated EC in supporting expansion and self-renewal of OCC in a residual disease context. Conclusion. Our data point out the role of an activated endothelium in the constitution of the residual disease and resistance to bevacizumab. Citation Format: Bella S. Guerrouahen, Jennifer Pasquier, Nadine Abu Kaoud, Marie-Claude Beauchamp, Pegah Ghiabi, Mahtab Maleki, Raphael Lis, Ahmed Saleh, Walter H. Gotlieb, Shahin Rafii, Arash Rafii. Akt-activated endothelium constitute a niche for residual disease and resistance to bevacizumab in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B70.