Abstract
Abstract Vascular Endothelial Growth Factor (VEGFA/VEGFC) are over-expressed and secreted in large amount in epithelial ovarian cancer (EOC) (Maneneti et al, 2013; Decio et al, 2013). Cediranib, a potent inhibitor of VEGF receptor tyrosine kinases has recently shown to improve PFS and OS in women with recurrent platinum sensitive ovarian cancer (ICON6 trial). The aim of this study was to investigate the efficacy of cediranib (AZD2171; AstraZeneca, Alderley Park, Macclesfield, UK) on a platform of patient derived human ovarian carcinoma xenografts (EOC-PDX; n=12), which recapitulates the histopathological and fundamental genetic diversity of the patient tumors and the pharmacological heterogeneity of this type of cancer. The efficacy of cediranib alone and in combination with the-standard-of-care chemotherapy for ovarian cancer (platinum, DDP and paclitaxel, PTX) was investigated on EOC-PDX growing orthotopically and disseminating in the peritoneal cavity of nude mice. Tumor progression (tumor dissemination; soluble VEGFR) and overall survival were investigated. The response of EOC-PDX to cediranib was heterogeneous with some tumors being extremely sensitive, other marginally responsive to the treatment (ILS from 12% to 85%); the length of response depended on the duration of the treatment. Cediranib was significantly active also on advanced stage tumor. Cediranib added to DDP based therapy improved the response to chemotherapy treatment without increase of toxicity; the sensitivity of the EOC-PDX to DDP (platinum sensitive vs. platinum resistant) determined the final outcome. The histopathological analysis at the end of treatment (interim) shows that the combination affected the spread of solid tumor into the peritoneal cavity and ascites formation. The combination of cediranib with combined chemotherapy (DDP/PTX) was studied on one EOC-PDX platinum responsive. The addition of cediranib to DDP/PTX marginally increased the survival of the mice compared to chemotherapy; cediranib continued after chemotherapy (maintenance regimen for 60 days) significantly improved the survival of the mice, with 70% tumor free at the end of the treatment. These results show that the response to cediranib of EOC-PDX reflects the behavior in patients. The heterogeneous response of EOC-PDX to cediranib warrants further studies for better understanding the mechanism of response /resistance to this type of treatment. AD is a fellow of the Italian Foundation for Cancer Research (FIRC). Citation Format: Alessandra Decio, Marta Cesca, Francesca Bizzaro, Dorina Belotti, Raffaella Giavazzi. Cediranib affects tumor progression and survival of mice bearing patient derived ovarian carcinoma xenografts (EOC-PDX). [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 2994. doi:10.1158/1538-7445.AM2014-2994
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