Role Of Epithelial To Mesenchymal Transition In Response To Cisplatin In Patient-Derived Ovarian Carcinomas

Epithelial ovarian cancer has the highest mortality rate in the western world among gynecological malignancies. Approximately 70% of patients achieve complete remission after first-line cisplatin (DDP)-based therapy, but almost all patients relapse with resistant disease. Understanding the mechanisms at the basis of the resistance to therapy is of pivotal importance and xenografts models are instrumental to address this topic. We have recently been able to stabilize a panel of ovarian cancer xenografts that represent human tumors of origin both at the histological and molecular level. Seven xenografts were characterized for their sensitivity to DDP given once a week for 3 weeks at the dose of 5 mg/kg. A second DDP cycle was given to the regrowing tumors, mimicking clinical conditions. Xenografts were classified as “Responder” (R) or “Non-Responder” (NR) on the basis of their DDP-response. Interestingly, almost all xenografts were less sensitive to the second cycle of DDP. In an attempt to study the role of genes involved in Epithelial-Mesenchymal Transition (EMT), we evaluated by RT-PCR (by the Qiagen RT 2 Profiler TM PCR Array System) in untreated and DDP-treated R and NR xenografts the expression level of 86 EMT genes. By these analysis we wanted to investigate if some EMT genes could be predictive for DDP response, and if DDP treatment could itself induced EMT genes responsible for the observed DDP resistance. 12 genes (KRT14, BMP1, JAG1, PPPDE2, TFPI2, MSN, ITGA5, ITGAV, KRT7, FGFBP1, AHNAK and ESR1) were found to be more expressed in “NR” then “R” xenografts, and few were validated (i.e. AHNAK, JAG1). To address the second point, the fold change of gene expression was considered in DDP-treated versus control samples. 8 genes (ZEB2, TGFB1, WNT5B, MST1R, COL3A1, FN1,PLEK2, FGFBP1) involved in EMT activation were found to be upregulated by the DDP treatment, and are currently under validation. These studies would suggest a predictive role of upregulation of specific EMT genes in response to DDP treatment, and possibly in the development of its resistance. The validation of these genes in patients whose clinical response to a DDP based therapy is known, will help in defining predictive markers to tailor DDP therapy in ovarian cancer patients. Citation Format: Francesca Ricci, Federica Guffanti, Fratelli Maddalena, Patrizia Perego, Robert Fruscio, Romina Baldo, Sonia Magni, Massimo Broggini, Giovanna Damia. Role of epithelial to mesenchymal transition in response to cisplatin in patient-derived ovarian carcinomas. [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 3760. doi:10.1158/1538-7445.AM2014-3760