Abstract NT-106: PIN1: A PROMISING TARGET FOR PLATINUM-RESISTANT HIGH GRADE SEROUS OVARIAN CANCER

Abstract

Abstract Epithelial ovarian cancer is the leading cause of death in gynaecological cancers in developed countries and the fifth most common cause of cancer mortality in women. High-grade serous epithelial ovarian cancer (HGS-EOC) is derived from the surface of the ovary and/or the distal fallopian tube: the relative contribution to the EOC remains to be determined. Currently, debulking surgery and chemotherapy are the standard therapy in ovarian cancer treatment. Evidence from different clinical trials established the paclitaxel and carboplatin combination regimen as the first-line chemotherapeutic treatment, although resistance occurs. Pin1, a peptidyl prolyl cis-trans isomerase, which controls different oncogenes and tumor suppressor genes, is overexpressed in about fifty percent of HGS-EOC suggesting that it may be a potential therapeutic target. Although many efforts have been dedicated to the development of Pin1 inhibitors, up to now a few are effective on cancer cells or in vivo mouse models. Our group recently published the first liposomal formulation of a potent and specific Pin1 inhibitor, which successfully constrains tumor growth in a mouse model of ovarian cancer. We demonstrated the involvement of Pin1 in HGS-EOC showing that it is overexpressed in ovarian cancer tissue samples and when genetically or chemically inhibited, promotes ovarian cancer cell death in vitro and in vivo (PMID: 29746956). Spheroids derived from SKOV3 cell line were utilized to better reproduce the spreading of cancer cells from ascitic fluids to secondary sites. After Pin1 chemical inhibition, the cells fail to form spheroids or spheroid growth and migration. Since platinum-resistance occurs in almost all HGS-EOC patients, we investigated the role of Pin1 as effective advanced therapy in 2D and 3D in vitro systems. In literature, it is reported that the genetic inhibition of Pin1 synergizes with cisplatin in cervical cancer. Our preliminary data showed that chemical or shRNAs inhibition of Pin1 in HGS- EOC cell lines sensitize the cells to carboplatin. To investigate which molecular pathways are involved, different key cancer proteins were examined. Pin1 affects PI3K/Akt pathway, by decreasing the expression of activated Akt protein, a key regulator of cancer cell proliferation, migration and survival. In conclusion, we propose Pin1 as promising targeted therapy of HGS-EOC patients with platinum-resistance. Citation Format: Concetta Russo Spena, Lucia De Stefano, Barbara Salis, Carlotta Granchi, Maguie El Boustani, Stefano Palazzolo, Nayla Mouawad, Tiziano Tuccinardi, Vincenzo Canzonieri, Isabella Caligiuri, Flavio Rizzolio. PIN1: A PROMISING TARGET FOR PLATINUM-RESISTANT HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-106.