New Targeted Molecules for the Therapy of Ovarian Cancer

Patients with high-grade serous ovarian cancer (HGSOC), the most aggressive epithelial ovarian cancer (EOC) subtype, have a 5-year survival rate of about 93% when diagnosed at an early stage, but it drops to 30-40% when diagnosed in the advanced stage. HGSOC aggressiveness is mainly caused by the late diagnosis (51% stage III, 29% stage IV) when the tumor has already spread in the peritoneal cavity. PIN1 is a unique peptidyl-prolyl isomerase that targets the phosphorylated Ser/Thr(Pro) motifs to regulate several key proteins in different signaling pathways. Pin1 is overexpressed in several cancer types and it regulates more than 40 oncogenes and 20 tumor suppressors. Many functions are modulated through PIN1-mediated isomerization such as cell cycle progression, cellular proliferation, invasion, migration, and apoptosis. Downregulation of Pin1 decreases tumor progression. Recently, Pin1 was shown to be overexpressed in ovarian cancer (OC) which, together with the high number of interactions with other proteins, makes Pin1 a promising target for HGSOC. The aim of this work is to investigate the effects of the PIN1 inhibitor VS10 on cancer cell lines and to find the molecular signaling pathways in which Pin1 is involved. Migration, mesothelial clearance assay, and the effects on spheroid formation and preformed spheroids were studied to better understand the effects on the metastatic process. Furthermore, in order to clarify the molecular mechanism that triggers the cytotoxicity induced by Pin1 inhibition in several OC cell lines, silencing Pin1 has been demonstrated to be associated with Ser473pAkt dephosphorylation by Western Blot (WB) analysis. Additionally, cell viability and colony-forming assays showed that Akt overexpression rescued the lethal phenotype due to Pin1 knockdown in OVCAR3 and KURAMOCHI OC cell lines. Among PIN1 inhibitors, All-trans retinoic acid (ATRA), a drug in clinic for the treatment of acute promyelocytic leukemia, has been demonstrated to be active on PIN1. Our group developed many PIN1 inhibitors including VS10, a non-covalent and selective molecule, which is active in killing cancer cells. ATRA and VS10 have been combined with first- and second-line chemotherapy drugs to treat SKOV3 cell line whether these drug combinations could work synergistically to improve current therapy. This drug combination screening showed that Doxorubicin and Caelyx act in synergy with both VS10 and ATRA. This drug combination was studied in 5 sensible and 2 OC cell lines resistant to cisplatin treatment. These results candidate Pin1 as a promising new molecular target for HGSOC patients' therapy.