Epithelial Ovarian cancer (EOC) is a rare but highly letal disease, as acquired resistance to standard Platinum (PT)-based therapies occurs frequently and predicts poor prognosis. Recurrent resistant EOCs almost grow as metastatic disease commonly involving peritoneum, omentum and secondary organs located in the abdominal cavity. In this scenario, elucidating which pathways are involved in EOC aggressive behaviour becomes a paramount issue in order to improve PT-response, which is still a great challenge. Notch signaling is frequently activated in OC and contributes to tumor formation and angiogenesis in xenograft models. In particular, Notch3 activation is frequently associated with OC progression, tumor invasion and metastasis, thus suggesting its potential involvement in PT-resistance. Both chemoresistance and tumor dissemination have been linked to the Epithelial-mesenchymal transition (EMT) process as well as to the cancer stem cell (CSC)-like phenotype acquisition. It has been demonstrated that Notch3 significantly interferes both with the EMT regulation and the metastatic capacity of malignant cells in OC. This suggests that Notch3 may represent both a prognostic marker and a therapeutic target that can be exploited to improve PT
efficacy in EOC patients.
We have shown that the prolyl-isomerase Pin1 positively regulates Notch3 protein in T-cell acute lymphoblastic leukemia and we hypothesized to observe the same relationship also in OC context. Therefore, the main aim of the proposed research is to broaden our knowledge of the role of Notch3 in EOC metastasis and chemotherapy resistance, focusing our attention on its function and regulation by Pin1 isomerase. Evaluating how Pin1 inhibition affects Notch3-dependent EOC behavior may aid in developing novel therapeutic strategies to restore chemo-sensitivity and reduce the incidence of metastasis.
