Dottorato in MEDICINA MOLECOLARE

Titolo della tesi: Molecular dissection of Notch3-Pin1 cross-talk to overcome Platinum resistance in Ovarian Cancer

Ovarian Cancer (OC) is one of the most lethal gynecological malignancies as acquired resistance to standard Platinum (PT)-based therapies frequently occurs. Notably, an increasing number of studies proved that Notch3 receptor is altered in a wide panel of OC and it confers Platinum resistance to OC cell lines. Therefore, effective targeting of Notch3 may restore Platinum sensitivity. A growing body of evidence sustains a pivotal role of Post-Translational Modifications (PTMs) in regulating protein function as they may influence protein activity and stability. Therefore, the exploitation of Notch receptors PTMs is emerging as a novel therapy approach, as it allows the identification of potential Notch interactors regulating its function. In this scenario, we previously demonstrated that the peptidyl- prolyl cis/trans isomerase Pin1 positively regulates Notch3 protein expression in T-cell acute lymphoblastic leukaemia (T-ALL), by binding specific phosphorylated residues. In the present study we wondered whether and how Pin1-Notch3 cross-talk might occur also in ovarian cancer context. Collectively, the main aims of the present project are: 1. to investigate the relevance of Pin1-N3 axis targeting in the response to Platinum therapies; 2. to dissect the key molecular oncogenic mechanisms involved in Pin1/Notch3 cross-talk by focusing our attention on the “less known” Notch3 PTMs potentially related to other Notch3-regulators activities. Therefore, investigate the potential relevance of Pin1/Notch3 cross-talk could allow the escape from this regulation process in the OC context. Targeting Pin1 can influence Notch-dependent OC behavior by maximizing the efficacy of platinum-based therapies in order to restore chemo- sensitivity and reduce tumor spread. The final goal of this project is the possibility to exploit this relationship to develop a new therapeutic strategy for the treatment of Notch3 overexpressing tumors which rely on Notch3 protein function to survive and spread to the secondary organ.