angelica mancusi

PhD Graduate

PhD program:: XXXV


supervisor: saula checquolo
advisor: saula checquolo
co-supervisor: isabella screpanti

Thesis title: 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.

Research products

Connessione ad iris non disponibile

© Università degli Studi di Roma "La Sapienza" - Piazzale Aldo Moro 5, 00185 Roma