Phd in MOLECULAR MEDICINE

Thesis title: NOTCH3 INHIBITION IN THE DEVELOPMENT OF NEW COMBINED THERAPEUTIC STRATEGIES

Since cancer is the second cause of death after cardiovascular diseases around the world, adequate and effective treatments are required, especially because every cancer type is different. To date, the common treatment modalities used are surgery, radiotherapy or chemotherapy but they are often unsuccessful. Therefore, the study of the molecular pathways which are mainly involved in tumor initiation and progression may contribute to the development of more effective targeted therapy. Among them, the Notch signaling pathway, which comprises four evolutionary conserved single-pass transmembrane proteins, is involved in the regulation of the balance between cell proliferation and apoptosis during embryogenesis and in adult tissues. Given its pleiotropic effects, Notch signaling aberration, deriving from mutations or genetic alterations, has been confirmed in the context of various tumor types, where often correlates with the patients prognosis. Despite some Notch inhibitors are clinically used in different cancer contexts, they did not give significant responses and cures, also due to the known adverse effects deriving from monotherapy. However, it has been demonstrated that they are very useful in combination with current available treatment modalities, including chemotherapy, radiation and/or other pathways inhibitors, particularly for the additive or synergic effects resulting from the combination therapy. Additionally, considering Notch pathway implication in the acquisition of tumor resistance, Notch inhibitors can re-sensitised the drug-resistant cancers to common therapies. Thus, the “Notch- combination therapy” may be considered a promising therapeutic strategy. The main objective of this work is to dissect the advantages of the combination therapy based on the inhibition of the Notch3 pathway, in order to display how its modulation could be productive and beneficial to cancer-bearing patients. In the article exposed at Chapter 1, we observed how Notch3 inhibition in T-ALLs can be used to amplify the anti-tumour effect of the associated treatment and to decrease the potentially toxic effects deriving from the higher doses associated with both monotherapies. In both Chapter 2 and Chapter 3 we proposed the Notch3 inhibition as a potential approach for overcoming drug resistance. Thus, these projects highlight the Notch pathway, and specifically the Notch3 pathway, as a crucial drug target in the development of new combination therapeutic approaches.