Novel potential treatments in the challenging scenario of drug resistance in pancreatic ductal adenocarcinoma

According to the prediction of the Global Cancer Observatory (GCO), an interactive web platform that presents global cancer statistics, pancreatic ductal adenocarcinoma (PDAC) will be second cause of death in Western societies within the next decade. To date, the overall survival of patients at 5 years after diagnosis is only 6%, and 25% in patients undergoing surgical resection, but these represent only 15% of total cases. These data emphasize the need to find new effective drug treatments. Indeed, current therapeutic approaches have great limitations such as chemoresistance, both innate and acquired after the treatment, lack of biomarkers for prediction of therapy response, and intrinsic toxicity of chemotherapeutic agents that causes several side effects. In this thesis highlights two novel anticancer agents that could be used for the treatment of particularly resistant PDAC tumors: gemcitabine molecules capable of releasing nitric oxide (NO-GEMs) and selective and reversible benzylpiperidine-based MAGL inhibitors. The first ones act on mechanisms of direct resistance to GEM by increasing its concentration inside the cells through the use of NO; the second ones, act at the level of lipid metabolism by preventing the formation of signal molecules. The use of MAGL inhibitors has been further studied and are proposed to may be use as target therapy to treat PDAC patients with GOF mutant p53 R273H.