Characterization of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel pharmacological target in ovarian cancer

Ovarian cancer (OC) is one of the most lethal cancers worldwide. Currently, OC treatment is limited to surgery and systemic chemotherapy but about 80% of patients develop disease relapse and treatment resistance. Despite research advances, the mechanisms underlying OC recurrence and chemotherapy resistance are still unclear; thus, new insights are needed in order to identify the patients with higher risk of recurrence and set-up more personalized therapeutic strategies. Nicotinamide phosphoribosyltransferase (NAMPT) possesses a vital role in mammalian cells due to its activity as a rate-limiting enzyme in the biosynthesis of NAD from nicotinamide. Beside its intracellular functions, the extracellular NAMPT (eNAMPT) secreted outside of the cell exerts cytokine-like functions and mediates pro-inflammatory conditions activating signaling pathways and showing a key role in cancer. Given its involvement in several tumor cellular processes, including DNA repair, gene expression, signaling pathways, proliferation, invasion, stemness, phenotype plasticity, metastatization, angiogenesis, immune regulation, and drug resistance, eNAMPT targeting is emerging as a promising anti-cancer strategy. However, its contribution in OC is poorly characterized, leaving many questions unanswered. In this context, the present project aims to investigate the possibility to pharmacologically target eNAMPT. Initially the project will investigate the pathological role of eNAMPT in OC with the hypothesis that this cytokine is responsible for reprogramming of cancer cells toward a more aggressive and invasive phenotype, modulating EMT and stemness and increasing metastasis formation. Subsequently, a selective anti-eNAMPT monoclonal antibody will be used to restore the eNAMPT physiological level. To evaluate the feasibility of the project, eNAMPT was preliminarly evaluated in ascitic fluid of OC patients, highlighting high levels of the protein; this also suggests that ascites - which is produced in large volumes in OC - is particularly enriched in eNAMPT, and that it is an excellent biological source to elucidate the role of eNAMPT. To achieve the described goals, the project will be divided in four interrelated specific working packages (WPs). WP1 will analyze NAMPT levels in biological samples from OC patients, evaluating their association with clinical features, prognosis and therapy response. Integration of the results with radiomics will allow to develop a prognostic/predictive model. WP2 will analyze the functional role of eNAMPT in OC through 2D and 3D in vitro models. WP3 will evaluate the functional role of eNAMPT in OC through in vivo models. WP4 will test the potential use of C269, the anti-eNAMPT neutralizing antibody developed by RU2, in in vitro and in vivo models. The final goals of the project are to evaluate eNAMPT as a new player in OC recurrence and chemotherapy resistance and to evaluate if it may represent a new therapeutic target in OC.