ATeNA - Technological Applications of New Antineoplastic

In the last two decades the possibility of altering the functionality of the ubiquitin-proteasome system (UPS) has aroused much interest in oncology research and for the drug development strategies of Biotech companies. The UPS is a system dedicated to protein degradation; the neoplastic cells are very dependent on it because, accumulating mutations, they produce altered proteins that must be rapidly degraded. Inhibition of UPS, through the induction of a proteotoxic stress, results in the death of neoplastic cells. Bortezomib and carfilzomib are two first-generation UPS inhibitors, used clinically for the treatment of multiple myeloma and mantle cell lymphoma. These inhibitors, although having not shown benefits in the treatment of solid tumors, have stimulated the interest of companies and research groups to identify new UPS inhibitors. The global R&D market for UPS in 2013 was estimated at 2.9 billion dollars with a forecast for 2018 of 5.5 billion. The ATeNA project aims, in a multidisciplinary perspective, to evaluate the therapeutic potential of a new lead compound, 2cPE, capable of inhibiting the UPS and inducing proteotoxic stress. 2cPE is an inhibitor of isopeptidases, enzymes components of UPS. ATeNA will focus on ovarian cancer studies, which represent 5% of neoplasms and a challenge that is still unresolved for both diagnosis and treatment. Surgical removal associated with systemic chemotherapy does not achieve good results and the prognosis is often poor. In this context, new therapeutic approaches based both on the use of new molecules and innovative delivery tools are urgently required. A further need is also to have effective and rapid tools for evaluating therapeutic benefits. The multidisciplinary nature of ATeNA guarantees an integrated and innovative approach by supplying the antineoplastic associated with its effectiveness markers. The UNIUD beneficiary, in collaboration with the UNITS beneficiary, identified the isopeptidase inhibitor and the same was suitably modified as a pro-drug for in vivo use. Early pre-clinical studies in animal models have shown low toxicity and confirmed the anti-neoplastic action. With ATeNA it will be possible to generate more powerful versions of 2cPE, improve delivery, characterize mechanisms of action, identify prognostic markers to better target in vivo studies and initiate an evaluation of the efficacy of 2cPEon ovarian cancer, directly using the cells of the patients.