Being correlated to aged men, the PCa disease, beside leading to lethal consequences, is able to negatively affect the quality of life on a man in his final years. Being a complex disease, it must be fight throughout a multidisciplinary approach able both to effectively cure the disease itself, increasing the life expectance, and to creating the social conditions for its early diagnosis its prevention. This project is directed to the identification of proof-of-concept for the early diagnosis and cure of Prostatic Cancer, both in its early appaerance as well as in the CRPC form.
Inside the project, we identify few key directions to follow:
1) Development of innovative approaches to target CRPC (Targeting AKR1C3). In CPRC, one of the most effective acquired drug resistance mechanisms is the overexpression of aldo-keto reductase 1C3 (AKR1C3, also named 17?-hydroxysteroid dehydrogenase type 5). AKR1C3 plays a pivotal role in the biosynthesis of androgens inside the so called backdoor pathway, catalysing the conversion of the weak androgen precursors 4-androstene-3,17-dione (?4-AD) and 5?-androstane-3,17-dione to the potent androgens T and DHT. This allows the tumor cells to divert trace androgens that remains after ADT to potent androgens within the tumor. The central role of AKR1C3 in androgen biosynthesis and its up-regulation measured after ADT and abiraterone treatment in tumor cells, made this enzyme an attractive target for CPRC therapy. Although AKR1C3 has already been validated, using a range of approaches including siRNA and small molecule inhibitors, no AKR1C3-targeted agent has been approved for clinical use yet.
2) Eradication of PCa by targeting the androgen axis as well as other tumorigenic mechanisms (Targeting NFkB). Rel/NF-?B transcription factors are key regulators of genes implicated in inflammatory and ?immune activation, cell growth and protection from apoptosis?. NF-?B, inducing prosurvival genes (Bcl-2 and Bcl-xL), pro-inflammatory cytokines, interleukin-6 and -8, growth factors, urokinase-type plasminogen activator (uPA), uPA receptor and matrix metalloproteinase- 9 (MMP- 9), stimulate the tumor growth, angiogenesis, invasiveness and metastasis. Quite recently, NF-?B has being suggested as critical factor involved in PCa development and progression to metastatic androgen-independent phenotype. Moreover, NF- ?B pathway is a potential target for CRPC treatment.
3) Design innovative early diagnosis tools for PCa. The deep study the biochemical pathways involved the evolution of PC to CRPC will the possibility design biochemical early diagnose tools of the tumor evolution. Inside all 24 months project, the drug discovery affords will be supported a deep study the biochemical pathways involved both inside the PCa first appearance as well as to its evolution to CRPC. Beside guarantee all the in vitro and in vitro evaluation of the designed compound, this task is quite important because here we will look for occasion of investigate the possibility of design biochemically tool for the early diagnose of the tumor appearance as well as evolution to CRPC.