Identification and validation of novel prostate cancer targets for the development of original pharmacological approaches

Prostate cancer has recently been classified as the second most frequently diagnosed malignancy among men and the fifth leading cause of cancer-associated death worldwide. Although the 5-year survival rate for patients diagnosed with localized and regional prostate cancer is almost 100%, metastatic and castration-resistant prostate cancers are currently difficult to treat. Therefore, there is an urgent need to develop new tools for prognostic patients’ stratification and novel pharmacological strategies. While pathological, surgical and biochemical prognostic factors are useful tools for risk stratification, novel biomarkers are required to improve the reliability of these conventional determinants. In this setting, next-generation sequencing revealed the existence of many genetic alterations and allowed the development of novel prognostic markers. For instance, the loss of the tumor suppressor gene PTEN has been identified as crucial to the disease progression, while further genomic aberrations can accelerate carcinogenesis, increase the aggressiveness and promote the onset of resistant phenotypes. The aim of this project is the identification of new genetic targets capable to affect prostate cancer progression and therefore potentially targetable with existing or innovative pharmacological strategies. To this end, RNA-sequencing and polysome profiling analysis has been performed on prostate specimens isolated from five different genetically engineered mouse models of prostate cancer. Next, bioinformatic analyses have been carried out to select metabolic genes differentially expressed at polysomal level in all the mouse models tested. Ten metabolism-related gene candidates have been identified and, among them, six have been found upregulated in prostate cancer. Within the three top-ranked upregulated genes, TARGET1 has been selected. Interestingly, by evaluating different available datasets, TARGET1 has been found to be frequently amplified at the gene level and overexpressed in both primary prostate and metastatic tumors. Lastly, to assess the clinical relevance of TARGET1 cognate protein, its expression has been immunohistochemically evaluated in a large well-annotated human cohort of FFPE prostate cancer samples. Consistently, immunohistochemical analysis showed that, despite the heterogeneity in TARGET1 immunostaining intensity among the samples, TARGET1 is strongly expressed in higher Gleason prostate adenocarcinomas. In conclusion, this multidisciplinary and translational approach has allowed the identification of one novel gene candidate potentially compatible with the role of oncogene. These promising, but still preliminary results, will be further validated in in vivo and in vitro models, while the generation of a novel PTENpc-/-;TARGET1pc-/- mouse model of prostate cancer will pave the way for the discovery of original therapeutic approaches.