PROSTarget · Understanding the aggressive nature and key molecular drivers of metastatic dissemination in lethal PCa.

PROSTarget: Understanding the aggressive nature and key molecular drivers of metastatic dissemination in lethal PCa.

Prostate cancer (PCa) is the most diagnosed cancer in men worldwide, with 1.5 million new cases in 2020 across 112 countries and the second leading cause of death. PCa arises from the aberrant proliferation of epithelial cells, termed prostate intraepithelial neoplasia (PIN), and is an androgen-dependent cancer type. Neoplastic cells can further alter the structure of the gland leading to the loss of basal membrane structure and the onset of invasive PCa lesions which typically metastasize to sites in the bone marrow2. While effective treatments have led to an excellent prognosis for localized PCa confined to the prostate gland (T1, T2 stage) (with nearly a 100% 5-year-survival rate3 (96.6% in 2022), metastatic and lethal PCa remains incurable. The 5-year-survival rate drops to 29%, with tumor cells invading the gland and disseminating via bloodstream (T3 stage). Patients with lethal PCa already exhibit metastases at initial diagnosis, prior to being treated with androgen-deprivation therapy (ADT), and their median survival is 42 months. Newly introduced treatment options have improved the overall survival of patients but not definitively. In particular, those patients associating ADT to mitotic inhibitors such as docetaxel as second line treatment, show encouraging but not effective results. They frequently experience disease relapse and poor outcomes due to the development of resistance to treatments. Lethal PCa frequently acquires androgen-independent (AR) features and resistance to standard therapy, gaining metastatic potential and lethality with bone metastasis development, which accounts for a large fraction of the relapse and morbidity of the disease. Despite huge efforts and advances in the therapeutic landscape, a meaningful therapeutic option for those patients is lacking and 50% of patients will die. Thus, they represent an unmet clinical need. Why is the outcome so severe in PCa? Loss of PTEN is essential for the dissemination of PCa in metastasis but additional critical events are required in this process. Emerging evidence shows that metabolic rewiring in PCa drives the metastatic cascade by the remodeling the tumor microenvironment to support survival during the invasive progression of disease. In particular, metabolic adaptations are needed after cancer cell extravasation to produce metastases that quickly arise in hostile new microenvironments. These dynamic metabolic changes which compete in the aggressive metastatic progression of PCa are poorly understood. Further research is needed to understand the impact of metabolic drivers on metastasis adaptation under selective pressure, and to design more effective therapies that tackle this lethal condition. How can we change the landscape? Through guided-RNAi screens combined with high-throughput next generation sequencing (NGS) we provided molecular characterization of PCa including driver mutations and have helped us identify a subset of potential candidate mediators to explore. To this, we used clinically available data sets. Genes that changed in primary tumor (PT) were compared to their expression in metastatic lesions (M) of patient-matched specimens. Genes whose expression was modulated differently in M and PT were termed putative metastatic driver genes and explored. This promising preliminary data indicates that some of the targets identified in our metabolic PCa signature screen do play a role in the metastatic potential of the tumors.

Data: CORDIS, © European Union