The biological role of PSMA for prostate cancer

Prostate cancer is the most common and the second most lethal cancer in men in Western countries. Various risk factors such as age, race, family history or dietary and environmental factors have been associated with prostate cancer development. Although many tumors are indolent and do not progress to aggressive tumors, locally advanced and metastatic tumors constitute a major health burden. Therapy options are limited and mostly associated with low efficacy due to tumor heterogeneity. In order to improve the clinical management of advanced tumors, a better biological comprehension of prostate cancer is essential. We aim to address this, by focusing on the prostate-specific membrane antigen (PSMA), a protein that is frequently overexpressed in advanced prostate cancers representing an interesting diagnostic and therapeutic target for prostate cancer. Although PSMA has been used as a tracer for positron-emission-tomography (PET) for some while, its biological role as a potential oncogenic driver for prostate cancer has just been emerging. We hypothesize that PSMA expressing tumors depend on specific oncogenic and metabolic pathways and are associated with DNA methylation signatures that distinguish them from PSMA negative tumors. We will combine computational and systems biology-based approaches to identify genes and pathways that are functionally related to PSMA expression in advanced and metastatic tumors. We expect that our project will provide novel insights into prostate cancer biology with high translational impact for patient management and development of novel therapeutic options in the future.

Prostate cancer is the most common cancer among men in Europe, with 1 in 8 men expected to be diagnosed with prostate cancer during their lifetime. In many cases, prostate cancer is non-aggressive and has a high cure rate with effective treatment options. However, advanced stages of the disease are still linked to poor patient outcome. The prostate-specific membrane antigen (PSMA), has gained attention in recent years as a biomarker for both diagnosis and therapy, and high PSMA expression is observed in advanced stages of disease. Despite this, the exact biological function of PSMA in cancer remains unclear. To better understand its role, we used a combination of bioinformatics and laboratory experiments. By analyzing publicly available datasets and samples from our own PSMA-positive prostate cancer patient cohorts, we discovered significant metabolic changes in tumors with high PSMA expression. These changes were particularly prominent in lipid metabolism, and we found that specific metabolic inhibitors were highly effective in killing prostate cancer cells in laboratory tests. A major limitation in prostate cancer research has been the lack of suitable preclinical models. To address this, we developed a biobank of prostate cancer organoids-3D cell culture systems grown from mouse tumors with relevant genetic mutations. These organoids closely mimic the diversity of actual prostate tumors and can be easily modified for research purposes. Using these models, we conducted a drug screening of 388 compounds, including some already approved for clinical use. From this screen, we identified two promising drugs that have not been previously used to treat prostate cancer. Both showed strong potential in stopping the growth of human prostate cancer cells. In summary, our study sheds new light on the role of PSMA in tumor progression and metabolism, revealing potential vulnerabilities that could be targeted in future therapies. Importantly, we also created novel, flexible model systems that can be used to test drugs and support the development of personalized treatments for prostate cancer.