Early Detection of Prostate Cancer using Activity-based Biomarkers from Plasma Extracellular Vesicles |
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| Background In 2020, prostate cancer (PCa) was the most common male cancer with an incidence of 25.1% in Germany, causing 15,507 deaths. Serum PSA level is currently the standard screening tool. It shows high sensitivity (90%) but low specificity (20% at 4 ng/mL cutoff), often leading to avoidable, invasive diagnostic procedures such as prostatic biopsy. Minimally-invasive, low-cost screening procedures with higher accuracy are needed. Plasma extracellular vesicles (pEV) are a novel source of biomarkers, as their number and content change during cancer development. We developed an activity-based test system based on pEV-associated proteases as well as proteomic analysis of non-enzymatic factors. |
| Methods pEV were isolated via dual-mode chromatography. The activity of pEV-associated proteases was determined using a FRET-based fluorescence assay. Proteomic content of pEV was analysed using a commercially available proximity extension assay (Olink Proteomics). To correct for possible confounders, we included a matched control group with similar metabolomic and medical history profiles as the PCa patients. Machine learning algorithms were employed to build classifiers. |
| Results When comparing the aforementioned patient groups, an AUC of 0.9 could be generated using PAA compared to an AUC of 0.67 from PSA measurements. Notably, we observed significant correlations between specific liver enzymes and increased protease activity in pEV. This underlines the importance of appropriate control groups to correctly classify patients. |
| Conclusion Our results suggest that PAA could be used in a clinical setting, for early recognition of PCa as well as therapy and relapse monitoring. Its high accuracy, reproducibility and simplicity, enable the PAA to be integrated in diagnostic cancer management. However, the association of EVs with hepatic issues points to possible test confounders. Currently, we are evaluating the test performance in patients with benign prostate hyperplasia and different cancer stages. In addition, we are optimizing the PAA by designing novel FRET peptides for additional proteases. |
| Keywords prostate cancer, protease activity, liquid biopsy |
| Funding/Acknowledgments Bundesministerium für Bildung und Forschung, Bayerisches Staatsministerium für Wirtschaft, Landesentwicklung und Energie, Hahn Schickard |
| Authors Cuno Laurin Lange1 (Corresponding Author: cuno.lange[at]fau[dot]de), Christian Schott1, Jan Van Deun1, Sven Wach2, Helge Taubert2, Andreas Baur1, Bernd Wullich2
1 Department of Dermatology, Uniklinikum Erlangen, Erlangen, Germany 2 Department of Urology and Pediatric Urology, Uniklinikum Erlangen, Erlangen, Germany |