The Rigor and Clinical Utility of PSMA Enriched Extracellular Vesicles for Prostate Cancer Detection

前列腺癌的筛查可以挽救生命，但也会导致大量男性遭受前列腺癌的折磨

Screening for prostate cancer saves lives but results in an overwhelming number of men being subjected to unnecessary, invasive prostate biopsies, and the risk of over diagnosis and treatment of indolent cancer. Multi- parametric MRI (mpMRI) of the prostate and molecular biomarkers are used to evaluate the risk of clinically significant prostate cancer (csPCa) and need for biopsy, however they are limited in their accuracy for detecting csPCa, resulting in many men still needing to undergo biopsy for fear of missing a significant tumor. This proposal addresses an important issue in enhancing the precision of csPCa detection to reduce the burdens of prostate cancer screening. Extracellular Vesicles (EVs) that are released into body fluids by cancer cells are promising biomarkers for liquid biopsy since they can be extracted from blood and urine and carry molecular constituents reflecting the parent tumor. The problem is selectively extracting EVs released from prostate cancers can be challenging, and contribution by EVs of non-prostate origin can lessen detection and specificity. In collaboration with the research and development team at Exosome Diagnostics, who are experts in the field of clinical-grade EV biomarker analysis, we have developed a method to enrich for EVs expressing the Prostate Specific Membrane Antigen (PSMA) surface protein. We have found that PSMA EV capture enrichment results in the detection of a different, and potentially more prostate specific profile of EV mRNAs and long non-coding RNAs. However while EV contents are well protected by lipid membranes, optimal conditions for the collection and processing of EVs expressing PSMA surface protein have not yet been rigorously defined. In our proposed project, we will focus on development of a urine PSMA EV assay that is more specific for csPCa than the other currently available tests for PCa. Specifically, we will test the hypothesis that the urine EVs obtained by PSMA enrichment can provide a panel of EV RNA markers that can substantially enhance prostate cancer risk assessment. In Specific Aim 1, we have developed an innovative multi-factor assay development plan to address previous limitations in the rigor and reproducibility of surface antigen capture and develop an optimal workflow for PSMA enrichment. In Specific Aim 2, we will conduct RNAseq comprehensive profiling of PSMA enriched and total EVs from men in an ongoing U Miami (MDSelect: NCT04240327) clinical trial enrolling 250 patients undergoing biopsy for evaluation of csPCa to determine the additive value of PSMA enrichment over total EVs for csPCa detection. In Specific Aim 3, we will develop and validate a novel urinary EV signature to enhance the accuracy of csPCa detection using RNAseq data from PSMA enriched and total EVs, with multi-institutional validation in an ongoing NCI EDRN (NCT03784924) clinical trial. Based on our preliminary data and the combined expertise of our research team we are well positioned to develop and deliver an EV based urine biomarker assay that significantly enhances csPCa detection with validation in clinical trials. This proposal will substantially enhance csPCa detection and lay the foundation for future EV based prostate cancer markers.