Exosomal micrornas as epigenetic biomarkers of disease progression in Hispanic men with metastatic castration-resistant prostate cancer

Background: Metastatic castration-resistant prostate cancer (mCRPC) arises when localized prostate tumors become unresponsive to androgen deprivation therapy (ADT) and develop metastatic potential. Despite therapeutic advances, mCRPC remains incurable, with a median survival of only 9-13 months. Identifying epigenetic biomarkers, such as exosomal microRNAs (exo-miRNAs), that can aid in early detection and monitoring disease progression is therefore critical, particularly among underrepresented populations such as Hispanic men. Methods: Matched plasma samples from Puerto Rican men with prostate cancer at localized and metastatic stages (n=11) were analyzed to identify exo-miRNAs associated with progression to mCRPC. Exosomes were isolated from plasma, total exo-miRNAs were extracted, and expression profiling was performed using the nCounter Human v3 miRNA Expression Assay (NanoString Technologies) at Moffitt Cancer Center. Data were normalized, and statistical significance was evaluated using two-sample t-test and the Welch's t-test. All analyses were performed in R (v4.5.1) using the tidyverse, readr, and ggplot2 packages. Results: The initial expression matrix (M) contained 798 miRNAs after excluding controls and spike-ins. Homogeneity assessment yielded a refined matrix of 66 targets. Applying an SD=1 threshold identified 18 candidate miRNAs differentially expressed during disease progression. Among these, miR-302d-3p (p=0.01) and miR-23a-3p (p=0.045) were significantly altered between localized and metastatic disease. Six additional candidates (miR-1246, miR-16-5p, miR-199a-3p/miR-199b-3p, miR-2053) showed borderline significance (p<0.05), suggesting potential biological relevance. This study provides novel insight into the epigenetic landscape of prostate cancer progression among Hispanic men, highlighting circulating exo-miRNAs as minimally invasive biomarkers for disease monitoring. Given the limited availability of clinical specimens from this population, these findings are particularly significant. The identification of circulating exo-miRNA signatures offers a minimally invasive approach to monitor disease progression and could ultimately support the development of blood-based biomarkers for early detection and risk stratification in advanced prostate cancer. Funding: Supported by the American Cancer Society Institutional Research Grant (ACS-IRG Subaward No. 60-21510-99-20), the Catalyzer Research Grant from the Puerto Rico Science, Technology & Research Trust (PRST), and the NIH/NCI U54 Partnership Grants (U54CA163071 & U54CA163068) between Ponce Health Sciences University and Moffitt Cancer Center.