Project 1: Epigenetic variations associated with aggressiveness in prostate cancer among Puerto Rican men

H. Lee Moffitt Cancer Ctr & Res Inst, Tampa FL

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Abstract

This project addresses health drivers that contribute to differences in prostate cancer (PCa) outcomes in our catchment area. While socioeconomic status and access to healthcare are contributors, manifest differences in molecular features between groups within our catchment area highlight the role of tumor biology in disparate outcomes in PCa. Our long-term goal is to identify DNA methylation biomarkers driving gene expression changes that underlie PCa therapy resistance and aggressiveness in at-risk populations. The central hypothesis is that differences in tumor DNA methylation patterns and population admixture are associated with drug response and aggressiveness in PCa. The rationale is that identifying the molecular basis of PCa differences will serve to reduce the burden of lethal PCa affecting Americans. Our goals will be accomplished through two Specific Aims: Aim 1) Investigate associations between aggressiveness and methylated genes in PCa, addressing health drivers of cancer outcomes in PCa patients and compare with methylation data from the Florida PCa biobank, and PCa patients from MCC, and TCGA. (1b) Evaluate differential DNA methylation on gene expression patterns. We will establish comparisons with previous data obtained from MCC and TCGA. (1c) Evaluate whether population admixture will modify the methylation level of specific methylated genes. Further, we will investigate whether genes that contain genetic variability determinants are associated with the aggressiveness of PCa and outcomes. Aim 2. Assess the contribution of DNA methylation to PCa resistance to standard therapies using drug-resistant PCa sublines and liquid biopsies from PCa patients progressing after treatment. (2a) Identify differentially methylated genes associated with drug-resistant phenotypes using cell-based models of drug resistance, including castration resistance, enzalutamide resistance, and docetaxel resistance. (2b) Evaluate the expression of differentially methylated genes in resistant sublines compared to sensitive cell lines. (2c) Assess the effect of DNA methylation inhibition on drug sensitivity in resistant phenotypes. (2d) As an exploratory aim, we will evaluate resistance-associated methylation profiles in blood samples from PCa patients from our catchment areas previously treated with androgen deprivation therapy, androgen receptor-targeting agents, or taxane-based chemotherapy. The identification and validation of novel DNA methylation signatures associated with aggressive and drug-resistant PCa have the potential to improve risk stratification and treatment selection in patients with PCa.