Identification of epigenetic drivers of advanced prostate cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Epigenomic profiling of patient biopsies have provided critical insight into mechanisms of prostate tumorigenesis and treatment resistance - insights that could not have been gained through genomic or transcriptomic profiling. However, obtaining serial patient biopsies during treatment to study real time changes in the epigenome is not feasible due to technical and logistical challenges. To address this, one of the major objectives of this project is to develop and optimize methods to profile the prostate cancer epigenome from other sources such as cell-free plasma or archival formaldehyde fixed paraffin embedded (FFPE) specimens. In FY25 we successfully published our initial study profiling approximately 80 cell free plasma samples using plasma chromatin immunoprecipitation followed by sequencing (plasma ChIP-seq). Using a bespoke analysis that incorporates circulating tumor DNA (ctDNA) fraction we showed that plasma ChIP-seq captures epigenomic features of prostate cancer associated with disease progression such as lineage switching. Additionally, we developed a statistical framework to correlate epigenomic alterations with clinical and genetic features. We have subsequently expanded this approach to a cohort of prostate cancer patients receiving targeted therapies as part of a clinical trial. In addition to providing insight for follow up functional studies in experimental models, we anticipate that plasma ChIP-seq will be a powerful tool to validate preclinical studies in patient samples. In parallel we also optimized the ChIP-seq protocol for FFPE specimens and are currently profiling radical prostatectomies from patients that received 6 months of neoadjuvant antiandrogen. In FY25 we have processed 50 of approximately 90 available samples. This cohort will help us investigate how untreated prostate cancers respond to intensive antiandrogen therapy and why a subset of patients fails to respond to neoadjuvant therapy, eventually progressing to more aggressive disease.