Identification of epigenetic drivers of advanced prostate cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Performing epigenomic profiling across disease states facilitates identification of recurrent alterations that are biologically meaningful. For example, identifying differential enhancers between treatment-sensitive versus castration-resistant prostate cancers revealed somatically acquired regulatory elements critical for resistance. These results provided insight into disease progression that could not be obtained through genomic and transcriptomic approaches. We are using a similar strategy to identify enhancers that are activated during relevant disease states in prostate cancer. We are focusing on two disease states associated with poor responses to treatment and represent clinical challenges: 1) localized prostate cancers with an intraductal component and 2) localized prostate cancers with significant residual disease at the time of surgical resection despite neoadjuvant hormone treatment. We have identified FFPE samples from radical prostatectomies that have already completed pathology review and transcriptomic and genomic profiling. We have successfully modified and optimized our profiling methods for clinical specimens that are embedded in paraffin. We are currently performing chromatin immunoprecipitation using antibodies to the H3K27ac histone mark to identify enhancers that are activated or decommissioned across disease states. We will then prioritize and functionally assess differentially activated enhancers by performing pooled CRISPR based screens in cell line models. For enhancers that are functionally validated, we will subsequently determine downstream target genes and upstream activators.