Project 2 - Investigating Clinical and Biological Implications of a Novel Hypermethylated Subtype of Metastatic Castration Resistant Prostate Cancer (mCRPC)

PROJECT SUMMARY/ABSTRACT – PROJECT 2 (SMALL): INVESTIGATING CLINICAL AND BIOLOGICAL IMPLICATIONS OF A NOVEL HYPERMETHYLATED SUBTYPE OF METASTATIC CASTRATION RESISTANT PROSTATE CANCER (MCRPC) The lethal phenotype of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), inevitably

evolves from metastatic castration-sensitive prostate cancer (mCSPC) following androgen deprivation therapy (ADT). While recent studies have identified genomic and transcriptomic drivers of mCRPC, the epigenetic landscape of this disease is less well understood. In order to examine the methylation landscape of mCRPC,

whole-genome bisulfite sequencing (WGBS) was performed for 100 mCRPC metastases from the West Coast Prostate Cancer Dream Team (WCDT) cohort, which previously had been profiled with whole-genome and transcriptome sequencing. Using unsupervised hierarchical clustering of the methylome, a novel hypermethylated subtype of mCRPC, the CpG methylator phenotype (CMP) was identified. Accounting for

22% of patients in the WCDT cohort, CMP-positive patients constitute one of the most prevalent molecularly defined subsets of mCRPC. Despite accounting for this substantial proportion of patients, much remains unknown about this phenotype, including its molecular underpinnings, potential prognostic or predictive

biomarkers, and potential therapeutic vulnerabilities. To address these gaps in knowledge this application proposes to explore the following three aims: (1) To investigate how the CMP phenotype promotes disease progression, providing a comprehensive view of how the CMP methylation phenotype affects biological

pathways and oncogenic functions; (2) To identify clinically relevant therapeutic approaches for the CMP mCRPC patient subset, assessing the use of currently available epigenetic agents to treat CMP+ disease, as well as discover other potential therapeutic targets; (3) To develop and evaluate non-invasive clinical

methylation biomarkers of CMP status, providing a comprehensive assessment of methylation biomarkers across a range of disease states. Successful completion of these aims will result in defining the clinical relevance of the hypermethylated CMP mCRPC subtype, and the identification of novel therapeutic targets and

approaches for this phenotype. Ultimately this will set the stage for therapeutic trials in the cohort of CMP- positive mCRPC patients, as well as a co-targeting strategy together with AR-directed therapies in CMP- positive CSPC patients.