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

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $511,680

## Abstract

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.

## Key facts

- **NIH application ID:** 10769616
- **Project number:** 1P50CA275741-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ERIC J SMALL
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $511,680
- **Award type:** 1
- **Project period:** 2024-09-02 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769616

## Citation

> US National Institutes of Health, RePORTER application 10769616, Project 2 - Investigating Clinical and Biological Implications of a Novel Hypermethylated Subtype of Metastatic Castration Resistant Prostate Cancer (mCRPC) (1P50CA275741-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10769616. Licensed CC0.

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