# Project 1: Determining and Exploiting Mechanisms of AR-Mediated Suppression of Cell Proliferation and Survival

> **NIH NIH P01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $366,979

## Abstract

Since the inception of clinical efforts in prostate cancer (PCa) to suppress androgen receptor (AR)
signaling by reducing AR ligands (androgen deprivation therapy, ADT), it was recognized that the
administration of testosterone (T) to men who have relapsed after ADT (castration-resistant prostate
cancer, CRPC) could result in substantial clinical responses. However, these reports were largely
anecdotal and remissions were highly variable. In contrast, abundant data from preclinical models have
reproducibly shown biphasic responses of hormone-sensitive cancers, whereby at physiological T
concentrations proliferation is induced, but at higher, supraphysiological androgen (SPA) concentrations,
proliferation is suppressed and in some instances apoptotic programs are engaged. Though often
considered to be an in vitro phenomenon of little clinical importance, recent rigorously controlled clinical
trials of SPA produced substantial clinical responses in subsets of men with CRPC. Collectively, these
findings support studies designed to determine the molecular mechanism(s) driving these responses.
Based on these preclinical and clinical findings to date, we hypothesize that the genomic and
epigenomic adaptive processes that contribute to CRPC progression also sensitize tumor cells to the
differentiation, quiescence and apoptotic programs regulated by the AR under conditions of SPA. We will
test this hypothesis through three linked aims: AIM 1. Determine the primary mechanism(s) by which
SPA represses CRPC. AIM 2. Define the AR cistrome in prostate cancers reprogrammed by SPA and
identify cooperating genes and pathways that are essential or suppressive of SPA effects. AIM 3.
Identify drug combinations that synergize with SPA to repress tumor growth and optimize the effects of
AR agonism based on a mechanistic understanding of SPA-mediated growth arrest.

## Key facts

- **NIH application ID:** 10112187
- **Project number:** 5P01CA163227-08
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** PETER S NELSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,979
- **Award type:** 5
- **Project period:** 2013-05-24 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112187

## Citation

> US National Institutes of Health, RePORTER application 10112187, Project 1: Determining and Exploiting Mechanisms of AR-Mediated Suppression of Cell Proliferation and Survival (5P01CA163227-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112187. Licensed CC0.

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