# Project 4: Clinical Development of Therapeutic Strategies Targeting Damage Repair

> **NIH NIH P50** · FRED HUTCHINSON CANCER CENTER · 2024 · $283,564

## Abstract

PROJECT SUMMARY/ABSTRACT
Prostate cancer (PC) is notable for the expression and activity of a unique therapeutic target – the androgen
receptor (AR). PC growth and survival is driven by AR, a nuclear transcription factor activated by androgens
such as testosterone (T) and dihydrotestosterone (DHT). AR activity can be suppressed through ligand
reduction in the form of androgen deprivation therapy (ADT). While ADT is initially effective in treating
metastatic PC, disease progression, termed metastatic castration-resistant prostate cancer (mCRPC),
inevitably occurs after several years. Additionally, long-term ADT is associated with significant mental and
physical quality of life complications. Consequently, there has been a longstanding interest in the development
of therapeutic modalities that can further exploit AR signaling to enhance treatment responses and also
improve quality of life. In this proposal, our objective is to integrate and leverage two key aspects of PC
biology: AR activity and DNA damage/repair. Integrating AR signaling and HDR has important treatment
ramifications as a substantial body of preclinical and clinical work indicates that HDR deficiency (HDR-D) result
in vulnerabilities to at least two drug classes: platinum (PLAT) chemotherapy and PARP inhibitors (PARPi) as
well as radiation therapy.
We propose three Specific Aims:
Specific Aim 1. Conduct a Phase 2 clinical trial genotoxic therapeutics and supraphysiological androgen (SPA)
in patients with mCRPC to determine response rates, identify resistance mechanisms, and establish
biomarkers that associate with clinical responses.
Specific Aim 2. Identify the mechanism(s) by which therapeutics overdriving AR activity induce DNA damage,
regulate DNA repair processes, and enhance genotoxic chemotherapy.
Specific Aim 3. Identify therapeutic drug combinations and dosing/administration strategies that optimize the
therapeutic window resulting from AR expression and activity in mCRPC.
The research plan is structured to drive bidirectional assessments of clinically-relevant mechanisms involving
AR signaling and DNA repair in the context of treating advanced prostate cancer.

## Key facts

- **NIH application ID:** 10919795
- **Project number:** 5P50CA097186-23
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** PETER S NELSON
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $283,564
- **Award type:** 5
- **Project period:** 2002-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10919795

## Citation

> US National Institutes of Health, RePORTER application 10919795, Project 4: Clinical Development of Therapeutic Strategies Targeting Damage Repair (5P50CA097186-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10919795. Licensed CC0.

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