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

> **NIH NIH P50** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $142,859

## Abstract

PROJECT SUMMARY/NARRATIVE
Metastatic prostate cancer (mPC) is a lethal disease with essentially no curative therapy. However, in unselected
patients, widely divergent responses to conventional and experimental therapeutics are routinely observed, with
occasional ‘outlier’ or ‘exceptional’ responders exhibiting durable complete responses and others exhibiting
immediate disease progression. This diversity suggests that underlying biological mechanisms accounting for
treatment responses can be identified and exploited to prioritize specific therapeutics predicted to have benefit
and avoid treatments predicted to lack activity.
The genomic landscapes of mPC demonstrate that a substantial fraction of mPC tumors harbor somatic defects
in DNA repair genes (DRGs) including BRCA1, BRCA2, ATM, MSH2/6 and others. This finding has important
treatment ramifications as a substantial body of preclinical and clinical work indicates that particular types of
DNA repair deficiency, particularly Homology Directed Repair (HDR) Deficiency (HDR-D) result in heightened
vulnerabilities to at least two drug classes: platinum (PLAT) chemotherapy and PARP inhibitors (PARPi). Also
of importance, tumors without a HDR-D genotype/phenotype are less responsive to these drugs.
In this proposal we will test the hypothesis that specific aberrations (germ-line or somatic) in genes involved in
repairing DNA strand breaks by HDR are predictive of meaningful clinical responses to FDA-approved genotoxic
therapeutics and drugs that impair mechanisms of repairing DNA. We will also determine if rational combinations
of novel therapeutics targeting DNA repair processes or inducing DNA damage in cancers with HRD will bypass
or overwhelm resistance pathways. We have 3 aims:
Specific Aim 1: Conduct Phase 2 clinical trials of genotoxic therapeutics in patients with mCRPC to determine
 response rates, identify resistance mechanisms, and establish associations between specific HDR genomic
 defects and the depth and duration of clinical responses.
Specific Aim 2: Evaluate rational combinations of pharmacological agents targeting DNA repair pathways using
 Patient Derived Xenograft (PDX) models of mCRPC with inherent or engineered HDR aberrations.
Specific Aim 3: Develop minimally-invasive biomarkers involving the capture and analysis of circulating tumor
DNA capable of distinguishing patients for therapeutics targeting DNA repair pathways.

## Key facts

- **NIH application ID:** 10247719
- **Project number:** 5P50CA097186-19
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** PETER S NELSON
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $142,859
- **Award type:** 5
- **Project period:** 2002-09-19 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247719

## Citation

> US National Institutes of Health, RePORTER application 10247719, Project 4: Clinical Development of Therapeutic Strategies Targeting DNA Damage Repair (5P50CA097186-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10247719. Licensed CC0.

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