# Research Project 1: Understanding the Molecular Evolution of Castration-Resistant Prostate Cancer

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $170,181

## Abstract

An age of genomically directed oncology has arrived, catalyzed by efforts to rationally design therapies
targeting the molecular aberrations that promote individual tumor growth and progression. This has led to the
prospective clinical sequencing of patients with active disease to guide their cancer care. Nevertheless, the
utility of such prospective profiling is limited in many cancer types, perhaps most so in men with prostate
cancer. In fact, due in part to their profound clinical and mutational heterogeneity, we know very little about
how to therapeutically target the molecular lesions in the genomes that drive the emergence of the most
aggressive metastatic castration-resistant prostate cancers (CRPC). We must address this urgent challenge to
improve the survival of men with CRPC. We have recently shown that prospective clinical sequencing of
active, advanced prostate cancers with linked clinical annotation can reveal both gene- and pathway-level
genomic aberrations enriched in CRPC. We went on to show that both germline and somatic lesions targeting
genes mediating homologous recombination (HR) were far more common in CRPC than even advanced
castration-sensitive metastases. These findings underscore the potential therapeutic utility of defining the
lesions that drive CRPC, but without a clinical-translational approach that tests these hypotheses clinically, the
gap in our understanding will only widen. We propose to overcome this urgent clinical challenge by first
developing and comprehensively analyzing a one-of-kind cohort of approximately 2,000 sequenced advanced
prostate cancers from patients under active care with detailed clinical annotation, outcome, and treatment-response
data. A major goal of this effort will be to identify alterations associated with progression to
castration-resistance, a strategy that will facilitate the testing of novel approaches to treat such tumors. We will
then assess the extent to which genomic loss of heterozygosity and related hallmarks of HR deficiency are
correlated with different underlying somatic or germline HR/DNA repair genotypes, specific clinical variables,
disease-specific progression, and outcome. Finally, we will clinically test the hypothesis that men with CRPCs
bearing the hallmark of HR dysfunction, including those with germline or somatic BRCA mutations, derive
clinical benefit from PARP inhibition. We will also seek to identify genomic aberrations that condition PARP
inhibitor response and resistance in pre- and post-treatment samples and longitudinally collected tumor-derived
cell-free DNA. Together, these studies seek to establish a translational genomic framework to facilitate
effective, evidence-based precision oncology in men with CRPC by efficiently targeting essential pathways that
drive the progression to advanced disease.

## Key facts

- **NIH application ID:** 9998859
- **Project number:** 5P50CA092629-20
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Barry Stephen Taylor
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $170,181
- **Award type:** 5
- **Project period:** 2001-09-14 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998859

## Citation

> US National Institutes of Health, RePORTER application 9998859, Research Project 1: Understanding the Molecular Evolution of Castration-Resistant Prostate Cancer (5P50CA092629-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9998859. Licensed CC0.

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