# Targeted sequencing of cell-free DNA for monitoring of prostate cancer progression

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2021 · $31,970

## Abstract

PROJECT SUMMARY / ABSTRACT Prostate cancer (PCa) results in more than 160,000 diagnoses in the US
each year with essentially all patients eventually progressing to metastatic castration-resistant prostate cancer
(mCRPC), the more lethal form of the disease. Early stratification of mCRPC patients is critical since 20-40%
exhibit primary resistance to first-line treatments and those with resistance have a median survival of only 5.5
months. The standard-of-care circulating tumor cell assay (monitoring the AR-V7 splice variant) highlights the
potential for a non-invasive method for monitoring PCa disease progression, but it gives 80-90% of patients a
false-negative and has only ~3% sensitivity when used pre-treatment. The long-term objective of this proposal
is to investigate the potential of a cell-free DNA (cfDNA)-based assay for mCRPC patient stratification to improve
upon the current standard-of-care. To address this, the current proposal leverages our published cfDNA assay
that monitors the recently discovered tandem duplication of an enhancer region upstream of the androgen
receptor (AR), additional AR mutations, and 83 additional genes commonly mutated in mCRPC. Our gene panel
and cfDNA analysis method (EnhanceAR-Seq) outperformed the current standard-of-care in a prospectively
collected cohort of mCRPC patients. While this highlights the clinical utility of monitoring SVs non-invasively, no
automated pipelines exist for SV calling using targeted cfDNA assays. Copy number variation (CNV) and SV
analysis of cfDNA using a targeted sequencing approach requires specific considerations not accounted for in
traditional pipelines, such as the influence of probe density on read depth. This in turn results in researchers
developing custom scripts and parameters for running multiple tools for analysis of different variant classes (SV,
CNV, single nucleotide variants) and ultimately impairing the reproducibility of clinically relevant work. This
serves as a strong rationale for the following aims to (1) develop a standardized and robust unified pipeline for
somatic variant calling of all classes using cfDNA and (2) assess the clinical utility of EnhanceAR-Seq across (a)
an independent validation mCRPC patient cohort, (b) across ethnicities and (c) in an earlier clinical setting. The
research will be completed with mentorship from Dr. Christopher Maher and through the Human and Statistical
Genetics program at Washington University, one of the top ranked genetics programs in the country. The Maher
lab is an ideal environment for this project given their extensive bioinformatics, software development, structural
variation, genomics, and prostate cancer biology expertise. Training will focus on (1) developing computational
skills through software development and the application of bioinformatics tools, (2) improving knowledge of
translational tumor biology, and (3) professional development, all of which will support the goal of a career in
cancer research. ...

## Key facts

- **NIH application ID:** 10313093
- **Project number:** 1F31CA265010-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jace Webster
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $31,970
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313093

## Citation

> US National Institutes of Health, RePORTER application 10313093, Targeted sequencing of cell-free DNA for monitoring of prostate cancer progression (1F31CA265010-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10313093. Licensed CC0.

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