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Novel ctDNA biomarker for androgen therapy in metastatic prostate cancer

Award Number: R01CA286127
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/06/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Novel ctDNA biomarker for androgen therapy in metastatic prostate cancer - PROJECT SUMMARY The deadliest form of advanced-stage prostate cancer is treatment-resistant metastatic castration- resistant prostate cancer (mCRPC), which occurs in ~35% of patients after exposure to androgen receptor (AR)-directed therapies such as Abiraterone and Enzalutamide, resulting in a dismal median survival of only ~5.5 months. Unfortunately, detection of treatment-resistant disease typically occurs too late, when patients are already progressing on AR-directed drugs, after which they succumb rapidly to their disease. There is therefore a critical need to detect AR resistance more sensitively and earlier in the disease course. To address this, our team designed a novel cell-free DNA assay called Enhancer and Neighboring Loci of Androgen Receptor Sequencing (EnhanceAR-Seq), built upon the Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) platform, and demonstrated superb sensitivity for detecting AR gene body and enhancer locus alterations in plasma collected from mCRPC patients. Notably, we applied our EnhanceAR-Seq technology to mCRPC patient plasma and showed that the results correlate strongly with clinically verified resistance to AR-directed therapy, and significantly outperform circulating tumor cell (CTC) AR-V7 detection. Building upon this, the current proposal will evaluate whether our EnhanceAR-Seq technology can be used to predict both (Aim 1) pre-treatment and (Aim 2) on-treatment resistance to AR-directed therapy in mCRPC patients. Further, in Aim 3 we will investigate whether integrating EnhanceAR-Seq with genome-wide methylation sequencing can granularly refine our ability to predict treatment resistance and monitor both clonal and phenotypic evolution in mCRPC. We are uniquely positioned to accomplish this through our interdisciplinary team comprised of cell-free DNA genomicists, bioinformaticians, oncologists, and statisticians. Overall, this study has significant translational impact by establishing cell-free genomic and epigenomic biomarkers of tumor evolution and resistance to AR-directed therapy in men with lethal prostate cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $610,019 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Detection and Diagnosis Research	002	2	6/2/2025	NON-COMPETING CONTINUATION	$61,002
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Detection and Diagnosis Research	000	2	11/14/2024	NON-COMPETING CONTINUATION	$549,017
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Detection and Diagnosis Research	001	2	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $610,019

Issue Date FY: 2024 ( Subtotal = $596,475 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Detection and Diagnosis Research	000	1	12/6/2023	NEW	$596,475
														Subtotal = $596,475

Grand Total All Awards = $1,206,494

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Novel ctDNA biomarker for androgen therapy in metastatic prostate cancer

Award Number: R01CA286127

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/06/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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