Investigating the Role of AR Extrachromosomal DNA (ecDNA) in Bipolar Androgen Therapy for Advanced Prostate Cancer

Prostate cancer is one of the most common malignancies and a leading cause of cancer-related deaths in American men. In advanced prostate cancer, androgen deprivation therapy (ADT) is the standard of care. While most patients initially respond to ADT, they will eventually develop castration resistant prostate cancer (CRPC). CRPC is a lethal and aggressive disease stage with limited treatment options. A novel therapeutic strategy for CRPC is bipolar androgen therapy (BAT). Clinical trials have demonstrated both safety and efficacy, as well as improvements in quality of life with the use of BAT. However, the patient populations best suited for BAT and the mechanism of anti-tumor activity in patients who respond to BAT remain undefined. CRPC is associated with amplification and overexpression of the androgen receptor (AR). One mechanism of AR amplification is extrachromosomal DNA (ecDNA). ecDNAs are Mb-sized circular structures located in the nucleus that allow for increased rates of transcription and replication, with new studies estimating that 1/3 of CRPC tumors likely contain AR ecDNA. Preliminary data in this project indicate that CRPC patient-derived xenografts (PDXs) classified as positive for AR ecDNA are sensitive to BAT. Based on this finding, my research training will explore AR ecDNA as a therapeutic vulnerability and biomarker to identify patient populations that should be considered for BAT. The central hypothesis is that AR ecDNA levels are dynamic during ADT and BAT, and that BAT inhibits AR ecDNA-positive CRPC by inducing R-loops, transcription-replication collisions, and DNA damage on ecDNA. Aim 1 will utilize computational tools to investigate the composition of ecDNA and how treatment affects quantity of AR ecDNA structures. Aim 2 will investigate the mechanism of BAT in ecDNA- positive tumors, assessing the vulnerability of these structures to excess DNA damage during treatment. This project is specifically designed to provide rigorous training in key areas for my development as an independent physician-scientist. Aim 1 will provide hands-on training in computational biology and who genome sequencing data. Aim 2 will build my expertise in advanced molecular biology techniques to probe mechanisms by which BAT enhances transcription and DNA damage. Completing this project will advance our understanding of the role of AR ecDNA in BAT sensitivity and biological mechanisms of action and provide me with the conceptual knowledge and technical skills necessary to lead a research project focused on translating mechanistic discoveries into novel cancer therapies. Project Number: 1F30CA314114-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Emily Egusa | Institution: UNIVERSITY OF MINNESOTA, MINNEAPOLIS, MN | Award Amount: $44,819 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F09A-R (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11387392