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2025 PCF Challenge Award

Targeting Extrachromosomal DNA in Prostate Cancer: A Novel Approach to Overcome Treatment Resistance

Principal Investigators: Rana McKay, MD (University of California, San Diego), Christina A. Jamieson, PhD (University of California, San Diego)

Co-Investigators: Ludmil B. Alexandrov, PhD (University of California, San Diego), Jingjing Zou, PhD (University of California, San Diego), Vineet Bafna, PhD (University of California, San Diego)

Young Investigator: Yu-Wei Chen, MD (University of California, San Diego)

Description:

  • Metastatic castration-resistant prostate cancer (mCRPC) remains invariably lethal with a median survival of only 2-3 years despite therapeutic advances. Androgen receptor (AR) amplification occurs in up to 50% of mCRPC cases and correlates with significantly worse clinical outcomes. A critical breakthrough in understanding treatment resistance is the recognition that these amplifications frequently occur on extrachromosomal DNA (ecDNA) – circular DNA structures that enable rapid oncogene amplification and therapeutic adaptation.
  • Unlike chromosomal DNA, ecDNAs lack centromeres, segregate unequally during cell division, and can harbor multiple copies of oncogenes and their regulatory elements, creating a dynamic and adaptable genomic architecture that allows rapid evolution in response to therapeutic pressure. ecDNA-containing cancer cells exhibit heightened replication stress and are hypothesized to be sensitive to inhibitors of Checkpoint Kinase 1 (CHK1), a master regulator of the replication stress response.
  • Dr. Rana McKay and team are investigating a selective CHK1 inhibitor that has shown promise in AR-amplified prostate cancer models compared to non-amplified models.
  • In this project, Dr. McKay and team will determine the efficacy of CHK1 inhibitors in AR-amplified prostate cancer models and investigate the mechanisms of action. They will also characterize ecDNA presence, structure, and dynamics in AR-amplified prostate cancer patient samples, and determine whether AR amplification and ecDNA status may act as biomarkers of response to CHK1 inhibitors in patients with mCRPC.
  • If successful, this project will represent the first therapeutic approach targeting ecDNA-mediated oncogene amplification in prostate cancer and could lead to a new treatment for a large proportion of patients with mCRPC.

What this means to patients: AR amplification is present in ~50% of patients with CRPC and drives resistance to AR-targeted therapies in prostate cancer. AR is often amplified on extrachromosomal DNA (ecDNA), suggesting that targeting ecDNA may be an effective therapeutic strategy for many patients. Dr. McKay and team will investigate the efficacy of a therapy that targets DNA replication stress caused by the presence of ecDNA, will comprehensively characterize ecDNA and AR amplification in patient samples, and explore how this genomic architecture correlates with treatment response and clinical outcomes. This could transform the treatment landscape for mCRPC patients with AR amplifications while establishing new therapeutic principles applicable to many other malignancies where ecDNA drives disease progression.