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2023 Milken Scholars, Merkin Family Foundation – PCF Young Investigator Award

Defining Mechanisms of AR Transcriptional Regulation to Improve Outcomes in Advanced Prostate Cancer

Sarah Hsu, MD, PhD
University of California, San Francisco (UCSF)

Mentors: Luke Gilbert, Franklin Huang, Eric Small

Description:

  • Metastatic castration resistant prostate cancer (mCRPC) is a lethal disease that invariably becomes resistant to existing therapies targeting androgen signaling.
  • Persistent or increased androgen receptor (AR) activity is thought to be a major driver of treatment resistance. As such, there is an urgent need to understand how AR expression is controlled in mCRPC to identify better therapeutic strategies.
  • AR expression can be supported through the activity of an enhancer – a genomic element with the capacity to activate gene expression over large distances. The genomic region containing the AR enhancer is frequently amplified in mCRPC and likely plays a key role in sustaining AR expression in advanced and treatment resistant disease.
  • Dr. Sarah Hsu is defining the mechanisms regulating AR expression and enhancer activity in mCRPC, which may lead directly to new therapeutic strategies.
  • In this project, Dr. Hsu will define protein factors that control AR enhancer activity and modulate AR expression, with the goal of identifying potentially druggable targets.
  • Dr. Hsu will also aim to characterize additional or alternative AR enhancers that may be active in different contexts and disease states, and that could also contribute to disease progression and treatment resistance.
  • If successful, this project will define mechanisms of AR expression in advanced prostate cancer and identify new approaches for treating mCRPC.

What this means to patients: Androgen signaling and AR activation are key drivers of prostate cancer, and AR is the primary therapeutic target in patients with advanced disease. Importantly, AR is also frequently central to the development of treatment resistance, through a variety of adaptive mechanisms that can increase AR levels and/or activity. In this project, Dr. Sarah Hsu aims to comprehensively characterize how the AR gene is regulated, with the goal of identifying druggable targets that circumvent resistance mechanisms.