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2022 Todd Boehly – PCF Young Investigator Award

Investigating Chromatin Reprogramming to Overcome Treatment Resistance in Advanced Prostate Cancer

Raunak Shrestha, PhD
University of California, San Francisco (UCSF)

Mentors: Felix Feng, MD, David Quigley, PhD

Description:

  • The development of resistance to second generation AR-signaling inhibitors (ARSIs) and progression to metastatic castrate-resistant prostate cancer (mCRPC) represents a huge obstacle to the improvement of patients’ clinical outcomes.
  • A common mechanism that drives development of mCRPC are epigenetic alterations – changes in the physical structure of DNA and its accessibility that control which genes can and can’t be expressed.
  • In this project, Dr. Raunak Shrestha will characterize epigenetic changes in different molecular subtypes of mCRPC that have developed resistance to ARSI, compared with mCRPC that have not been treated with ARSI.
  • Molecular regulators of ARSI resistance will be identified.
  • The role of known mCRPC drivers, such as AR and FOXA1, in epigenetic changes during ARSI resistance will be defined.
  • If successful, this project will create the largest integrated analysis of how epigenetic alterations contribute to mCRPC lineage plasticity and ARSI treatment resistance and identify transcriptional regulators of these changes.

What this means to patients: The development of mCRPC and resistance to ARSI is a major clinical problem in prostate cancer. Dr. Shrestha and team will comprehensively define the epigenetic alterations and molecular drivers that underlie these features, which will potentially help nominate candidate therapeutic targets and new strategies to counter ARSI resistance as well as identify potential biomarkers of ARSI resistance.