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2021 John Black Charitable Foundation-PCF Young Investigator Award

Identifying and Overcoming Resistance to AR/DDR-Targeting Therapies using Orthogonal Single-Cell CRISPR and Peptide Screening Platforms

Harveer Dev, MD, PhD
University of Cambridge

Mentors: Stephen Jackson, PhD, Charlie Massie, PhD, Ian Mills, PhD

Description:

  • Prostate cancers are driven by the Androgen Receptor (AR), and androgen deprivation therapy (ADT) together with radiotherapy is a common treatment option in patients with localized disease. AR plays a role in repair of damaged DNA, and this likely contributes to the synergy seen with the combination of ADT and radiotherapy.
  • In addition to radiotherapy, other prostate cancer treatments that work by damaging DNA include PARP inhibitors, which are now FDA-approved for patients with alterations in certain DNA damage repair (DDR) genes, and experimental treatments including ATM inhibitors.
  • Dr. Harveer Dev is studying the role of AR in DNA repair, in order to develop biomarkers to guide treatment selection and to inform the development of improved AR/DDR-targeting therapies.
  • In this project, Dr. Dev will use genome-wide screening technologies to identify and characterize regulators of AR-DDR function, and to identify AR-regulated genes that confer resistance to radiotherapy, PARP-inhibitors, and ATM-inhibitors.
  • Whether patient responses to ADT + radiotherapy can be predicted using a panel of experimentally-derived biomarkers will be investigated in African-American and overall populations.
  • ADT and ADT+DDR-targeting treatment-resistant models will be developed and used to screen for novel therapeutic targets that can overcome treatment resistance.
  • If successful, this project will improve the understanding of AR in DNA repair biology, define biomarkers that better predict the response to AR/DDR-targeting combination treatment, and identify new treatment targets which will form the basis of small molecule inhibitor development with industry partners.

What this means to patients: The development of resistance to ADT/DDR-targeting combination therapies is an increasingly important clinical challenge in prostate cancer. Dr. Dev will better define how AR functions in DDR activities, identify novel biomarkers for ADT+DDR-targeting treatments, and identify new therapeutic targets that may prevent the development of resistance to ADT+DDR-targeting treatments.