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2019 PCF Challenge Award

Donald McDonnell, PhD

HOXB13 as a Therapeutic Target in Prostate Cancer

Principal Investigator: Donald McDonnell, PhD (Duke University)

Co-Investigators: Damian Young, PhD (Baylor College of Medicine), Ryan Soderquist, PhD (Duke University), Andrew Armstrong, MD (Duke University), Kris Wood, PhD (Duke University)

Description:

  • The androgen receptor (AR) is a critical driver of prostate cancer and a major therapeutic target. However, cancers often develop resistance to AR-targeted therapy and progress to lethal disease.
  • HOXB13 has been identified as a major co-factor of AR in prostate cancer but also drives the growth of AR-negative castration-resistant prostate cancer.
  • Donald McDonnell and team will investigate the therapeutic potential for targeting HOXB13 in prostate cancer.
  • The team will employ drug discovery and chemistry approaches to develop small molecules that cause the degradation of HOXB13 proteins in prostate cancer cells.
  • The anti-cancer activity of the most promising HOXB13-targeting drugs developed will be evaluated in preclinical models.
  • The team will study whether HOXB13 expression in circulating tumor cells (CTCs) may serve as a pharmacodynamic marker for evaluating the activity of HOXB13-targeting drugs in patients and to identify patients appropriate for therapy.
  • Other genes that promote the expression or activity of HOXB13 in prostate cancer will be identified and their potential as therapeutic targets alone and in combination with HOXB13-inhibitors will be investigated. If promising targets are identified, the team may develop drugs against these targets.
  • If successful, this project will develop a promising new class of HOXB13-targeting drugs that can enter testing in clinical trials and define the patient populations in whom these drugs are most likely to be successful.

What this means to patients: HOXB13 has been identified as a critical driver of AR-dependent and AR-independent prostate cancers but has not yet been explored as a therapeutic target. Dr. McDonnell and team will develop a novel class of HOXB13-targeting drugs as well as identify other HOXB13-regulators that are promising therapeutic targets. This may lead to a new treatment that may have utility at all stages of prostate cancer.