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2021 National Institutes of Health-PCF Young Investigator Award

Leveraging HER2 Inhibition to Sensitize High-Risk Localized “Low AR” Prostate Tumors to Neoadjuvant Intense Androgen Deprivation Therapy

Anson Ku, PhD
National Institutes of Health

Mentors: Adam Sowalsky, PhD, Eytan Ruppin, MD, PhD

Description:

  • Neoadjuvant intense androgen deprivation therapy (iADT) is an emerging clinical paradigm in which patients with localized but high-risk prostate cancer are treated with systemic agents currently approved for use in later stage disease (such as enzalutamide or abiraterone in combination with ADT), prior to radical prostatectomy.
  • Results from multiple clinical trials have shown that approximately 30-60% of men will inherently be resistant to neoadjuvant iADT, and that the volume of disease remaining after treatment is prognostic for long-term clinical outcome.
  • Dr. Anson Ku is studying the mechanisms of inherent resistance to neoadjuvant iADT.
  • Data from a recent trial analyzed by Dr. Ku and colleagues revealed greater AR activity at baseline was associated with the most durable responses, while greater activity of the EGF receptor pathway proteins HER2/HER3 were associated with increased residual disease after treatment.
  • In this project, Dr. Ku will evaluate the biological relationship between AR and the EGF receptor pathway and the role of HER2/HER3 in resistance to iADT.
  • Whether pharmacological inhibition of the EGF Receptor pathway family has potential to sensitize prostate cancer to treatment with iADT will be investigated.
  • A classifier will be developed that can identify patients who are unlikely to respond to neoadjuvant iADT, and may benefit from anti-HER2 and iADT combination therapy.
  • In addition, the source of the ligands that activate the HER2 pathway in prostate cancer will be identified.
  • If successful, this project will establish mechanisms and biomarkers for a subset of low-AR prostate tumors that respond poorly to neoadjuvant iADT. Moreover, as HER2-targeted therapies are FDA approved in other settings, this project will generate preclinical evidence to support clinical trials of HER2-targeted therapies in the neoadjuvant setting in combination with iADT.

What this means to patients: Neoadjuvant intense androgen deprivation therapy (iADT) is an experimental strategy in which patients with localized prostate cancer are treated with systemic androgen targeted therapies prior to receiving surgery or radiation therapy. Dr. Ku will determine how the EGF receptor pathway may confer resistance to iADT in a subset of patients, and identify biomarkers and promising new combination treatment strategies for these patients.