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2022 Eustace Wolfingon – PCF Young Investigator Award

Overcoming NRG-1-mediated resistance in CRPC

Jacob Orme, MD, PhD
Mayo Clinic

Mentors: Alan Bryce, MD, Sean Park, MD, PhD, Haojie Huang, PhD

Description:

  • The identification of new therapeutic targets and treatments for advanced prostate cancer remains critical, as current treatment options will nearly always eventually fail.
  • Dr. Jacob Orme and colleagues identified NRG-1 as a driver in the development of resistance to hormonal therapies in prostate cancer and as a promising biomarker and therapeutic target. They also found that mesenchymal cells, a type of non-cancer cell within tumors, are the main source of NRG-1 production.
  • These findings served as rationale for initiating a phase 2 clinical trial testing enzalutamide in combination with pertuzumab and trastuzumab, which block the NRG-1 signaling partners HER2 and HER3, in patients with castration resistant prostate cancer (CRPC) with elevated NRG-1.
  • In this project, Dr. Orme and team will determine the safety and efficacy of this combination treatment approach in patients with CRPC.
  • The PARP pathway appears to drive NRG-1 production in mesenchymal cells. These mechanisms and whether PARP-inhibitors can prevent NRG-1 production, will be investigated using patient-derived prostate tumor models.
  • If successful, this project will identify new treatment paradigms for preventing and reversing the progression of prostate cancer to the treatment-resistant CRPC state.

What this means to patients: Hormonal therapy is the backbone of treatment for aggressive and advanced prostate cancer, however treatment resistance inevitably occurs and patients progress to the CRPC state. Dr. Orme and team are conducting a clinical trial to test whether targeting NRG-1 may be effective in patients with CRPC, identifying the mechanisms, and investigating alternate therapeutic strategies for targeting this tumor driver.