Hormonal Shock Therapy for Metastatic Castrate Resistant Prostate Cancer

Principal Investigators: Samuel Denmeade, MD (Johns Hopkins University), Robert Casero, PhD (Johns Hopkins University), Erika Pearce, PhD (Johns Hopkins University)

Co-Investigators: Laura Sena, MD, PhD (Johns Hopkins University), Angelo DeMarzo, MD (Johns Hopkins University), Hao Wang, PhD (Johns Hopkins University), David Sanin, PhD (Johns Hopkins University)

Description:

• Prostate cancer cells maintain androgen receptor (AR) activity at a level optimal for growth and survival. Bipolar androgen therapy (BAT) is a promising experimental treatment that cycles patients between extremely high and extremely low levels of androgens; this causes prostate cancer cells to die, and those that survive by adapting to the new conditions are then sensitive to the next extreme shift in androgen levels. Unfortunately, only ~30% of patients benefit from BAT, and this treatment is not curative.  Methods to improve on this strategy remain needed.
• Samuel Denmeade and team have identified the polyamine pathway as a potential driver of BAT resistance and therapeutic target to improve on the efficacy of BAT.
• In this project, Denmeade and team will perform a clinical trial testing BAT in combination with the polyamine inhibitor DFMO, in sequence with enzalutamide, in patients with castration resistant prostate cancer (CRPC).
• Samples from patients on this trial will be studied to confirm the ability of DFMO to inhibit the polyamine pathway in tumors, and the impact of this treatment combination on tumor metabolism and gene expression.
• Whether and how this treatment impacts the anti-tumor immune response will also be studied using samples from this trial.
• If successful, this project will identify a promising new treatment strategy for CRPC and define the mechanism of action in patients.

What this means to patients:  Bipolar androgen therapy (BAT) is promising treatment strategy that requires further optimization for maximum patient benefit.  This project will test a new combination treatment strategy that targets the polyamine pathway to block treatment resistance and define the mechanisms by which this treatment blocks tumor growth in patients.