Galeterone to target proteasomal degradation of the androgen receptor in prostate tumor cells: A novel mechanism of action for treatment of AR-V7+ CRPC.

Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics
Session Type and Session Title: 
This abstract will not be presented at the 2016 ASCO Annual Meeting but has been published in conjunction with the meeting.
Abstract Number: 


J Clin Oncol 34, 2016 (suppl; abstr e14092)
Daniel T. Dransfield, Douglas B Jacoby, Nivedita Namdev, Andrew Kwegyir-Afful, Vincent Njar; Tokai Pharmaceuticals, Boston, MA; University of Maryland School of Medicine, Baltimore, MD

Abstract Disclosures


Background: Galeterone is an oral small molecule that disrupts androgen receptor (AR) signaling via multiple pathways: AR degradation, CYP17 inhibition, and AR antagonism. By enhancing ubiquitin-mediated AR degradation within the cellular proteasome, galeterone is a first-in-class degrader of the full-length AR and the AR-V7 splice variant. AR-V7 expression is associated with resistance to abiraterone or enzalutamide in patients with castration-resistant prostate cancer (CRPC). Methods: Normally, proteins can be enzymatically flagged for proteasomal degradation with ubiquitin (Ub); however, proteins can be saved from degradation by the removal of Ub through deubiquitinating enzymes (DUBs). We utilized a series of biochemical and cell-based in vitro studies to further elucidate and characterize additional signaling molecules in the proteasomal dependent mechanism of galeterone-induced AR degradation. Results: Galeterone binds to 2 key DUBs involved in sparing the AR from degradation, USP12 and USP46, and inhibits their activity in a dose-dependent manner (IC50 3.4 μM, 4.2 μM, respectively). By comparison, abiraterone and enzalutamide do not inhibit USP12 or USP46 activity. Pre-clinically, the galeterone-mediated degradation appears to be specific for AR as there was no impact on the levels of other nuclear hormone receptors (ERβ, PR, RARα, RARβ). Galeterone also activates AKT, which then phosphorylates the E3 ligase enzyme Mdm2 and ubiquitinates the AR, further inducing proteasomal degradation Conclusions: By directly inhibiting the activity of the DUBs, and indirectly activating Mdm2, galeterone targets multiple points in the proteasomal degradation pathway. This results in a shift of the equilibrium from deubiquitination to ubiquitination of AR, enhancing degradation of both full-length AR and the AR-V7 splice variant. A Phase 3 trial, ARMOR3-SV, of galeterone vs. enzalutamide in AR-V7+ metastatic CRPC patients is underway.