Project Team

Felix Kim, PhD, Pharmacology

Joseph Salvino, PhD, Pharmacology

Martin Lehr, Context Therapeutics

Elahe Mostaghel, MD, PhD, Clinical Research (Fred Hutch)

Abstract

Androgen receptor (AR) signaling is the primary driver of prostate cancer (PCa) disease progression, resulting in about 27,500 deaths per year in the US. First line treatment of PCa is androgen deprivation therapy through castration (chemical or surgical), thus blocking androgen binding to AR and subsequent AR signaling (the “AR axis”). While castration negates AR signaling for a period of time, castration resistant prostate cancer (CRPC) emerges due to compensatory mechanisms that constitutively activate AR pro-survival pathways. Current anti-androgen drugs do not address, and often enhance, these resistance mechanisms. Thus, there is a significant need in CRPC patients for novel approaches that overcome the inevitable resistance to current AR targeted therapies.

Sigma1 is novel therapeutic target for CRPC. Sigma1 is a stabilizing protein that coordinates the maturation and transport of client proteins that are critical to the AR Axis. Sigma1 is enriched in prostate cancer cells and RNAi-mediated knockdown of Sigma1 results in tumor growth inhibition. Upon screening known Sigma1 inhibitors, we identified only haloperidol as a potent inhibitor of Sigma1-mediated AR signaling. Despite being FDA approved, the utility of haloperidol is limited by side effects.

We have developed a novel, potent, drug-like Sigma1 inhibitor series exemplified by CT-110. CT-110 potently binds to Sigma 1, Ki < 50 nM in relevant native cell lines, and most importantly it is efficacious in the aggressive C4-2 CRPC mouse xenograft model where tumor regression is associated with AR degradation