Proceedings - Boulder Peptide Foundation

BPS 2025

An AR protein degrader for prostate cancer therapy

Benyi Li

Professor, KANSAS UNIV MEDICAL CENTER

ABSTRACT

Prostate cancers in the late stage after androgen deprivation therapy plus anti-androgen treatment with Xtandi (a.k.a. Enzalutamide or MDV3100) or Zytiga. (a.k.a. Abiraterone) often become treatment-resistant without any means to cure. Recent studies from our group and others revealed that eliminating AR protein (full-length or truncated) will overcome treatment resistance in advanced prostate cancers. Although the recently reported PROTAC approach can enhance AR protein degradation, it is not suitable for patients who harbor a truncated AR protein that escapes PROTAC-mediated degradation. Our preliminary studies identified a small peptide that triggers the androgen receptor protein (including full-length and truncated variants) degradation in prostate cancer cells. In this talk, I will discuss the optimization of small peptide to improve its drug-like properties. We will show the results of our investigation in multiple prostate cancer cell lines-derived animal xenograft models, and patient tissue-derived xenograft models in animals. We will confirm the therapeutic efficacy of the optimized peptides in promoting AR protein degradation in animal models. I will also show how this peptide triggers AR protein degradation based on our strong preliminary data that AR stability was attenuated due to the small peptide-induced disruption of AR association with a protein complex of PHKA1 and PHKB. The novel therapeutic peptide will provide new hope for patients who developed anti-AR drug resistance.

BIO

Dr. Li received his medical education in China and Ph.D. work in Japan. After moved to the US in 1998, he stayed away from clinical work but focused on urological research. After 2 postdoc fellowships at Moffitt Cancer Center and Baylor College of Medicine, he joined the KUMC Urology faculty at the end of 2001 and established the basic research program for the department. His research topic is mainly on prostate cancer, aiming to develop novel and clinically beneficial therapeutics for patients with advanced prostate cancers.

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