A Multivalent Peptoid Conjugate Modulates Androgen Receptor Transcriptional Activity to Inhibit Therapy-resistant Prostate Cancer.

Abstract

Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance due to ongoing AR expression and function. To counter this, we developed a new approach to modulate the AR and inhibit castration-resistant prostate cancer (CRPC) using multivalent peptoid conjugates (MPC) that contain multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic scaffold. Here, we investigated the antitumor effects of compound MPC309, a trivalent display of ethisterone conjugated to a peptoid oligomer backbone that binds to the AR with nanomolar affinity. MPC309 exhibited potent antiproliferative effects on various enzalutamide-resistant prostate cancer models, including those with AR splice variants, ligand-binding mutations, and noncanonical AR gene expression programs, as well as mouse prostate organoids harboring defined genetic alterations that mimic lethal human prostate cancer subtypes. MPC309 is taken up by cells through macropinocytosis, an endocytic process more prevalent in cancer cells than in normal ones, thus providing an opportunity to target tumors selectively. MPC309 triggers a distinct AR transcriptome compared with DHT and enzalutamide, a clinically used antiandrogen. Specifically, MPC309 enhances the expression of differentiation genes while reducing the expression of genes needed for cell division and metabolism. Mechanistically, MPC309 increases AR chromatin occupancy and alters AR interactions with coregulatory proteins in a pattern distinct from DHT. In xenograft studies, MPC309 produced significantly greater tumor suppression than enzalutamide. Altogether, MPC309 represents a promising new AR modulator that can combat resistant disease by promoting an AR antiproliferative gene expression program.

• Authors: Justine Habault, Jeffrey A Schneider, Susan Ha, Rachel Ruoff, Luiza D Pereira, Joseph Puccini, Michela Ranieri, Ruveyda Ayasun, Jiehui Deng, Amanda C Kasper, Dafna Bar-Sagi, Kwok-Kin Wong, Amina Zoubeidi, Frank Claessens, David R Wise, Susan K Logan, Kent Kirshenbaum, Michael J Garabedian
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 22 Issue 10 Pg. 1166-1181 (10 02 2023) ISSN: 1538-8514 [Electronic] United States
• PMID: 37486978 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2023 American Association for Cancer Research.

Chemical References

• enzalutamide
• Receptors, Androgen
• Peptoids
• Ligands
• Ethisterone
• Nitriles
• Androgen Receptor Antagonists

Topics

• Male
• Animals
• Mice
• Humans
• Receptors, Androgen (metabolism)
• Peptoids (pharmacology)
• Ligands
• Ethisterone (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Prostatic Neoplasms (pathology)
• Nitriles (pharmacology)
• Androgen Receptor Antagonists (pharmacology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, metabolism)