Targeting the N-terminal domain of the androgen receptor: A new approach for the treatment of advanced prostate cancer

Emmanuel S. Antonarakis, Chandtip Chandhasin, Erica Osbourne, Jun Luo, Marianne D. Sadar, Frank Perabo

Research output: Contribution to journalArticle

Abstract

Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration-resistant prostate cancer (CRPC), this disease still poses significant management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR-related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand-independent AR splice variants, and gain-of-function mutations involving the AR ligand-binding domain (LBD), among others. Therefore, the development of AR-targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N-terminal domain (NTD) inhibition as a novel concept in the field of AR-directed therapies for prostate cancer. AR NTD-targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR-mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway.

Original languageEnglish (US)
Pages (from-to)1427-1435
Number of pages9
JournalOncologist
Volume21
Issue number12
DOIs
StatePublished - Dec 2016

Keywords

  • Androgen receptor
  • EPI-506
  • N-terminal domain
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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