Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer

John T. Isaacs, Jason M. D'Antonio, Shuangling Chen, Lizamma Antony, Susan P. Dalrymple, Georges H. Ndikuyeze, Jun Luo, Samuel R. Denmeade

Research output: Contribution to journalArticlepeer-review

Abstract

Cell culture/xenograft and gene arrays of clinical material document that development of castration resistant prostate cancer (CRPC) cells involves acquisition of adaptive auto-regulation resulting in >25-fold increase in Androgen Receptor (AR) protein expression in a low androgen environment. Such adaptive AR increase paradoxically is a liability in castrated hosts, however, when supraphysiologic androgen is acutely replaced. Cell synchronization/anti- androgen response is due to AR binding to replication complexes (RC) at origin of replication sites (ORS) in early G1 associated with licensing/restricting DNA for single round of duplication during S-phase. When CRPC cells are acutely exposed to supraphysiologic androgen, adaptively increased nuclear AR is over-stabilized, preventing sufficient degradation in mitosis, inhibiting DNA re-licensing, and thus death in the subsequent cell cycle. These mechanistic results and the fact that AR/RC binding occurs in metastatic CRPCs directly from patients provides a paradigm shifting rationale for bipolar androgen therapy (BAT) in patient progressing on chronic androgen ablation. BAT involves giving sequential cycles alternating between periods of acute supraphysiologic androgen followed by acute ablation to take advantage of vulnerability produced by adaptive auto-regulation and binding of AR to RC in CRPC cells. BAT therapy is effective in xenografts and based upon positive results has entered clinical testing.

Original languageEnglish (US)
Pages (from-to)1491-1505
Number of pages15
JournalProstate
Volume72
Issue number14
DOIs
StatePublished - Oct 1 2012

Keywords

  • Cdc6
  • Cdt1
  • DNA Licensing
  • Mcm
  • Orc
  • androgen receptor
  • bipolar androgen therapy
  • origin of replication
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Urology

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