title: Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer.
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.
authors.affiliation: The Chemical Therapeutic Program, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. isaacjo@jhmi.edu
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.forename: Jason M
authors.initials: JM
authors.lastname: D'Antonio
authors.forename: Shuangling
authors.initials: S
authors.lastname: Chen
authors.forename: Lizamma
authors.initials: L
authors.lastname: Antony
authors.forename: Susan P
authors.initials: SP
authors.lastname: Dalrymple
authors.forename: Georges H
authors.initials: GH
authors.lastname: Ndikuyeze
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004261:DNA Replication; D005434:Flow Cytometry; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D015741:Metribolone; D013739:Testosterone; C053541:bicalutamide