title: A novel HSP90 inhibitor delays castrate-resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis.
abstract: OBJECTIVE
  Prostate cancer responds initially to antiandrogen therapies; however, progression to castration-resistant disease frequently occurs. Therefore, there is an urgent need for novel therapeutic agents that can prevent the emergence of castrate-resistant prostate cancer (CRPC). HSP90 is a molecular chaperone involved in the stability of many client proteins including Akt and androgen receptor (AR). 17-Allylamino-17-demethoxy-geldanamycin (17-AAG) has been reported to inhibit tumor growth in various cancers; however, it induces tumor progression in the bone microenvironment.
  
  
  METHODS
  Cell growth, apoptosis, and AR transactivation were examined by crystal violet assay, flow cytometric, and luciferase assays, respectively. The consequence of HSP90 therapy in vivo was evaluated in LNCaP xenograft model. The consequence of PF-04928473 therapy on bone metastasis was studied using an osteoclastogenesis in vitro assay.
  
  
  RESULTS
  PF-04928473 inhibits cell growth in a panel of prostate cancer cells, induces cell-cycle arrest at sub-G(1), and leads to apoptosis and increased caspase-3 activity. These biological events were accompanied by decreased activation of Akt and Erk as well as decreased expression of Her2, and decreased AR expression and activation in vitro. In contrast to 17-AAG, PF-04928473 abrogates RANKL-induced osteoclast differentiation by affecting NF-κB activation and Src phosphorylation. Finally, PF-04929113 inhibited tumor growth and prolonged survival compared with controls. Surprisingly, PF-04929113 did not reduce serum prostate-specific antigen (PSA) levels in vivo; in parallel, these decrease in tumor volume.
  
  
  CONCLUSIONS
  These data identify significant anticancer activity of PF-04929113 in CRPC but suggest that serum PSA may not prove useful as pharmacodynamic tool for this drug.
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Francois
authors.initials: F
authors.lastname: Lamoureux
authors.forename: Christian
authors.initials: C
authors.lastname: Thomas
authors.forename: Min-Jean
authors.initials: MJ
authors.lastname: Yin
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kuruma
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009919:Orchiectomy; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D047029:Lactams, Macrocyclic; D017430:Prostate-Specific Antigen; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; C534922:SNX 2112; C112765:tanespimycin; C508053:ERBB2 protein, human