title: Potent activity of the Hsp90 inhibitor ganetespib in prostate cancer             cells irrespective of androgen receptor status or variant receptor expression.
abstract: Androgen ablation therapy represents the first line of therapeutic intervention             in men with advanced or recurrent prostate tumors. However, the incomplete efficacy             and lack of durable response to this clinical strategy highlights an urgent need             for alternative treatment options to improve patient outcomes. Targeting the molecular             chaperone heat shock protein 90 (Hsp90) represents a potential avenue for therapeutic             intervention as its inhibition results in the coordinate blockade of multiple             oncogenic signaling pathways in cancer cells. Moreover, Hsp90 is essential for             the stability and function of numerous client proteins, a number of which have             been causally implicated in the pathogenesis of prostate cancer, including the             androgen receptor (AR). Here, we examined the preclinical activity of ganetespib,             a small molecule inhibitor of Hsp90, in a panel of prostate cancer cell lines.             Ganetespib potently decreased viability in all lines, irrespective of their androgen             sensitivity or receptor status, and more effectively than the ansamycin inhibitor             17-allylamino-17-demethoxygeldanamycin (17-AAG). Interestingly, while ganetespib             exposure decreased AR expression and activation, the constitutively active V7             truncated isoform of the receptor was unaffected by Hsp90 inhibition. Mechanistically,             ganetespib exerted concomitant effects on mitogenic and survival pathways, as             well as direct modulation of cell cycle regulators, to induce growth arrest and             apoptosis. Further, ganetespib displayed robust antitumor efficacy in both AR-negative             and positive xenografts, including those derived from the 22Rv1 prostate cancer             cell line that co-expresses full-length and variant receptors. Together these             data suggest that further investigation of ganetespib as a new therapeutic treatment             for prostate cancer patients is warranted.
authors.affiliation: Synta Pharmaceuticals Corp., Lexington, MA 02421, USA.
authors.forename: Suqin
authors.initials: S
authors.lastname: He
authors.forename: Chaohua
authors.initials: C
authors.lastname: Zhang
authors.forename: Ayesha A
authors.initials: AA
authors.lastname: Shafi
authors.forename: Manuel
authors.initials: M
authors.lastname: Sequeira
authors.forename: Jaime
authors.initials: J
authors.lastname: Acquaviva
authors.forename: Julie C
authors.initials: JC
authors.lastname: Friedland
authors.forename: Jim
authors.initials: J
authors.lastname: Sang
authors.forename: Donald L
authors.initials: DL
authors.lastname: Smith
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Weigel
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Wada
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D012333:RNA, Messenger; D011944:Receptors, Androgen; C533237:STA 9090; D014230:Triazoles; C112765:tanespimycin