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• W2323557097 abstract "You have accessJournal of UrologyProstate Cancer: Basic Research (II)1 Apr 2013325 TAK-441, A NOVEL INVESTIGATIONAL SMOOTHENED ANTAGONIST, DELAYS CASTRATION RESISTANT PROGRESSION IN PROSTATE CANCER BY DISRUPTING PARACRINE HEDGEHOG SIGNALING Naokazu Ibuki, Mazyar Ghaffari, Mitali Pandey, Ladan Fazli, Masahide Kashiwagi, Hideaki Tojo, Osamu Nakanishi, Haruhito Azuma, Martin Gleave, and Michael Cox Naokazu IbukiNaokazu Ibuki Vancouver, Canada More articles by this author , Mazyar GhaffariMazyar Ghaffari Vancouver, Canada More articles by this author , Mitali PandeyMitali Pandey Vancouver, Canada More articles by this author , Ladan FazliLadan Fazli Vancouver, Canada More articles by this author , Masahide KashiwagiMasahide Kashiwagi Fujisawa, Japan More articles by this author , Hideaki TojoHideaki Tojo Fujisawa, Japan More articles by this author , Osamu NakanishiOsamu Nakanishi Fujisawa, Japan More articles by this author , Haruhito AzumaHaruhito Azuma Takatsuki, Japan More articles by this author , Martin GleaveMartin Gleave Vancouver, Canada More articles by this author , and Michael CoxMichael Cox Vancouver, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1710AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hedgehog (Hh) signaling is a highly conserved inter- and intracellular communication axis that governs cell proliferation, differentiation, patterning and organogenesis of numerous tissues, including the prostate during embryogenesis and is involved in stem cell maintenance, tissue repair and regeneration in adults. Aberrant Gli activation has been implicated in carcinogenesis in of a variety of human cancers. In prostate cancer (PCa) expression of Shh is up-regulated in androgen-deprived and castration-resistant PCa (CRPC) and reactivation of Hh signaling is observed in regions of epithelial-mesenchymal transitions, during CRPC progression and in metastasis. We hypothesize that antagonizing castration-induced paracrine Hh signaling can suppress CRPC progression. METHODS To assess how hedgehog pathway influences CRPC progression, expression of Hedgehog ligands (Shh, Ihh, Dhh) was assessed in tissue microarrays of therapy naive, neoadjuvant hormone therapy-treated (NHT), and CRPC. We also tested the activity of a novel smoothened antagonist, TAK-441, to suppress in vitro and subcutaneous xenograft growth of LNCaP cells. The impact of TAK-441 on Hh signaling in the tumor microenvironment was assessed by QPCR analysis of human- and mouse-specific Gli1, Gli2 and Ptch1 expression. RESULTS Ihh was highly expressed in stroma of all specimens, while elevated Shh and Dhh expression was observed in NHT and CRPC tumor cells. While the TAK-441 did not impact in vitro growth of androgen stimulated or deprived LNCaP cells, it substantially delayed CR progression of LNCaP xenografts. In these xenografts, no change in human Gli1, Gli2 or Ptch expression was observed, but TAK-441 treatment suppressed expression of the corresponding murine transcripts. CONCLUSIONS These studies indicate that when combined with castration, antagonizing Hh signaling pathway with TAK-441 leads to delayed castration-resistant progression of LNCaP xenografts. Since LNCaP cells do not respond directly to Hh ligand stimulation, delay of CR progression appears to occur by disrupting paracrine hedgehog signaling. Thus, paracrine Hh signaling may offer unique opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring of PCa progression. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e131-e132 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Naokazu Ibuki Vancouver, Canada More articles by this author Mazyar Ghaffari Vancouver, Canada More articles by this author Mitali Pandey Vancouver, Canada More articles by this author Ladan Fazli Vancouver, Canada More articles by this author Masahide Kashiwagi Fujisawa, Japan More articles by this author Hideaki Tojo Fujisawa, Japan More articles by this author Osamu Nakanishi Fujisawa, Japan More articles by this author Haruhito Azuma Takatsuki, Japan More articles by this author Martin Gleave Vancouver, Canada More articles by this author Michael Cox Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ..." @default.
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• W2323557097 title "325 TAK-441, A NOVEL INVESTIGATIONAL SMOOTHENED ANTAGONIST, DELAYS CASTRATION RESISTANT PROGRESSION IN PROSTATE CANCER BY DISRUPTING PARACRINE HEDGEHOG SIGNALING" @default.
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