325 TAK-441, A NOVEL INVESTIGATIONAL SMOOTHENED ANTAGONIST, DELAYS CASTRATION RESISTANT PROGRESSION IN PROSTATE CANCER BY DISRUPTING PARACRINE HEDGEHOG SIGNALING
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Résumé
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 , Mazyar GhaffariMazyar Ghaffari Vancouver, Canada , Mitali PandeyMitali Pandey Vancouver, Canada , Ladan FazliLadan Fazli Vancouver, Canada , Masahide KashiwagiMasahide Kashiwagi Fujisawa, Japan , Hideaki TojoHideaki Tojo Fujisawa, Japan , Osamu NakanishiOsamu Nakanishi Fujisawa, Japan , Haruhito AzumaHaruhito Azuma Takatsuki, Japan , Martin GleaveMartin Gleave Vancouver, Canada , and Michael CoxMichael Cox Vancouver, Canada 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 ...
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».