325 TAK-441, A NOVEL INVESTIGATIONAL SMOOTHENED ANTAGONIST, DELAYS CASTRATION RESISTANT PROGRESSION IN PROSTATE CANCER BY DISRUPTING PARACRINE HEDGEHOG SIGNALING
Bibliographic record
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 , 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 ...
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".