1298 THE NOVEL HSP90 INHIBITOR, PF-04929113, INHIBITS AR ACTIVITY AND OSTEOCLASTOGENESIS AND DELAYS CASTRATE RESISTANT LNCAP PROSTATE CANCER TUMOR GROWTH
Bibliographic record
Abstract
You have accessJournal of UrologyProstate Cancer: Basic Research VII1 Apr 20101298 THE NOVEL HSP90 INHIBITOR, PF-04929113, INHIBITS AR ACTIVITY AND OSTEOCLASTOGENESIS AND DELAYS CASTRATE RESISTANT LNCAP PROSTATE CANCER TUMOR GROWTH Francois Lamoureux, Min-Jean Yin, Amina Zoubeidi, and Martin Gleave Francois LamoureuxFrancois Lamoureux Vancouver, Canada More articles by this author , Min-Jean YinMin-Jean Yin San Diego, CA More articles by this author , Amina ZoubeidiAmina Zoubeidi Vancouver, Canada More articles by this author , and Martin GleaveMartin Gleave Vancouver, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.882AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES While prostate cancer responds initially to anti-androgen therapies, progression to castrate resistant disease inevitably occurs. Consequently there is a need for new therapeutic agents to prevent this transition to castrate resistance. Heat shock protein (HSP) 90 is a molecular chaperone that may play a role in development of castrate resistance in prostate cancer by its involvement in maturation and stability of the Androgen Receptor (AR). In this study, we assessed the antitumor properties of a novel synthetic HSP90 inhibitor, PF-04928473 in vitro and PF-04929113 in vivo in prostate cancer and bone metastasis development. METHODS The effect of the PF-04928473 was evaluated on LNCaP, C4-2, PC3 and DU145 cell growth and apoptosis in vitro using crystal violet and FACS analysis. AR transactivation and other biochemical assays were used to study AR/HSP90 interaction. The anti-cancer effect of PF-04929113 was also evaluated in vivo in athymic mice bearing castrate resistant LNCaP xenografts. Effects of PF-04928473 on bone metastasis were studied using a osteoclastogenesis in vitro assay. RESULTS In the panel of prostate tumor cell lines, PF-04928473 inhibits cell growth in a dose-dependent manner (IC50 ± 30nM) and induces apoptosis with an increase of sub G1 and PARP cleavage. These biologic effects were accompanied by decreases in AR and PSA expression, AR transactivation, inhibition of Akt and Erk activation, and modulation of HSPs expression. When administered orally 3 times/week (50mg/kg) to mice bearing castrate resistant LNCaP tumors, PF-04929113 inhibited significantly tumor growth by 160% and prolonged survival compared to control mice, but induced a small lost of bodyweight. Moreover, unlike 17-AAG, PF-04928473 does not activate src and blocks osteoclast differentiation in vitro. CONCLUSIONS HSP90 inhibition using PF-04928473 and PF-04929113 inhibits castrate resistant LNCaP tumor growth in vitro and in vivo in part through AR disruption and may also inhibit bone metastasis by blocking of osteoclastogenesis. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e502 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Francois Lamoureux Vancouver, Canada More articles by this author Min-Jean Yin San Diego, CA More articles by this author Amina Zoubeidi Vancouver, Canada More articles by this author Martin Gleave Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".