Abstract 1516: Androgen-repressed and androgen-induced genes: challenging the traditional dogma of prostate cancer therapy
Notice bibliographique
Résumé
Abstract Background: Benign and malignant prostate tissues are dependent upon the activity of androgen receptor (AR). The primary function of full-length AR is as a ligand activated transcription factor to increase or repress gene expression. Many androgen-repressed genes regulate the cell cycle and proliferation. With castration, the main therapeutic approach for advanced prostate cancer (PC), these genes are believed to play a role in the initial clinical response. Current approved therapies for advanced PC and castration-resistant PC (CRPC), target the AR C-terminal ligand-binding domain (LBD), such as antiandrogens. Recent antagonists of the AR N-terminal domain (NTD) have been described with EPI-506, the prodrug of EPI-002, now in Phase 1 clinical trials. EPI-002 binds tau-5 in activation function-1 (AF-1) of the NTD that is essential for AR transcriptional activity. As expected with an AF-1 antagonist, EPI-002 is an excellent inhibitor of androgen-induced gene expression and at blocking the transcriptional activities of truncated AR splice variants lacking LBD, such as AR-V7. EPI-002 blocks expression of genes regulated by truncated AR-V7 such as UBE2C while antiandrogens have no effect. Here we reveal that the major difference in gene expression regulated by full-length AR between EPI-002 and antiandrogens is their abilities to de-repress genes that are turned off by androgen. Methods: The androgen sensitive human prostate cancer cell line LNCaP, which expresses full-length AR, was treated with antiandrogens (bicalutamide [BIC] and enzalutamide [ENZA]), EPI-002 and a control vehicle, with and without androgen. Gene expression was analysed using Affymetrix microarrays. Bioinformatical analysis was completed and a selection of androgen-repressed genes that were de-repressed with antiandrogens and/or EPI-002, were selected for validation using qRT-PCR. Results: EPI-002 de-repressed known androgen-repressed genes including SPLTLC3, ST7, PSAT1, TMEM140 and TNFRSF21. EPI-002 was as effective or better than BIC or ENZA in de-repressing a subset of androgen-repressed genes. Importantly, EPI-002 failed to de-repress expression of many androgen-repressed genes that antiandrogens de-repressed, such as SLITRK3, GPR63 and DAB1. Conclusions: EPI binds AR NTD which blocks the transcriptional activities of full-length AR and truncated AR splice variants. EPI-002 was excellent at inhibiting androgen-induced genes. However, EPI did not broadly de-repress expression of genes turned off by androgen when compared to antiandrogens. Such differences between EPI-002, a tau-5/NTD antagonist, and C-terminal LBD antiandrogens probably reflect the complexities of the mechanisms of repression of gene expression that may involve different domains of AR. Citation Format: Daniel P. Caley, Nasrin R. Mawji, Marianne Sadar. Androgen-repressed and androgen-induced genes: challenging the traditional dogma of prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1516. doi:10.1158/1538-7445.AM2017-1516
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,008 | 0,002 |
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 source (Gemma direct ou Codex distillé), 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 ».