PD05-12 COMBINATION OF AN ANTAGONIST TO THE ANDROGEN RECEPTOR N-TERMINAL DOMAIN WITH ENZALUTAMIDE FOR THE TREATMENT OF CASTRATION RESISTANT PROSTATE CANCER
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Résumé
You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (PD05)1 Apr 2019PD05-12 COMBINATION OF AN ANTAGONIST TO THE ANDROGEN RECEPTOR N-TERMINAL DOMAIN WITH ENZALUTAMIDE FOR THE TREATMENT OF CASTRATION RESISTANT PROSTATE CANCER Yukiyoshi Hirayama*, Kunzhong Jian, Raymond J. Anderson, and Marianne D. Sadar Yukiyoshi Hirayama*Yukiyoshi Hirayama* More articles by this author , Kunzhong JianKunzhong Jian More articles by this author , Raymond J. AndersonRaymond J. Anderson More articles by this author , and Marianne D. SadarMarianne D. Sadar More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000555072.71167.58AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Expression of androgen receptor splice variants (AR-Vs) is associated with resistance to current androgen deprivation therapies and antiandrogens. Constitutively active AR-Vs lack the ligand binding domain of androgen receptor (AR-LBD) which is the direct or indirect target of anti-androgens such as enzalutamide (ENZ) and abiraterone which blocks steroidogenesis. Recently the PLATO trial showed that the addition of abiraterone to ongoing ENZ did not improve progression-free survival in patients with castration resistant prostate cancer (CRPC). These data imply a limitation of combining AR-LBD targeting therapies. Therefore, novel therapeutic approaches are needed to improve the outcomes of CRPC patients. Both AR and truncated AR-Vs require a functional N-terminal domain (NTD) for activity and hence first-in-class antagonists of the AR NTD have been developed such as EPI-002 (ralaniten). Herein a next-generation EPI compound (EPI-7170) was evaluated as a monotherapy or in combination of ENZ in ENZ resistant prostate cancer cells that express AR-Vs. METHODS: We developed ENZ resistant VCaP cells (VCaP-MDVR) by chronic exposure to ENZ. These cells and C4-2B-MDVR cells were used as ENZ resistant prostate cancer cells to test monotherapies versus combination therapy with ENZ and EPI-7170. BrdU incorporation, clonogenic assays and flow cytometry were used to analyze effects on proliferation and cell cycle. Inhibition of expression of AR and AR-V7 target genes by ENZ, EPI-7170 or a combination was analyzed by qPCR. RESULTS: EPI-7170 had 10 times better potency than EPI-002 as measured using proliferation and PSA-reporter gene assays. VCaP-MDVR cells expressed significantly higher levels of AR-V7 protein and mRNA compared to the parental cell line. Knockdown of AR-V7 restored sensitivity of VCaP-MDVR cells to ENZ. A combination of EPI-7170 and ENZ caused synergistic inhibition of proliferation of ENZ resistant cells. Consistent results were also obtained with the clonogenic assay. While ENZ did not inhibited AR-V7 target genes, EPI-7170 inhibited both AR and AR-V7 target genes. A combination of EPI-7170 with ENZ led to a complete inhibition of DNA synthesis in S phase. CONCLUSIONS: The role of AR-Vs in the mechanism of ENZ resistance was provided by knockdown experiments and response to EPI-7170. Synergic inhibition was achieved with a combination of EPI-7170 with ENZ. These results suggest that targeting AR-NTD in addition to AR-LBD to block both FL-AR and AR-Vs could be a potential treatment option for CRPC. Source of Funding: US National Cancer Institute (R01 CA105304) awarded to Marianne D. Sadar Vancouver, Canada© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e85-e85 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yukiyoshi Hirayama* More articles by this author Kunzhong Jian More articles by this author Raymond J. Anderson More articles by this author Marianne D. Sadar More articles by this author Expand All 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 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 | 0,000 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,001 |
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 ».