Abstract 3661: Development of novel small-molecule inhibitors of ETS oncoproteins as anti-prostate cancer agents
Notice bibliographique
Résumé
Abstract Currently advanced prostate cancer is treated by suppressing androgen receptor (AR) signaling. Since AR could be activated via multiple mechanisms, inhibition of one or two of these mechanisms could be initially effective, but drug resistance can rapidly develop due to kick-in of other AR-activating mechanisms, resulting in lethal castration-resistant prostate cancer (CRPC). The therapeutic effects of all of the currently available AR-targeting agents are short-lived. To achieve long lasting therapeutic effect for prostate cancer, it appears we need to get out of the box of AR. Here, we propose to develop chemical inhibitors of oncogenic protein ERG, which is an ETS transcriptional factor. The rationale for inhibiting ERG as a possible treatment for prostate cancer has two folds: i) ERG plays a critical role in prostate cancer initiation and progression, and ii) Half of all prostate cancer patients are TMPRSS2-ERG fusion positive, which result in high level of ERG oncoprotein. ERG is a transcriptional factor that directly regulates EZH2, oncogene c-Myc and tumor suppressor Nkx3.1 and many other targets in prostate cancer. ERG cooperates with PI3K/AKT and AR in tumor initiation. ERG knockdown inhibits tumor growth in xenograft of VCaP cells. To date, accumulated studies in patients and experimental models have indicated that ERG overexpression as a result of TMPRSS2-ERG fusion plays a critical role in prostate cancer initiation and progression. However, ERG protein has no obvious functional sites or enzymatic activity to be inhibited and is considered ‘undruggable’. In contrast to such view, our laboratory has recently discovered a novel chemical inhibitor of ERG by combining virtual screening and reporter assay. We have built a structural model of ERG DBD and identified a putative binding-site for virtual screening study. We discovered a novel compound, which substantially inhibits ERG-dependent reporter activity in HEK293 cells and inhibits expression of ERG-regulated genes, such as EZH2 and c-Myc, in VCaP cells. We further showed that our compound inhibits proliferation of VCaP cells, and disrupts association of ERG with its essential coactivator PARP1 by co-IP assay. Surface Plasmon Resonance (SPR) analysis has confirmed that our compound has direct binding with recombinant ERG protein. As recent studies indicated that advanced prostate cancer with TMPRSS2-ERG fusion have substantial higher tendency to metastasize to lymph nodes, ERG inhibitors could be an effective therapeutics to prevent this progression. Importantly, ERG inhibitors could be effective therapeutics for advanced prostate cancer. Citation Format: Xiaohong Tian. Development of novel small-molecule inhibitors of ETS oncoproteins as anti-prostate cancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3661. doi:10.1158/1538-7445.AM2015-3661
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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) | 0,001 | 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) | 0,004 | 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 ».