Abstract 5381: Therapeutic potential of HDAC inhibitors in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)
Notice bibliographique
Résumé
Abstract SCCOHT is a rare but deadly type of ovarian cancer. It mainly affects young women with the median age about 28 years. Although often diagnosed at an early stage, the prognosis of SCCOHT is nonetheless dismal with a 2-year survival less than 35% due to lack of effective treatments. Unlike common malignancies, the genome of SCCOHT is minimally disturbed. Recently, we and others have discovered inactivating mutations of SMARCA4, the ATPase of the SWI/SNF chromatin remodeling complex, in the majority of SCCOHT along with loss of SMARCA4 protein. Interestingly, SMARCA2, the alternative ATPase of the SWI/SNF complex is also inactivated in SCCOHT without apparent mutations. Re-expression of either SMARCA4 or SMARCA2 robustly inhibited the growth of SCCOHT cells. Therefore, the dual deficiency of SMARCA4 and SMARCA2 may be the primary driver in SCCOHT tumorigenesis by creating distinct epigenetic features that promote oncogenic transformation and can serve as promising therapeutic targets. In an attempt to identify epigenetic drugable targets, we performed the drug screening using an epigenetic drug library (Cayman Chemical) in two SCCOHT cell lines and four other ovarian cancer cell lines with intact SMARCA4 and SMARCA2. We identified several HDAC inhibitors that selectively inhibited the viability of SCCOHT cells (BIN67 and SCCOHT1) compared to that of other ovarian cancer cell lines. We confirmed that in comparison to other ovarian cancer cell lines, SCCOHT cells were significantly more sensitive to the treatment of several pan-HDAC inhibitors including SAHA, an FDA-approved HDAC inhibitor for treatment of cutaneous T cell lymphoma, and two selective HDAC6 inhibitors (CAY10603 and Nexturastat A), but not to Romidepsin, a selective HDAC1/2 inhibitor. Furthermore, the expression of HDAC6 was significantly higher in SCCOHT cells compared with other ovarian cancer cell lines and re-expression of SMARCA4 suppressed the expression of HDAC6. Interestingly, SCCOHT cells were also more sensitive to Pracinostat, a broad HDAC inhibitor with minimum effect on HDAC6. Using Agilent gene expression array, we identified a subset of genes whose expression was upregulated by both SMARCA4 re-expression and SAHA treatment in BIN67 cells. Taken together, our data suggest that the SMARCA4/SMARCA2 dual deficiency may promote hypersensitivity to HDAC inhibitors through both HDAC6-dependent and independent pathways. Ongoing studies will address the detailed mechanisms and evaluate the efficacy of using HDAC inhibitors for the treatment of SCCOHT cell line-derived and patient-derived mouse xenografts to provide requisite evidence for initiating a clinical trial for defeating this notorious disease. Citation Format: Yemin Wang, Pilar Ramos, Anthony N. Karnezis, Jeffrey M. Trent, David G. Huntsman. Therapeutic potential of HDAC inhibitors in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). [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 5381. doi:10.1158/1538-7445.AM2015-5381
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, 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 ».