Abstract NTOC-084: THE PROMISE OF COMBINATIONAL TREATMENT OF HISTONE DEACETYLASE 6 INHIBITOR ACY-1215 AND PROTEASOME INHIBITOR BORTEZOMIB IN SCCOHT
Notice bibliographique
Résumé
Abstract PURPOSE: Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a rare ovarian cancer that predominantly affects young women with a median age of 24 years. Although half of the tumors are diagnosed at an early stage, the prognosis is dismal due to lack of effective treatment options. In response to drastic increase of protein translation and cellular stress during malignant transformation, cancer cells have evolved to highly depend on protein surveillance pathways to correct or degrade unfolded and misfolded proteins to ensure protein homeostasis. Inhibition of these protein surveillance pathways has been proven to selectively target cancer cells. Particularly, inhibition of proteasome, which degrades more than 80% of cellular proteins, by selective inhibitors leads to accumulation of its substrates and consequently results in activation of apoptotic pathways in highly proliferative cancer cells. However, resistance occurs frequently. As a result several combinational treatments have been investigated in clinical trials with various drugs, such as HDAC6 inhibitor, which shuts down the aggresome-mediated proteolysis. Therefore, we aimed to determine the promise of inhibiting both protein degradation pathways as a novel therapeutic strategy for SCCOHT. EXPERIMENTAL PROCEDURE: Concentration-effect relationships were determined for both proteasome and HDAC6 inhibitors, alone or in combination, in SCCOHT cell lines and other ovarian carcinoma cell lines using a 3-day cell viability assay measured by crystal violet staining. Cell apoptosis was measured by live cell imaging with activated caspase-3/7. Drug action mechanism was interrogated by Western blotting. RESULT: SCCOHT cells are hypersensitive to both proteasome inhibitor (Bortezomib) and HDAC6 inhibitor (ACY-1215) with IC50 around low nM and μM, respectively. In addition, both Bortezomib and ACY-1215 inhibited cell proliferation and induced apoptosis in SCCOHT cells. Treatment with ACY-1215 led to inhibition of the aggresome as evidenced by an increased level of acetyl-tubulin, accumulation of polyubiquitinated proteins and upregulation of the unfolded protein response. Combination of Bortezomib and ACY-1215 led to an increased level of poly-ubiquitinated proteins, stronger suppression of cell proliferation and more apoptosis compared to either drug alone in SCCOHT cells, with some dosing having synergistic effect. CONCLUSION: Our data suggest that ACY-1215 or Bortezomib alone significantly suppressed the growth and induced apoptosis of SCCOHT cells. Combination of ACY-1215 and Bortezomib synergistically increased growth suppression and cell apoptosis and thereby may be a potential rational therapeutic strategy for SCCOHT. Citation Format: Yuting Shary Chen, Yemin Wang, Anthony Karnezis, Pilar Ramos, Holly Yine, Bernard Weissman, Jeffrey Trent, David Huntsman. THE PROMISE OF COMBINATIONAL TREATMENT OF HISTONE DEACETYLASE 6 INHIBITOR ACY-1215 AND PROTEASOME INHIBITOR BORTEZOMIB IN SCCOHT [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-084.
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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) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| 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) | 0,002 | 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 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 ».