Abstract B17: Dexamethasone synthetic lethal screens uncover two potential combination therapies for the treatment of multiple myeloma
Notice bibliographique
Résumé
Abstract Multiple myeloma (MM) is an incurable malignancy of plasma B lymphoid cells that occurs in the bone marrow. Treatment usually involves autologous stem cell transplantation followed by various combinations of chemotherapies all of which include dexamethasone (DEX) in first-line as well as end-stage therapies. DEX is a steroid hormone analog that binds to the glucocorticoid nuclear receptor and acts by differentially regulating the expression of genes involved in inflammation, and cell death. Despite the utility of glucocorticoids, resistance is common and MM remains an incurable disease. Using a pooled shRNA screening approach, MCL1 was identified as a gene whose knock-down confers increased sensitivity to dexamethasone. MCL-1 is an anti-apoptotic Bcl-2 family member often over-expressed in multiple cancers including MM, and has been linked with resistance to chemotherapy. Obatoclax is a pan BCL-2 family inhibitor that potently disrupts MCL-1/BAK interactions and is highly cytotoxic to MCL-1 dependent cell lines. The combination of dexamethasone with obatoclax results in a synergistic inhibition of MM cell line growth. The synergy is most pronounced when cells are pre-treated for 48h with dexamethasone suggesting the involvement of gene regulation in the combination therapy. BIM, a pro-apoptotic MCL-1 binding partner, is induced in multiple myeloma cells in vitro and in vivo in the Vk*myc murine MM model following dexamethasone treatment. BIM induction is important for BAK and BAX oligomerization at the mitochondrial membrane initiating the cell death response and is required for dexamethasone mediated cell killing of MM cells. Obatoclax is effective as a single agent in the Vk*myc model and is currently being evaluated in combination with dexamethasone. In a second genome-wide siRNA screen in MM cells, knockdown of Aurora kinase B (AURKB) was identified as a dexamethasone sensitizer. The AURKB specific inhibitor, AZD1152 synergizes with dexamethasone in several cell lines, when treatment with AZD1152 precedes that of dexamethasone. A KMS-11 cell line overexpressing BCL-2 can inhibit the synergy between AZD1152 and dexamethasone, demonstrating the involvement of the BCL-2 family of apoptotic regulators in cell death mediated by the combination. The synergy may be in part mediated through TP53 as knockdown of TP53 with siRNAs eliminates AZD1152-mediated cell death. SiRNA-mediated knockdown experiments show that two TP53 regulated genes and pro-apoptotic members of the BCL-2 family, NOXA and PUMA, are also involved in the mechanism of cell death. PUMA, like BIM, is an activator of BAK/BAX mediated outer mitochondrial memebrane permeabilization (MOMP) and NOXA is a sensitizer protein that can displace the activator proteins from MCL-1/BCL-2 inhibitors thus sensitizing cells to MOMP. The AZD1152/DEX combination is currently being tested in the Vk*myc murine model of MM. These results propose two potential new combination therapies that operate through a mechanism involving DEX mediated BIM induction and by modulation of BCL-2 family rheostat. Obatoclax inhibits the function of anti-apoptotic MCL-1 activity and AZD1152 leads to induction of NOXA and PUMA protein, sensitizing the cells to DEX mediated cell death. Citation Format: Anne Roulston, Cynthia Bernier, Mai Nguyen, Franziska Ertel, Francis Robert, Maryanne Bellomo, Xian Fang Huang, Alexandre Bramoullé, Michel Gravel, Michael Sebag, Jerry Pelletier, Gordon Shore. Dexamethasone synthetic lethal screens uncover two potential combination therapies for the treatment of multiple myeloma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B17.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 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 ».