Abstract PR19: Targeting DNA double-strand break repair to potentiate radio- and chemo-therapy of glioblastoma
Notice bibliographique
Résumé
Abstract Glioblastomas (GBMs) are lethal brain tumors which are treated with ionizing radiation (IR) in combination with the DNA alkylating agent temozolomide (TMZ). Unfortunately, not all GBMs respond to therapy, and most of them quickly acquire resistance to TMZ and recur. In order to better understand the molecular basis for therapy-driven TMZ resistance, mice bearing orthotopic GBM xenografts were subjected to protracted TMZ treatment, and cell lines were generated from the primary (untreated) and recurrent (TMZ-treated) tumors. We found that cell lines derived from recurrent tumors were more resistant to TMZ in vitro compared to cell lines derived from primary tumors. We also found that the increased resistance to TMZ was due to augmented repair of TMZ-induced DNA double strand breaks (DSBs). TMZ induces DNA replication-associated DSBs that are primarily repaired by the homologous recombination (HR) pathway. Augmented HR appears to underpin TMZ resistance in the recurrent lines as these cells were cross-resistant to other agents that induce replication-associated DSBs, exhibited faster resolution of damage-induced Rad51 foci, and displayed higher levels of sister chromatid exchanges (SCEs). We have recently shown that CDKs 1 and 2 promote HR in S and G2 phases of the cell cycle, in part, by phosphorylating the exonuclease EXO1. We hypothesized, therefore, that blocking CDKs 1 and 2 might be a viable strategy for re-sensitizing recurrent tumors to TMZ. Indeed, we found that CDK inhibitors, AZD5438 and Roscovitine, could attenuate HR in the recurrent TMZ-resistant cell lines, resulting in significant chemo-sensitization. While TMZ-induced DSBs are primarily repaired by HR, IR- induced DSBs are mainly repaired by the non-homologous end joining (NHEJ) pathway. We, therefore, developed another approach to sensitize GBMs to both radiation and TMZ by using a dual PI3K/mTOR inhibitor, NVP-BEZ235, to target both DNA-PKcs and ATM, key enzymes in the NHEJ and HR pathways, respectively. We found that NVP-BEZ235 inhibited both DNA-PKcs and ATM in orthotopic GBM xenografts, thus blocking the repair of TMZ- and IR-induced DSBs in these tumors. Hence NVP-BEZ235, administered with IR, could attenuate tumor growth, and extend survival of tumor-bearing mice. Importantly, inhibition of DSB repair was more pronounced in tumor cells compared to normal brain cells, thereby providing a larger therapeutic window. In sum, these studies indicate that augmented DSB repair may underlie radio- and chemo-resistance in GBM, and provide support for DNA repair inhibition as an effective strategy for improving the efficacy of GBM therapy. This abstract is also being presented as Poster B22. Citation Format: Bipasha Mukherjee, Carlos Gil del Alcazar, Pavlina Todorova, Sandeep Burma. Targeting DNA double-strand break repair to potentiate radio- and chemo-therapy of glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR19.
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 | 0,001 | 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 ».