Abstract B019: BRCA1:NRF2 pathway as a new therapeutic target in ewing sarcoma
Notice bibliographique
Résumé
Abstract Ewing sarcoma (EwS) constitutes a highly aggressive pediatric tumor driven by the oncogenic fusion protein EWSR1-FLI1. A critical clinical concern is EwS metastatic spread, and identification of therapeutic targets have been limited by a general lack of mechanistic understanding. However, we do know that EWSR1-FLI1 expression in EwS displays cell-to-cell heterogeneity, and low EWSR1-FLI1 expression level been proposed to increase metastatic phenotypes. This fits with an inherent program in the cells of origin where without the interference of EWSR1-FLI1 expression, these cells would have differentiated on to a more mesodermal/mesenchymal like cells that includes a migratory program. Therefore, identify this inherent program and prevent its activation may provide the key to block EwS metastatic progression. Recently our group showed that EWSR1-FLI1 traps BRCA1 with active RNAPII, resulting in an overactivation of the RNAPII transcription complex. This prevents BRCA1 to relocate to damage, providing a mechanistic basis for the sensitivity to PARP1 inhibition. Importantly, only a small amount of BRCA1 protein is required for its DNA repair function, and PARP1 inhibition only works in the context of BRCA1 absence. With only small amounts of BRCA1 protein needed to circumvent PARP1 inhibitor efficacy it should not be surprising that PARP1 inhibitors failed in EwS clinical trials. Apart from its role in DNA repair, BRCA1 also supports NRF2 transcriptional activity. Analyzing RNAseq data from different EwS cell lines, we found that, due to BRCA1 unavailability, NRF2 pathway is downregulated in EwS. NRF2 role in response to oxidative stress has been extensively studied, and involves glutathione (GSH) recycling at the expense of intracellular glutamine/glutamate. Analyzing an immunohistochemical assay of a tissue microarray, we found that EwS tumors accumulate high level of glutamine, confirming that NRF2 pathway is partially muted in EwS. GSH is a ubiquitous molecule that fulfills xenobiotic detoxification processes, and is also key to prevent ferroptosis, an iron dependent lipid peroxide induced form of cell death. Combining the clinically approved PARP1 inhibitor Olaparib, and the ferroptosis inducer Sulfasalazine, we found a synergistic effect impairing clonogenic capacity, cell growth and survival. Unfortunately given the limited bioavailability and rapid Sulfasalazine systemic clearance, we were only able to stabilize EwS PDX-tumor growth only for the first weeks. Finally, we found that either depletion of EWSR1-FLI1 or KEAP1 (resulting in high levels of NRF2) increases EwS cell motility and that this occurs in an NRF2 dependent manner. Based on our findings we propose a model where fluctuations in EWSR1-FLI1 expression levels impacts BRCA1 dependent NRF2 activity, impacting the balance of stemness on one hand and migration on the other. Our model suggests that targeting NRF2 dependent functions may provide dual benefit first as a novel therapeutic target when EWSR1-FLI1 expression is high while impairing metastatic spread when EWSR1-FLI1 is low. Citation Format: Nicklas Bassani. BRCA1:NRF2 pathway as a new therapeutic target in ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B019.
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) | 0,000 | 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 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 ».