Abstract SSY01-03: An RNAi screen identifies a heme biosynthetic mediator as a novel radiosensitizing target for head and neck cancer
Notice bibliographique
Résumé
Abstract Introduction: Head and neck cancer (HNC) is a challenging disease due to its heterogeneity and complexity. Despite continued advances in therapeutic options, treatment-associated toxicities and overall clinical outcomes have remained disappointing. Even with radiation therapy (RT), which remains the primary curative modality for HNC, the most effective regimens achieve local control rates of 50-70%, with disease free survival rates of only 30-40% for patients with locally advanced HNSCC. Thus, the development of novel strategies to enhance tumor cell killing, while minimizing damage to the surrounding normal tissues, is critical for improving cure rates with RT. Methods: A siRNA-based high-throughput screen (HTS) was performed for the large-scale identification of novel genes that will selectively sensitize HNC cells to ionizing radiation (IR). The Dharmacon Protein Kinase and Druggable Genome siRNA Libraries were screened using FaDu cells (human hypopharyngeal squamous cell cancer). Radiosensitizing targets were subjected to functional validation studies and in vitro characterization of mechanisms for radiosensitization. In vivo validation studies including tumor formation assays and the treatment of established HNC xenograft models were also conducted. Results: The HTS identified 67 target sequences with potential radiosensitizing effects; the validity of the screen was corroborated by the identification of known radiosensitizing targets (e.g. ATM, ATR, AURKA). Targets reducing the surviving fraction by >50% at 2 Gy relative to their un-irradiated counterparts were selected for further evaluation. A key regulator of the heme biosynthetic pathway was thus identified as a novel tumor-selective radiosensitizing target. Down-regulation of the enzyme plus IR induced caspase-mediated apoptosis and cell cycle arrest in vitro, while delaying tumor growth in vivo. Radiosensitization appeared to be mediated via enhancement of tumor oxidative stress from perturbation of iron homeostasis and increased reactive oxygen species production. This radiosensitizing target was significantly over-expressed in HNC patient biopsies, wherein lower pre-RT mRNA levels correlated with improved survival, suggesting that this enzyme could also be a potential predictor for radiation response. Down-regulation of the enzyme also radiosensitized several different human cancer models, while sparing normal cells. Conclusion: We have successfully developed an RNAi-based radiosensitizer HTS, and uncovered a key regulator of heme biosynthesis as a potent sensitizer for RT, with potentially broad implications in the management of many human malignancies. Citation Format: Emma Ito, Shijun Yue, Eduardo H. Moriyama, Angela B. Hui, Inki Kim, Wei Shi, Nehad M. Alajez, Nirmal Bhogal, GuoHua Li, Alessandro Datti, Aaron D. Schimmer, Brian C. Wilson, Peter P. Liu, Daniel Durocher, Benjamin G. Neel, Brian O'Sullivan, Bernard Cummings, Rob Bristow, Fei-Fei Liu. An RNAi screen identifies a heme biosynthetic mediator as a novel radiosensitizing target for head and neck cancer [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SSY01-03
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 | 0,001 |
| 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) | 0,000 | 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 ».