Abstract 2879: Pre-clinical characterization of Dacomitinib, an irreversible pan-HER inhibitor, combined with radiation therapy in head and neck cancer models
Notice bibliographique
Résumé
Abstract Introduction: Head and neck cancer is the 5th most common cancer worldwide; the majority of cases (>90%) are squamous cell carcinomas (SCCHNs). Despite advances in treatment, the 5-year overall survival rate for SCCHN patients still remains at ∼40-50%, underscoring the need to develop novel therapeutic strategies. EGFR is over-expressed in ∼90% of SCCHN cases, and is associated with tumor progression and poor prognosis. Dacomitinib (D), an irreversible pan-HER inhibitor, has demonstrated clinical potential in patients with non-small cell lung cancer, leading us to explore its therapeutic efficacy in SCCHN pre-clinical models, in combination with radiation therapy (RT), a curative modality for HNC management. Methods: The basal expression of EGFR family members was assessed via qRT-PCR in three SCCHN models (FaDu (human hypopharyngeal), UTSCC-8 & -42a (both laryngeal) squamous cancer, and NOE (normal oral epithelial) cell lines. MTS-based cell viability and clonogenic assays were performed with various concentrations of D, both alone and in combination with irradiation (IR). Inhibition of EGFR signalling by D was confirmed via immunoblotting. Cell cycle analysis was performed to assess mode of cytotoxicity. In vivo therapeutic studies were performed using FaDu xenografts in SCID mice; tumors were extracted post-treatment and examined for TUNEL, CD31, Ki67, and pEGFR via IHC. Results: EGFR was over-expressed in all three SCCHN, compared to the NOE cells. PF (50 nM) reduced FaDu cell viability by ∼25%, with an additive interaction being observed when D was combined with 2 Gy IR (∼36%). Similar trends were observed in the other two cell lines and also in the clonogenic assays. Immunoblotting confirmed a dose-dependent inhibition of EGFR signalling in D-treated SCCHN cells, along with downstream reduction of p-Erk, p-Akt, and p-mTOR expression. Cell cycle analyses showed ∼20% increase in the G0/G1 cell population in D-treated FaDu cells, and ∼10% increase in the sub-G cell population when D and IR were combined. Mice treated with the combination of D + IR exhibited a maximum tumor growth delay of ∼21 days, as compared to the IR only group, determined by time to tumor-plus-leg diameter of 14mm. Preliminary histological analysis of the extracted tumor tissue show ∼40% reduction in Ki67 staining in the PF + IR treated mice. The addition of D to IR appeared to be well-tolerated, with no change in body weight, or extent of alopecia. Conclusion: Dacomitinib effectively inhibited EGFR signalling in SCCHN models, leading to a reduction in cell viability and clonogenic survival in vitro, along with tumor growth delay in vivo. When D was combined with IR, there was an additive interaction, both in vitro and in vivo. Thus, D combined with RT may have a therapeutic benefit for patients with SCCHN. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2879. doi:1538-7445.AM2012-2879
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 | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».