Interaction of combined administration of multi-targeted kinase inhibitors with ionizing radiation
Notice bibliographique
Résumé
Along with surgery and chemotherapy, radiation therapy is one of the three cancer treatment modalities to treat patients. Over the recent decades, thanks to technological progress, radiation techniques have been improved drastically. However, the same effort has not been put into the biology of the tumours and how different tumours interact with radiation beams. Moreover, it has been only recently that attention has been drawn towards the chemo-radiation or combination of radiation with molecular targeting agents. In this thesis we have studied the combination of ionizing radiation with a class of small molecule inhibitors that target defects in the MAPK/PI3K pathway in breast cancer cells. These pathways are often over-activated in human malignancies including breast cancer. Two of the multiple receptors involved in these pathways are EGFR and VEGFR, which have been shown to be over-expressed in cancerous tumours and have been associated with poor prognosis as well as drug and radiation resistance. The two inhibitors we have used in this study are ZRBA1, a combi-molecule that targets EGFR and also induces DNA lesions, and Sorafenib (Nexavar), which is an inhibitor of several RTKs including VEGFR and also Raf kinase. Using breast cancer cells, we have shown that these multi-functional inhibitors increased the sensitivity of cancer cells towards radiation as they induced a strong G2/M cell cycle arrest and apoptosis. Our in vivo results show that ZRBA1 and Sorafenib, if combined with radiation, can significantly increase tumour growth delay. When radiation is administered concurrently with ZRBA1, a significant tumour growth delay of 47 days is observed. Moreover, ZRBA1 in combination with radiation not only induced the DNA single and double strand breaks, but also delayed DNA repair process contributing to its higher potency against breast cancer cells. Interestingly, Sorafenib when it is combined with radiation has more persistent anti-tumour effect in our in vivo model.Overall, our results suggest that the combined administration of multi-targeting molecular inhibitors, a systemic targeted therapy, with radiation, a local and regional therapy, could be beneficial for patients as they potentiate the radiation response while not increasing adverse side effects.The results of these preclinical studies contribute to a better understanding of how radiation interacts with small molecule inhibitors such as ZRBA1 and Sorafenib and provide the rational basis for further preclinical and clinical studies.
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) | 0,001 | 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 | 0,000 |
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 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 ».