Abstract NTOC-083: TARGETED APPROACH WITH MOMELOTINIB TREATMENT ATTENUATES PACLITAXEL–INDUCED ENRICHMENT OF CANCER STEM CELLS (CSC)–LIKE AND SUPPRESSES OVARIAN CANCER TUMORIGENESIS AND RECURRENCE
Notice bibliographique
Résumé
Abstract INTRODUCTION: In the era of personalised medicine, chemotherapy treatment alone is inadequate to treat advanced-stage ovarian cancer patients, given that a steady 75% of patients relapse within five years and die of this disease. We have shown that chemotherapy-treated ovarian cancer cell lines express significantly elevated JAK2/STAT3 activation and CSC-like compared to untreated cells in vitro and in vivo mouse models. We aim to investigate the in vivo significance of targeting paclitaxel-induced ovarian CSC-like and the associated JAK2/STAT3 activation using the JAK2-specific inhibitor, Momelotinib. METHODS: Female Balbc nu/nu mice were injected ip with HEY cells and treated at day 19 with paclitaxel (15mg/kg bodyweight) weekly by ip injection and/or Momelotinib (25mg/kg bodyweight) daily by oral gavage. Study 1: All treatment groups (n=3/group) were sacrificed at the same time as the untreated control group (n=4). Study 2: All treatments were terminated after the endpoint of untreated group groups and were sacrificed at their respective endpoints (n=4). Study 3: Paclitaxel+Momelotinib-treated group was further divided into two groups (n=9/group) after the endpoint of the untreated group: (i) termination of paclitaxel and Momelotinib treatments, and (ii) termination of paclitaxel treatment alone for 13 weeks. One-way ANOVA was used to compare the tumour burden (tumour wt/mice wt), survival period, and immunohistochemistry analysis of the tumour xenograft for the activated JAK2/STAT3 and CSC-like markers (Oct3/4 and c-Kit) expressions between multiple groups. Statistical significance was defined as a p value < 0.05. RESULTS: In Study 1, paclitaxel+Momelotinib-treated group produced the smallest tumour burden compared to all groups, and had tumours that showed a reduction in the activated JAK2/STAT3 pathway and CSC-like markers expressions when compared to the paclitaxel-treated group. In Study 2, paclitaxel+Momelotinib-treated group survived the longest compared to all groups. In Study 3, paclitaxel+(ongoing)Momelotinib-treated group survived substantially longer and produced a significantly smaller tumour burden compared to the untreated and paclitaxel+(terminated) Momelotinib-treated groups. Expressions of the activated JAK2/STAT3 and CSC-like markers were significantly upregulated in the tumours isolated from paclitaxel+Momelotinib-treated group post-Momelotinib termination compared to pre-Momelotinib termination. CONCLUSION: Targeting the paclitaxel-induced JAK2/STAT3 activation and CSC-like using Momelotinib not only enhanced paclitaxel cytotoxicity but also prolonged the survival of HEY-bearing mice. This strongly supports the idea for future clinical testing using Momelotinib (currently in Phase 3 clinical trials for treating myelofibrosis) in combination with paclitaxel for advanced-stage ovarian cancer patients. These results also support the use of Momelotinib as a maintenance treatment for the ongoing suppression of the activated JAK2/STAT3 pathway in an attempt to prevent a relapse in ovarian cancer patients. Citation Format: Chan. E, Findlay. JK, Luwor. R, Hickey. M, Ahmed. N. TARGETED APPROACH WITH MOMELOTINIB TREATMENT ATTENUATES PACLITAXEL–INDUCED ENRICHMENT OF CANCER STEM CELLS (CSC)–LIKE AND SUPPRESSES OVARIAN CANCER TUMORIGENESIS AND RECURRENCE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-083.
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 | 0,000 |
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 ».