Abstract 1853: TH1902, a SORT1 docetaxel peptide-drug conjugate, inhibits tumor growth of human cancer stem-like cells (CD133+) from both triple-negative breast cancers and ovarian cancers
Notice bibliographique
Résumé
Abstract Cancer stem cells (CSC), typically associated with CD133 expression, represent a small proportion of cells residing within most tumors and which have high metastatic potential and enhanced drug resistance capacities. In cancer indications such as breast and ovarian cancers, CSC have been shown to be involved in vasculogenic mimicry (VM) and to express the receptor protein sortilin (SORT1). The newly developed SORT1-targeted peptide-docetaxel conjugate (TH1902) has been reported to inhibit both the growth of xenograft tumors in mice and the formation of VM. This work now examines the efficacy of TH1902 against CSC and its potential to circumvent some of the known drug resistance phenotype associated with this population of cells. The effects of TH1902 on human triple-negative breast cancer or ovarian CSC (hTNBCSC and hOvCSC respectively) were explored using two commercial CD133-positive cell lines which are highly resistant to docetaxel and doxorubicin, and which express SORT1 along with the drug efflux pump P-gp and other CSC markers such as CD44, Oct4, Nanog and Sox2. The cellular uptake of the fluorescent Alexa488-peptide from TH1902 was inhibited by SORT1 ligands and in cells where SORT1 expression was repressed using siRNA. In contrast to docetaxel, the addition of TH1902 in vitro induced a marked increase in cell apoptosis and produced cell cycle arrest in the G2/M phase. Interestingly, TH1902-mediated cell cycle arrest was unaffected by the presence of the P-gp inhibitors cyclosporine A or PSC-833. However, the cell cycle which was unaffected by docetaxel was arrested in the G2/M phase in the presence of P-gp inhibitors to levels similar to those of TH1902 alone. These results suggest that TH1902 bypasses the P-gp drug efflux pump. Also, in contrast to docetaxel, exposure to TH1902 inhibited in vitro migration of the hTNBCSC in a wound-healing assay. In vivo, in both CSC models, TH1902 significantly inhibited the growth of CSC-tumor xenografts when administered weekly as intravenous bolus for three cycles at a dose equivalent to the maximal tolerated dose of docetaxel (15 mg/kg) and TH1902-treated mice showed an increased tolerability when compared to those treated with docetaxel. A decrease of approximately 80% of hTNBCSC or hOvCSC tumor growth was observed in TH1902-treated animals while tumor volumes were diminished by about 35% in docetaxel-treated mice. Overall, these results demonstrate that TH1902 exerts superior anticancer activity than the unconjugated docetaxel in two CD133-positive CSC animal models. Furthermore, these results show that TH1902 can circumvent the chemoresistance phenotype of CSC through use of a SORT1-mediated internalization process and therefore could possibly reduce the potential recurrence of cancers associated with CSC. Citation Format: Christian Marsolais, Cyndia Charfi, Michel Demeule, Jean-Christophe Currie, Alain Zgheib, Alain Larocque, Richard Béliveau, Borhane Annabi. TH1902, a SORT1 docetaxel peptide-drug conjugate, inhibits tumor growth of human cancer stem-like cells (CD133+) from both triple-negative breast cancers and ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1853.
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 | 0,000 |
| 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 ».