Abstract 1079: Anti-cancer efficacy of TH1902, a SORT1 docetaxel peptide-drug conjugate, against ovarian and endometrial cancers xenografts alone or in combination with carboplatin
Notice bibliographique
Résumé
Abstract Effective, safe chemotherapy treatments for gynecological cancers remain a daunting challenge. One strategy to achieve greater selectivity and better anticancer drug delivery into cancer cells is to conjugate cytotoxic agents to specific peptide ligands that selectively target receptors abundantly expressed on these cells. Increased expression of sortilin (SORT1), a scavenging receptor, has been shown to be highly expressed in many cancers, including ovarian and endometrial cancers. The peptide-drug conjugate TH1902 (a peptide which targets SORT1 and is bis-linked to two docetaxel molecules) was investigated to determine whether it could be efficacious against SORT1-positive ovarian (ES-2, A-2780 and SKOV-3) and endometrial (AN3-CA) cancer models. The Alexa488-fluorescent peptide used to generate TH1902 was transported into ES-2 and SKOV-3 cells by a process requiring clathrin-coated vesicles, and which was strongly diminished by siRNA-mediated SORT1 silencing or by competition with SORT1 ligands. In vitro, TH1902 enabled an increase in apoptosis of over 2-fold compared to that of unconjugated docetaxel. The effects of TH1902 administration were also examined in multiple subcutaneous xenograft tumor models (ES-2, SKOV-3, A-2780 or AN3-CA cells). Following two weeks treatment at equivalent docetaxel doses, the ES-2 xenograft sizes in mice treated with vehicle or with docetaxel were statistically indistinguishable but there was a significant decrease in tumor size by 78% for mice treated with TH1902. In SKOV-3 xenografts, treatment with either drug both stopped tumor growth and induced similar tumor regressions. In AN3-CA xenografts, treatments administered at equivalent docetaxel maximum tolerated dose (MTD) induced similar initial tumor regressions. However, TH1902-treated mice showed prolonged tumors regression whereas tumors started to regrow upon docetaxel treatment interruption. At one quarter of the docetaxel MTD, TH1902 significantly inhibited AN3-CA tumor growth whereas docetaxel had minimal effect (-73% vs -11%, respectively). Mice bearing A-2780 xenograft tumors were treated with TH1902, paclitaxel or docetaxel alone, as well as with each in combination with carboplatin. Comparison of the tumor sizes between the various treatments showed that TH1902 alone caused stronger A-2780 tumor growth inhibition than did either of the unconjugated taxanes or carboplatin. Moreover, TH1902 combined with carboplatin also demonstrated better efficacy than did either of the taxane-carboplatin combinations. Overall, the results indicate that TH1902 possesses an in vivo efficacy superior to those of docetaxel against ovarian and endometrial cancers in the animal models tested, and that TH1902 could be safely combined with carboplatin to reach optimal inhibition of tumor growth. Citation Format: Christian Marsolais, Michel Demeule, Cyndia Charfi, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Richard Béliveau, Borhane Annabi. Anti-cancer efficacy of TH1902, a SORT1 docetaxel peptide-drug conjugate, against ovarian and endometrial cancers xenografts alone or in combination with carboplatin [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 1079.
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 ».