Abstract 1439: Increasing potency of anticancer drugs through SORT1+ technology: A new targeted approach for the treatment of ovarian and endometrial cancers
Notice bibliographique
Résumé
Abstract Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer.Whereas little therapy advances have been made in recent years, precise anticancer drug targeting modalities could be achieve by incorporating a peptide ligand that has the ability to specifically recognize cancer cells. High expression of sortilin (SORT1), a scavenging receptor, was observed in ovarian and endometrial cancers. In light of this, we developed a SORT1-targeted technology to increase both selectivity and efficacy of anticancer drug delivery. Docetaxel was conjugated to a sortilin-binding peptide (TH19P01 peptide). In vitro, high and saturable intracellular delivery of the fluorescent Alexa488-TH19P01 was confirmed in different SORT1+ cancer cell models, whereas internalization was reduced by 70-80% when SORT1 was silenced using siRNA, or by 50-70% upon competition with the SORT1 ligands neurotensin and progranulin. Sortilin expression level was assessed in tissue micro-arrays of biopsies from patients with high grade serous ovarian carcinoma (HGSC), from endometrial cancers, and from healthy tissues. A strong sortilin staining was effectively observed in more than 90% of the tumor biopsies and remained high in those from HGSC patients that received neoadjuvant chemotherapy. Immunoblotting also revealed high levels of SORT1 in a wide variety of human cancer cell lines including ovarian and endometrial cancer cells. In vivo, tumor xenografts were generated from two of the sortilin-expressing ovarian cancer cell lines (ES-2 and SKOV-3/Luc). Administration of TH1902, a docetaxel-TH19P01 conjugate, impeded ES-2 ovarian tumor xenograft growth when administered for three cycles at 35 mg/kg/week, versus unconjugated docetaxel at 15 mg/kg/week. A 78% decrease in tumor growth was observed in TH1902-treated animals, though docetaxel-treated tumor volumes were indistinguishable from either of the other groups. In contrast, administration of either docetaxel or TH1902 completely prevented tumor growth in SKOV-3/Luc ovarian tumor xenografts and even led to tumor regression. When TH1902 and docetaxel were administered to mice bearing AN3-CA endometrial tumor xenografts at an equivalent of docetaxel dose (3.75 mg/kg/week), a decrease in the rate of tumor growth by 73% was apparent in TH1902 group whereas docetaxel lacked any observable effect. In addition, higher equivalent dose of both TH1902 and docetaxel (15 mg/kg/week) inhibited tumor growth, however and in contrast to docetaxel group, TH1902-treated mice showed sustained tumor regression. These results strongly support the clinical development of this SORT1+ technology for both endometrial and ovarian cancers. Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Larocque, Alain Zgheib, Richard Béliveau, Christian Marsolais, Borhane Annabi. Increasing potency of anticancer drugs through SORT1+ technology: A new targeted approach for the treatment of ovarian and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1439.
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 ».