Abstract 4493: Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate for the treatment of sortilin-positive (SORT1+) TNBC and Her2-positive breast cancers
Notice bibliographique
Résumé
Abstract Over the last decade, the targeting of specific cell surface receptors such as human epidermal growth factor receptor 2 (Her2) in breast cancer cells has allowed the emergence of innovative strategies for the delivery of anticancer agents. High expression levels of the sortilin receptor (SORT1) have been reported in various tumors of breast cancer patients, including triple-negative breast cancer (TNBC), HR+ and Her2+ breast cancers. Given SORT1 function in ligand internalization, we addressed the sorting and trafficking of the newly designed TH19P01 peptide recognizing SORT1, and of TH1902, an anticancer TH19P01-docetaxel conjugate (PDC), and whether such PDC could target SORT1+ breast cancers. In vitro, high expression of SORT1 was found in several TNBC and Her2+ breast cancer cell lines as well as in in more than 88% of cases (H-score >100) from commercial breast cancer tissue microarrays. SORT1-mediated cell surface binding and internalization of TH19P01 was first investigated in TNBC-derived MDA-MB-231 cells. The binding and uptake of Alexa488-labeled TH19P01, at 4 and 37°C respectively, were found significantly reduced upon siRNA-mediated SORT1 silencing. This demonstrates that functional SORT1 processes are required for both cell surface recognition and internalization of TH19P01. Moreover, the internalization of TH19P01 and TH1902 in MDA-MB-231 cells were monitored by fluorescence microscopy using a polyclonal antibody generated against TH19P01. Both TH19P01 and TH1902 showed a rapid uptake and co-localized in the perinuclear region with the late endosomal marker Rab-7 and with the lysosomal marker Lamp-1 within 30 minutes indicating that both compounds are internalized through a receptor-mediated endocytosis pathway. In addition, TH19P01 internalization after 1 hour appeared significantly associated within intracellular compartments of MDA-MB-231 cells whereas Herceptin remained mostly localized at the cell surface of Her2+ BT-474 cells. In vivo, weekly administration of intravenous bolus of TH1902 (35 mg/kg) at an equivalent docetaxel MTD dose (15 mg/kg) led to complete tumor regression, while docetaxel only inhibited tumor growth by half in a murine MDA-MB-231 xenograft tumor model. Furthermore, in mice bearing Her2+ HCC-1954 breast tumor xenografts, TH1902 induced complete tumor regression in contrast to docetaxel and Herceptin. Taken together, these preclinical data demonstrate the high anticancer properties of TH1902 against SORT1+ TNBC and Herceptin resistant Her2+ breast cancers. These results demonstrate that TH1902 can be a promising avenue for personalized therapy in the treatment of all SORT1+ breast cancers. Citation Format: Cyndia Charfi, Michel Demeule, Jean-Christophe Currie, Alain Zgheib, Bogdan Alexandru Danalache, Richard Béliveau, Christian Marsolais, Borhane Annabi. Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate for the treatment of sortilin-positive (SORT1+) TNBC and Her2-positive breast cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4493.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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) | 0,000 | 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 tête enseignante, 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 ».