Abstract 2910: A novel Sortilin-targeted docetaxel peptide conjugate (TH1902), for the treatment of Sortilin-positive (SORT1+) triple-negative breast cancer
Notice bibliographique
Résumé
Abstract Rational: Breast cancers are comprised of several subtypes that share similar clinicopathological features, but that also exhibit several different biological characteristics. Triple-negative breast cancer (TNBC), which comprises 10-20% of breast cancers, or ~ 170,000 new cases per year worldwide and 70% of the basal-like subtype of breast cancers, is a cancer that does not express estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2). TNBC is considered more aggressive than other breast cancers and more difficult to treat because it still lacks a defined molecular signature. Over the last decade, the targeting of specific cancer cell surface receptors has emerged among the best anticancer strategies. Recently, increased expression of the Sortilin receptor (SORT1) has been reported in TNBC patients. Procedures: Given SORT1 functions in protein internalization, sorting and trafficking, we designed a new anticancer peptide-drug conjugation strategy to target SORT1-positive TNBC by linking Docetaxel to a peptide (TH19P01) that specifically binds to SORT1. Results: In vitro, the Docetaxel-TH19P01 conjugate (TH1902) exerted potent anti-proliferative and anti-migratory activities when tested on TNBC-derived MDA-MB-231 cells. The apoptotic and anti-migratory effects induced by TH1902 were reversed by neurotensin and progranulin, two SORT1 ligands, and upon siRNA-mediated silencing of SORT1. Similar to other taxanes, once internalized in the cancer cell, TH1902 altered microtubule polymerization. In vivo, i.v. administration of TH1902 led to greater tumor regression in a murine MDA-MB-231 xenograft tumor and a dose response was observed for TH1902. When docetaxel was injected i.v. at ¼ of its MTD (3.75 mg/kg/week), it had no apparent effect on tumor burden, compared to animals injected with vehicle alone. In contrast, a strong tumor growth inhibition (100%) and sustained effects were observed in mice treated with TH1902 at 8.75 mg/kg/week (equivalent to docetaxel dose of 3.75 mg/kg/week). At higher dose (35 mg/kg/week), a complete tumor regression was seen in mice, and near-total regression (75%) was found with the 17.5 mg/kg/week dosage. While the decreased neutrophil counts subsequent to administration of docetaxel (15 mg/kg/week) were statistically significant after the first intravenous injection, there was no apparent change in the neutrophil counts for mice which received up to 6 cycles of TH1902 (35 mg/kg/week). Conclusion: Taken together, these pre-clinical data demonstrate high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This novel approach allows for selective targeting of SORT1-positive breast cancers and makes TH1902 a promising clinical candidate for personalized therapy in the treatment of TNBC. Citation Format: Christian Marsolais, Cyndia Charfi, Michel Demeule, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Natacha Duquette, Richard Béliveau, Borhane Annabi. A novel Sortilin-targeted docetaxel peptide conjugate (TH1902), for the treatment of Sortilin-positive (SORT1+) triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2910.
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) | 0,001 | 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 ».