Abstract P3-10-07: Receptor-mediated chemotherapy using a new Docetaxel-peptide conjugate for Sortilin-positive triple-negative breast cancer
Notice bibliographique
Résumé
Abstract Background: Triple-negative breast cancer (TNBC) still lacks defined molecular biomarkers. Thus, targeting of specific gene/protein molecular signature of tumors emerged among the best anticancer strategies. Recently, increased expression of the cell surface receptor Sortilin was reported in tumors from patients with TNBC. Given Sortilin’s functions in protein internalization and trafficking; we developed a new Sortilin-targeted peptide-anticancer drug conjugate to treat Sortilin-positive breast cancer. The conjugate consists of 2 molecules of Docetaxel linked to a 17 amino acids peptide (TH-1902) which enables specific binding to Sortilin and subsequent internalization of TH-1902. Methods: MDA-MB-231 breast cancer cells were used as a TNBC model for in vitro and in vivo xenograft assays. Female CD-1 nude mice (Crl:NU-Foxn1nu) were used for xenograft tumor models, female athymic nude mice (Crl:NU(NCr)-Foxn1nu) were used in hematotoxicology and female Crl: CD-1 mice were used for pharmacokinetic evaluation. In vitro cell migration was assessed using the xCELLigence real-time system, whereas MTT assay was used for cell proliferation analysis. Apoptosis biomarkers expression was assessed by immunoblotting. The microtubule polymerization and depolymerization assay was performed by spectrofluorimetry, whereas fluorescent TH-peptide uptake was assessed by flow cytometry. Tissue microarrays included 9 normal adjacent tissues, 35 infiltrating ductal carcinomas (IDC), and 10 lymph nodes metastatic (LNM) carcinomas. Hematotoxicity assay allowed for blood neutrophil counts analysis in plasma samples. Results: Fluorescent Alexa488-labeled TH-peptide was found to be internalized in MDA-MB-231 cells and reduced by 72% upon transient SORT1 gene silencing. Alexa488-labeled TH-peptide uptake was inhibited by 65% in the presence of an excess of unlabeled TH-peptide and by the Sortilin ligands Neurotensin and Progranulin. TH-1902 exerted potent anti-proliferative and anti-migratory activities in vitro. TH-1902, like Docetaxel alone, triggered cell death mechanisms. The apoptotic and anti-migratory effects were reversed upon siRNA-mediated gene silencing of SORT1. Conjugation of Docetaxel to TH-peptide did not affect its capacity to alter microtubule stabilization, once internalized and cleaved from the TH-peptide within the cells. This further triggered the down-regulation of IL-6, Bcl-xL and mutant p53 pro-survival biomarkers. Sortilin immunolabeling showed very low levels in normal adjacent tissues, whereas high levels of Sortilin labeling were scored in IDC and LNM. In vivo, TH-1902 exhibited a greater tumor regression capacity with a prolonged survival in a murine MDA-MB-231 xenograft tumor model than did Docetaxel. Hematotoxic assays revealed that neutrophils count decreased significantly in Docetaxel-treated mice at MTD after 3 cycles, whereas they remained within normal limits in TH-1902-treated mice at an equivalent dose of Docetaxel even after six injections of TH-1902. Preliminary assessment of TH-1902 in normal CD-1 mice revealed that most Docetaxel remained associated with the peptide over the time course analyzed after a single IV bolus injection at 50 mg/kg. Absence of neutropenia in the presence of TH-1902 may be explained by the low levels of free Docetaxel in mouse plasma. Conclusions: The results demonstrate that Sortilin can be used as a target for treatment of TNBC. In addition, TH-1902 specifically internalized Docetaxel through a receptor-mediated mechanism exploiting Sortilin’s functions and significantly decreased the concentration of Docetaxel in normal cells. Overall, TH-1902 improved the efficacy and safety profiles compared to Docetaxel, which makes it a promising novel therapy for the treatment of TNBC. Citation Format: Michel Demeule, Cyndia Charfi, Jean-Christophe C Currie, Alain Larocque, Alain Zgheib, Christian Marsolais, Richard Béliveau, Borhane Annabi. Receptor-mediated chemotherapy using a new Docetaxel-peptide conjugate for Sortilin-positive triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-07.
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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) | 0,003 | 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 ».