Abstract LB-33: Pre-clinical evaluation of AB-16B5, a monoclonal antibody specific for tumor-associated sCLU, demonstrates therapeutic potential as an inhibitor of EMT in prostate, pancreatic and lung cancer
Notice bibliographique
Résumé
Abstract Secreted clusterin (sCLU) exhibits elevated expression in several cancer indications. sCLU plays a pro-survival role in tumors and, more recently, it was found to be a potent stimulator of the epithelial-to-mesenchymal transition (EMT). These findings led to the development of a monoclonal antibody, AB-16B5, that interacts with a specific EMT-inducing domain in sCLU resulting in abrogation of migration and invasion of many types of cancer cells. In previous studies, AB-16B5 reduced the invasion of tumors in models of metastatic breast cancer suggesting that the antibody blocked EMT in vivo. Here we present pre-clinical findings in models of prostate cancer, pancreatic cancer, and NSCLC. DU145 and PC-3 prostate cancer cells implanted in SCID mice grew slower in the groups treated with AB-16B5 as a monotherapy or in combination with docetaxel. This observation suggested that blocking sCLU with AB-16B5 enhanced the chemo-responsiveness to cytotoxic drugs, a finding that was consistent with the proposed role of sCLU as an inhibitor of apoptosis in cancer cells. Immunohistochemical examination of sections prepared from the prostate tumors exposed to AB-16B5 showed an increase in E-cadherin, a marker of epithelial cells, and a reduction of vimentin, a marker of mesenchymal cells, which indicated that EMT was blocked or even reversed in vivo. Additional analyses of tumors derived from human pancreatic cancer showed that sCLU was expressed in this indication as well, especially in tumors that were resistant to gemcitabine. In agreement with the role of sCLU as an inducer of EMT, AB-16B5 inhibited the invasion of PANC-1 pancreatic cancer cells in vitro. Importantly, treatment of SCID mice harboring BxPC-3 pancreatic tumors with AB-16B5 resulted in a significant enhancement of the response to gemcitabine. Similarly, the growth of tumors grown from the NSCLC cell line, A549, was also inhibited by AB-16B5. To explore the behavior of AB-16B5 in cynomolgus monkeys, the antibody was administered by i.v. infusion every 14 days at two doses of 10 and 50 mg/kg. Results indicated that AB-16B5 was well tolerated and no signs of toxicity were observed. Finally, to address the mechanism of action of sCLU, cell biology experiments indicated that sCLU is internalized in cancer cells, which leads to the activation of critical signaling pathways that favor cell proliferation and survival, including those pathways leading to a stimulation of NF-kappaB. Our studies imply that the combination of increased epithelial character of tumor cells exposed to AB-16B5 coupled with a reduction in the activation of survival pathways contribute to an increase in the sensitivity to chemotherapy and a significant reduction of tumor growth, in particular in cancer types such as pancreatic cancer, where EMT likely contributes to increased chemo-resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-33. doi:10.1158/1538-7445.AM2011-LB-33
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 | 0,004 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| 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 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 ».