Abstract 863: Inhibition of breast cancer metastaticprogression by a novel uPAR targeted monoclonal antibody, ATN-658, correlateswith the uPAR expression.
Notice bibliographique
Résumé
Abstract The urokinase plasminogen activator receptor (uPAR) has been implicated in the progression of metastatic disease in a number of different solid tumor types including breast cancer. We have developed a therapeutic monoclonal antibody, ATN-658, that targets uPAR in a novel manner. ATN-658 does not inhibit the binding of uPA to uPAR but appears to have pleiotropic effects on other uPAR interactions including those with various integrins. In the present study, we utilized 231LM2-4H2N, a novel highly metastatic variant of the triple negative breast cancer cell line cell line, MDA-MB-231, to evaluate the effect of ATN-658 on metastasis. This variant has been transfected to also express HER2 and metastases in this model are resistant to targeted treatments such as trastuzumab and sunitinib. Orthotopic 231LM2-4H2N xenograft tumor spontaneously metastasizes to lung and liver and forms large macroscopic metastases that lead to death. We transfected 231LM2-4H2N cells with dTomato and Luc2 to allow for real time assessment of metastatic progression using IVIS imaging. Primary orthotopic tumors were staged to 500 mm3, at which time they were resected and the mice followed using bioluminescence to detect metastases, which typically appear in the lungs within 2-3 weeks post-resection. Mice were randomized once lung metastases were visible and treatment was initiated using vehicle control, lapatanib (30 mg/kg QD), ATN-658 (10 mg/kg Q3D) or the combination of lapatanib and ATN-658. Growth of metastases was estimated using average radiance measurements. ATN-658 inhibited metastatic progression by ∼90% and doubled median survival compared to the vehicle control in this study. Lapatanib had no effect on the size of the metastases or survival and the combination of ATN-658+lapatanib inhibited metastatic progression and survival to the same extent as ATN-658 monotherapy. The activation of ERK was significantly inhibited by ATN-658 in vivo although this alone was insufficient to inhibit tumor growth since lapatanib also inhibited ERK to the same extent suggesting the other effects were being mediated by ATN-658. The effect of ATN-658 monotherapy on metastatic tumor growth was much greater in the 231LM2-4H2N model than in the parental MDA-MB-231 model. In order to probe the reason for this difference in effect, we analyzed the expression of uPAR in the various MDA-MB-231 variants. uPAR expression was significantly upregulated in HER2-transfected MDA-MB-231 breast cancer cells suggesting that the level of uPAR expression may dictate the degree of response to ATN-658. If this hypothesis can be validated, this would provide a patient enrichment strategy for the humanized version of ATN-658, huATN-658, which is getting ready to go into the clinic. Citation Format: Irawati Kandela, Andrey Ugolkov, Giulio Francia, Shafaat Rabbani, Robert S. Kerbel, Andrew P. Mazar. Inhibition of breast cancer metastaticprogression by a novel uPAR targeted monoclonal antibody, ATN-658, correlateswith the uPAR expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 863. doi:10.1158/1538-7445.AM2013-863
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) | 0,003 | 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 ».