Abstract 3142: Derivation and analysis of preclinical models of human her-2 positive breast cancer
Notice bibliographique
Résumé
Abstract Although a number of Her-2 targeting drugs are now available for the treatment of Her-2 positive breast cancers, resistance to these therapies rapidly emerges. There is therefore a need to study how Her-2 targeting strategies work in vivo, and the mechanisms by which tumors eventually become resistant to anti-Her-2 therapies. We report the in vivo selection of variants of the human Her-2 positive breast cancer cell lines BT474 and MDA-MB361. Both cell lines were initially implanted orthotopically into Severely Compromised Immunodeficient mice, and the resulting tumors were serially passaged into new hosts over a 4 year period. This selection process produced the BT474V3 and MDA361V3 variants, which grow rapidly in vivo and which retain their Her-2 over-expression, and which respond (p<0.05, relative to controls) to trastuzumab (20mg/kg i.p. every 3 days). Tumor variants were also derived from selected tumors that relapsed after 3 months of continuous trastuzumab monotherapy. MDA361V3 tumors showed a significant (p<0.05) response to the combination therapy of trastuzumab plus metronomic cyclophosphamide (20mg/kg/day, p.o.). Tumors eventually progressed under this combination therapy, and cell lines were derived from the drug resistant tumors. Non-invasive monitoring of the Her-2 positive models in vivo was achieved by luciferase transfection of the tumor variants, or by transfection of chorionic gonadotropin (hCG) cDNA which allows for relative tumor growth to be evaluated via the resulting hCG levels in the mouse urine. Luciferase transfected BT474V3 were implanted intracranially (coordinates for implantation from Bregma were AP, +1.1; LM, -2.0; and DV, -3), and bioluminescence was detectable 20 days later. The implanted tumors in the brain eventually showed a doubling of bioluminescence every 2 weeks, which provides ample time for therapeutic intervention in this model of Her-2 positive breast cancer brain metastasis. To further model the response of Her-2 positive metastatic breast cancer, we employed our met2.hCG model, derived from the human MDA-MB-231 human breast cancer cell line. Thus, MDA-MB-231 were transduced to overexpress Her-2, then tagged with hCG, and then selected for high spontaneous metastatic capacity. Orthotopically implanted met2.hCG tumors responded to trastuzumab as a monotherapy, and when given in combination with metronomic cyclophosphamide. Following surgical removal of the orthotopically implanted met2.hCG tumors, urine hCG levels indicated that the metastases also responded (p<0.05, compared to saline treated controls) to the combination of metronomic cyclophosphamide plus trastuzumab, but they did not respond to the trastuzumab monotherapy. Collectively, our data shows that we have derived models of Her-2 positive breast cancer that can be used to evaluate anti-Her-2 therapeutic strategies, and to study the emergence of resistance to anti-Her-2 based therapies. Citation Format: Paloma A. Valenzuela, Sarah N. Jallad, Karla Parra, Natzidielly Lerma, Irving Miramontes, Alejandra Gallegos, Ping Xu, William Cruz-Munoz, Shan Man, Robert S. Kerbel, Giulio Francia. Derivation and analysis of preclinical models of human her-2 positive breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3142. doi:10.1158/1538-7445.AM2014-3142
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,003 |
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 ».