Abstract 1684: Autophagy inhibition as an effective strategy for sensitizing triple-negative breast cancer cells to chemotherapy.
Notice bibliographique
Résumé
Abstract Introduction: Triple-negative breast cancer (TNBC), defined by a lack of expression of the estrogen, progesterone and HER-2 receptors, remains a major clinical challenge due to higher recurrence rates and poorer prognosis compared to other subtypes of breast cancer. Tumors that initially respond to chemotherapy - the core treatment option for the patients with an advanced disease - eventually develop resistance. New therapeutic options are urgently required for TNBC. Autophagy, a lysosome-mediated degradation and recycling process, has been shown to function as an adaptive survival response during chemotherapy. Previous studies in other cancer subtypes have indicated that autophagy inhibition can restore chemotherapeutic sensitivity and enhance treatment response. Objective: Generate proof-of-principle evidence for autophagy inhibition as an effective treatment strategy for TNBC. Experimental Design: We are employing in vitro models using TNBC lines MDA-MB-231 and SUM159PT, as well as their derivative lines (R8 and R75, respectively) resistant to Epirubicin (EPI) and other anthracyclines. In vivo xenograft mouse models of MDA-MB-231 and R8 are being used to evaluate the effects of combinatorial therapy with EPI and autophagy inhibitor hydroxychloroquine (HCQ). Methods: We assessed levels of autophagy in TNBC cell lines treated with EPI, developed EPI- resistant sub-lines, and compared basal autophagy levels in parental and resistant lines, using autophagy flux (degradative completion of autophagy) assays. We evaluated the effects of chemotherapy alone and in combination with autophagy inhibitors (HCQ or siRNAs targeting autophagy-related (Atg) proteins) on both parent and resistant sub-lines by assessing their viability. For in vivo studies, MDA-MB-231 cells were injected subcutaneously in Rag2M mice. After tumor formation, mice were treated with EPI, HCQ or their combination, and treatment efficacy was evaluated by tumor volume measurements. Autophagy levels in tumors were also assessed. Results: TNBC cells demonstrated increased autophagy in response to EPI treatment in vitro and in vivo. EPI- resistant lines showed at least 1.5 fold increased basal autophagy levels compared to their parental lines suggesting a possible adaptive role for autophagy in development of chemoresistance. Knock-down of Atg proteins by siRNA dramatically reduced the viability of EPI-resistant sub-lines, which indicates dependence of drug-resistant cells on autophagy for survival. Resistance of MDA-MB-231-R8 cells to EPI was reverted by autophagy inhibition in vitro. Combination of EPI with HCQ in vivo showed an enhanced tumor response to treatment compared to monotherapy with EPI. Additional in vivo studies are in progress. Conclusion: Our preliminary results suggest that autophagy inhibition may be an effective strategy for the treatment of chemo-refractory TNBC cells. Citation Format: Svetlana Bortnik, Suganthi Chittaranjan, Wieslawa H. Dragowska, Namal Abeysundara, Amy Chen, Lindsay DeVorkin, Nancy Dos Santos, Nancy Erro Go, Amy Leung, Dana Masin, Maria Rizza, Dita Strutt, Sherry Weppler, Jing Xu, Hong Yan, Karen Gelmon, Donald Yapp, Marcel Bally, Sharon M. Gorski. Autophagy inhibition as an effective strategy for sensitizing triple-negative breast cancer cells to chemotherapy. [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 1684. doi:10.1158/1538-7445.AM2013-1684
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) | 0,002 | 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 ».