Abstract 5831: Activated Wnt signaling for the treatment of recurrent medulloblastoma
Notice bibliographique
Résumé
Abstract Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current molecular subgroups of MB recognize distinct disease entities of which activated Wnt signaling (monosomy 6, exon 3 mutations in CTNNB1, and Wnt gene signature) is associated with a distinct subgroup and the best overall outcome. In contrast, only non-Wnt MBs are characterized by metastatic disease, increased rate of recurrence, and poor overall survivorship. Given the excellent clinical outcome in patients with Wnt-driven MB, we aimed to convert treatment-resistant MB subgroups into an ostensibly benign tumor through selective targeting by small molecules and transgenic patient-derived lines containing a stabilized beta-catenin mutant. Activated Wnt signaling by way of Wnt agonists in treatment-refractory MBs resulted in decreased in vitro self-renewal and promoted differentiation. Comparative gene expression profiling of control and transgenic lines containing a stabilized beta-catenin mutant demonstrated a reduction in stem cell self-renewal genes following beta-catenin overexpression, including Sox2 and Bmi1. In order to validate the therapy-sensitive nature of Wnt-activated cells, we developed stable patient-derived lines containing a 7XTOPFlash reporter for endogenous Wnt signaling. Rare subclonal Wnt-active cells demonstrated a reduced self-renewal and tumor-initiating capacity through in vivo limiting dilution assays when compared to bulk Wnt-inactive cells. The therapeutic relevance of these findings were demonstrated with an in vivo survival advantage in mice with orthotopic injections of cells containing a stabilized beta-catenin mutant representative of constitutively active Wnt signaling or endogenous Wnt-active cells. Xenografts generated from Wnt-activated tumors were smaller in size, maintained a lower rate of proliferation, and reduction in MB self-renewal genes. To further illustrate the clinical utility of activated Wnt signaling, we modified the Children’s Oncology Group therapy protocol for childhood MB so that xenografts may receive chemo/radiotherapy. Tumors generated from Wnt-active xenografts were much more radiosensitive and displayed a significant reduction in spinal metastasis when compared to mice receiving standard therapy without Wnt activation. To develop a rationale clinical therapeutic, we developed unique agonist antibodies that target the Wnt co-receptor LRP5. Treatment with LRP5 antibodies showed a significant reduction in tumor burden and increase in survival of patient-derived tumors that were otherwise treatment-resistant. Our work establishes for the first time activated Wnt signaling as a novel treatment paradigm in childhood MB, identifies a rationale therapeutic approach for recurrent MB, and provides evidence for the context-specific tumor suppressive function of the canonical Wnt pathway. Note: This abstract was not presented at the meeting. Citation Format: Branavan Manoranjan, Chitra Venugopal, Zvezdan Pavlovic, David Bakhshinyan, Michelle Kameda-Smith, Minomi Subapanditha, Sujeivan Mahendram, Jason Moffat, Bradley W. Doble, Sheila Singh. Activated Wnt signaling for the treatment of recurrent medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5831. doi:10.1158/1538-7445.AM2017-5831
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) | 0,001 | 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 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 ».