Abstract LB-380: Direct targeting of the Hedgehog pathway in primary chondrosarcoma xenografts with the Smoothened inhibitor IPI-926
Notice bibliographique
Résumé
Abstract Chondrosarcoma is a malignant cartilage tumor in which there is constitutive activation of Hedgehog-mediated signaling. Pharmacologic agents that inhibit Hedgehog (Hh) signaling have the potential to be used as novel targeted anti-tumor therapies. IPI-926, a novel, selective, molecule that antagonizes the Hh pathway by binding to Smoothened, is currently in clinical trials. The activity of IPI-926 was assessed in human primary chondrosarcoma tumors obtained at surgery from six different donors and grown as subcutaneous xenografts in NOD/SCID mice. Studies were conducted in primary chondrosarcoma xenografts to assess the activity of IPI-926 either at time of implant or in established tumors and to compare the anti-tumor activity of IPI-926 to chemotherapy and targeted agents. Tumor tissue was collected post-treatment at the end of each study for histopathological analysis or for evaluation of expression of Hh pathway genes by RT-PCR for GLI1, PTCH-1, and SMO mRNA. The chondrosarcoma tumor sizes were significantly smaller in the IPI-926 treated groups, compared to either control or chemotherapy-treated groups. There was also less cellularity, with cells appearing more differentiated, in the IPI-926 treated group. The tumors from mice treated with IPI-926 had significantly reduced expression of Hedgehog target genes GLI1 and PTCH1 compared to those from mice treated with vehicle or other chemotherapies. In addition, inhibition of GLI1 and PTCH1 gene expression was detected in the human tumor cells, a finding that has not been previously demonstrated in carcinomas, where the Hedgehog blockade seems to affect primarily the murine-derived stromal cells. As expected, inhibition of Hh target gene expression was also detected in the tumor stroma in these xenografts. Initial results from gene expression profiling of the tumor cells suggest that several additional genes may be affected by IPI-926 treatment. In summary, IPI-926 administration to mice bearing tumors derived from primary human chondrosarcoma tumors results in down-modulation of the Hh pathway in the tumor cells, as demonstrated by evaluation of the Hh-dependent genes GLI1 and PTCH1. Hh pathway gene expression is also inhibited in the tumor stroma. Down-modulation of the Hh pathway with IPI-926 results in inhibition of growth of both newly implanted and established chondrosarcoma tumors. Decreased tumor growth is accompanied by histopathological changes, including loss of cellularity and calcification. Thus, IPI-926 directly targets the Hh pathway in chondrosarcoma tumor cells and results in growth inhibition and changes in the tumor histopathology. These studies provide strong scientific rationale for further evaluation of Hh pathway inhibition with IPI-926 in humans with chondrosarcoma. 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-380. doi:10.1158/1538-7445.AM2011-LB-380
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 | 0,001 | 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 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 ».