Abstract A51: Dianhydrogalactitol (VAL-083) offers potential therapeutic alternatives in the treatment of pediatric brain tumors
Notice bibliographique
Résumé
Abstract Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for 15-30% of all childhood intracranial neoplasms. High grade gliomas (HGG) are much rarer in children than in adults, comprising only 5%-10% of childhood brain tumors. Although multidisciplinary treatment has improved the 5-year survival rates in children significantly, the prognosis for recurrent MB and HGG remains poor with median overall survival <1 year. Temozolomide (TMZ) is frequently employed in the treatment of MB and pediatric HGG; however, clinical evidence is lacking and poor outcomes due to high-expression of the repair protein O6-methylguanine-DNA methyltransferase (MGMT), which is correlated with TMZ resistance, have been reported. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional alkylating agent causing DNA crosslinks at N7 position of guanine. VAL-083 readily crosses the blood brain barrier and has been shown to accumulate in brain tumor tissue. Furthermore, VAL-083 demonstrated clinical activity against MB and HGG in historical NCI-sponsored clinical studies. We have recently shown that VAL-083 demonstrates cytotoxic activity in GBM independent of MGMT expression in vitro and in vivo. We have further shown that VAL-083 is highly effective against GBM cancer stem cells (CSC) and non-CSC and that it acts as a radiosensitizer in GBM cell lines, in vitro. VAL-083 is currently in phase II clinical trials for recurrent GBM in adults. In the current adult GBM clinical trial VAL-083 displayed a favorable safety-profile and preliminary analysis supports a survival benefit at doses chosen for further investigation. Based on these recent results and data supporting VAL-083's clinical activity in historical MB and HGG studies, we sought to investigate the cytotoxic activity of VAL-083 as a potential therapeutic alternative for pediatric brain tumors by studying the drug against MB and pediatric HGG cell lines in vitro. Methods: Human MB cell lines DAOY, UW228, ONS-76 and UW426 and pediatric HGG cell line SF188 were treated with VAL-083 at concentrations of 0.1 100 μM for 72 h. Growth inhibition was measured by high content screening analysis. Neurosphere formation of DAOY and SF188 cells was determined by neurosphere colony assay. Results: VAL-083 inhibited growth of all cell lines (DAOY, UW228, ONS-76 UW426 and SF188) with IC50 at low micro-molar concentrations. DAOY, UW228 and SF188 cells were most sensitive to VAL-083. Primary neurosphere formation of DAOY cells was completely inhibited at 5 μM VAL-083 and VAL-083 was superior to TMZ against primary neurospheres formation of SF-188 cells; complete inhibition of SF-188 neurospheres was observed with the combination of VAL-083 and TMZ. Conclusion: These results suggest that VAL-083 is active against MB and pediatric HGG cells as well as CSC in vitro. Taken together with the results of historical NCI-sponsored clinical trials, these data warrant further investigations of VAL-083 as a possible therapeutic alternative for the treatment of recurrent pediatric MB and HGG. Citation Format: Jeffrey A. Bacha, Abbas Fotovati, Kaiji Hu, Anne Steino, Sarath Kanekal, Dennis M. Brown. Dianhydrogalactitol (VAL-083) offers potential therapeutic alternatives in the treatment of pediatric brain tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A51.
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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) | 0,004 | 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 ».