Abstract 900: Dianhydrogalactitol (VAL-083) has the potential to overcome major challenges in the treatment of DIPG
Notice bibliographique
Résumé
Abstract Despite decades of clinical trials, children with diffuse intrinsic pontine gliomas (DIPG) continue to have a very poor prognosis and dismal survival. DIPG is inoperable and standard treatment is radiation alone. Major obstacles to the successful treatment of DIPG include 1) an intact blood brain barrier impeding drug penetration, 2) inherent tumor cell resistance mechanisms to conventional chemotherapeutics, and 3) a lack of drug-induced potentiation of radiotherapy. VAL-083 is a structurally unique bi-functional DNA targeting agent that has the potential to overcome these barriers. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue where it rapidly forms interstrand DNA crosslinks at guanine-N7, leading to persistent DNA double strand breaks, cell cycle arrest, and cancer cell death. VAL-083 has cytotoxic activity in several pediatric brain tumors as assessed in NCI-sponsored clinical trials, both as a single agent and in combination with other chemotherapeutics. We recently completed a Phase I/II clinical trial in refractory GBM and established a well-tolerated dosing regimen of VAL-083 in adult brain tumor patients. We have previously demonstrated that VAL-083 cytotoxicity is independent of both the primary, DNA repair protein O6-methylguanine DNA methyltransferase (MGMT), and the secondary, DNA mismatch repair (MMR) system, mechanisms of resistance to temozolomide (TMZ) in vitro. TMZ is commonly used in combination with radiation for the treatment of adult brain tumors but has failed to improve the effect of radiation in DIPG. Importantly, VAL-083 potentiates the effect of radiation and overcomes TMZ resistance in TMZ-resistant adult glioblastoma cancer stem cells (CSCs) and non-CSCs at concentrations that are physiologically achievable in the CNS. Additionally, VAL-083 demonstrated synergistic efficacy in prostate and lung cancer cells with topoisomerase (Topo) inhibitors camptothecin and etoposide, commonly used in the treatment of pediatric brain tumors. In conclusion, VAL-083 is able to 1) cross the blood brain barrier, 2) overcome resistance mechanisms to chemotherapeutics commonly used in the treatment of adult gliomas, and 3) potentiate the effects of radiation in adult glioma cells at physiologically achievable concentrations. Thus, VAL-083 may have the potential to overcome major challenges in DIPG treatment as a single agent, in combination with radiotherapy, or as part of a combination regimen with Topo inhibitors. In the present study, we investigated the effects of VAL-083 in combination with radiation, irinotecan (Topo 1 inhibitor), or Wee1 inhibitor AZD1775 in a panel of DIPG cell lines with varying genetic profiles. The results will provide guidance for the design of animal models studying VAL-083 treatment of DIPG, either as part of a chemo-radiation regimen or in combination with Topo or Wee1 inhibitors. Citation Format: Anne Steino, Beibei Zhai, Jeffrey A. Bacha, Dennis M. Brown, Mads Daugaard, Sabine Mueller. Dianhydrogalactitol (VAL-083) has the potential to overcome major challenges in the treatment of DIPG [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 900.
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 | 0,001 |
| 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 ».