Abstract NTOC-108: ACTIVITY OF DIANHYDROGALACTITOL (VAL–083) IN OVARIAN TUMOR MODELS, SENSITIVE OR RESISTANT TO CISPLATIN
Notice bibliographique
Résumé
Abstract PURPOSE: Platinum drug resistance is a major clinical impediment that is normally ascribed to several mechanisms, with dysfunctional p53 playing a critical role, particularly in the highly lethal high-grade ovarian serous carcinoma, where p53 mutations can be >80%. Since restoration of p53 function could restore drug-dependent cytotoxicity, the goal of this study was to examine dianhydrogalactitol (VAL-083) for its potential in an ovarian tumor panel representing different p53 statuses and cisplatin-resistance. VAL-083 has demonstrated clinical activity against a range of tumor types, including ovarian cancer, in historical NCI-sponsored clinical studies, but its activity in a cisplatin-resistance setting is not known. VAL-083 is a bi-functional alkylating agent with a distinct mechanism of action, forming DNA interstrand cross links at the N7 position of guanine, whereas cisplatin and carboplatin predominantly form intrastrand DNA cross-links. METHODS: The tumor panel was composed of cisplatin-sensitive wild type (wt) p53 ovarian cancer cell line A2780, cisplatin-resistant A2780-derived heterozygous p53-V172F mutant 2780CP/Cl-16 cells, and three other cisplatin-resistant models harboring mutant (OVCAR-10) or wt p53 (Hey and OVCA-433). Cells were exposed to cisplatin or VAL-083 and the IC50 cytotoxic parameter was determined by fitting the 5-day MTT cell survival data to a 4-parameter sigmoidal curve. MTT assay was used in conjunction with Bliss Independence Model and combination index approaches to assess VAL-083/cisplatin combinations. Immunoblot analysis assessed p53 response. RESULTS: The IC50 of cisplatin in the cisplatin-sensitive A2780 model was 0.2-0.3 µM. In contrast, the IC50 in the four cisplatin-resistant models (2780CP/Cl-16, OVCAR-10, Hey and OVCA-433) was 3-8 µM; a 10- to 27-fold increase. The corresponding IC50 for VAL-083 was about 0.5 µM in A2780 cells and 2-4 µM in the four cisplatin-resistant models; a 4- to 7-fold increase, suggesting a distinct mode of action of VAL-083 and the ability to circumvent cisplatin resistance. In addition, these results further indicate that VAL-083 activity is less dependent on p53 status. However, immunoblots of 2780CP/Cl-16 cells suggest partial dependency on p53 by demonstrating that VAL-083, unlike cisplatin, can activate mutant p53-V172F through Ser20 phosphorylation, thereby preventing binding to p53 of inhibitory MDM4. VAL-083 thus restores p53 function, which is consistent with its greater potency in p53 mutated cisplatin-resistant ovarian cancer. These results suggest that VAL-083 have two mechanisms: one dependent on p53 and another on a different pathway. The apparent differences in the mechanism between cisplatin and VAL-083 prompted a combination study with the two agents, and consistent synergy was demonstrated. CONCLUSIONS: VAL-083 can circumvent cisplatin-resistance in ovarian tumor models, and its activity is less dependent on p53 status. Together with overt synergy between VAL-083 and cisplatin, our results demonstrate the effectiveness of VAL-083 against cisplatin-resistant ovarian cancer as a single agent or in combination with cisplatin. Citation Format: Anne Steino, Michelle Martinez-Rivera, Guanghan He, Xiaolei Xie, Jeffrey A. Bacha, Dennis M. Brown and Zahid H. Siddik. ACTIVITY OF DIANHYDROGALACTITOL (VAL–083) IN OVARIAN TUMOR MODELS, SENSITIVE OR RESISTANT TO CISPLATIN [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-108.
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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 | 0,000 |
| 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 ».