Abstract 2157: Enhanced <i>in vitro</i> activity of dianhydrogalactitol (VAL-083) in combination with platinum drugs: Impact of p53 and platinum-resistance
Notice bibliographique
Résumé
Abstract Cisplatin is an important frontline drug for ovarian carcinoma and non-small cell lung cancer (NSCLC). However, the initial response rates of up to 70% are usually followed by relapse due to the onset of drug resistance. Mechanistically, platinum resistance is multifactorial, with loss of p53 function (by mutation or inhibitory protein binding to wild-type (wt) p53) playing a central role. The appearance of drug resistance is a major clinical barrier and, therefore, new agents are needed to overcome this limitation. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that induces DNA interstrand cross-links at N7-guanine, a mechanism that is distinct from the intrastrand cross-links by platinum-based drugs. VAL-083 is clinically approved in China for lung cancer, and is undergoing clinical trial in the US for glioma. In the present study, we have examined the in vitro cytotoxicity of VAL-083 as a single agent and in combination with cisplatin or oxaliplatin using the 5-day MTT assay. In the isogenic HCT-116p53+/+ and HCT-116p53-/- colorectal models, loss of p53 increased IC50 of (or resistance to) cisplatin and oxaliplatin by 3- to 6-fold, whereas resistance to VAL-083 was increased only 1.7-fold by loss of p53. These results indicate that the cytotoxicity of VAL-083 is less impacted than the platinum drugs by loss of p53. When tested in cisplatin-sensitive (A2780) vs. cisplatin-resistant wt p53 ovarian tumor models (2780CP-16, OVCAR-10, Hey and OVCA-433) there was a 10- to 40-fold increase in IC50 for cisplatin, while the corresponding increase in IC50 for VAL-083 was only 4- to 7-fold. This indicates only partially cross-resistance between VAL-083 and cisplatin and thus suggests a distinct mode of action for VAL-083 as compared to cisplatin. To further investigate, immunoblots were developed after a 24-h exposure of isogenic A2780 or 2780CP-16 models to cisplatin or VAL-083. The two drugs were equally effective at stabilizing and activating p53 in A2780 cells. However, in cisplatin-resistant 2780CP-16 cells, VAL-083 was more effective than cisplatin at increasing p53 and p21 levels, and at inducing Ser-15 and Ser-20 phosphorylation of p53. This is consistent with the ability of VAL-083 to circumvent cisplatin resistance and demonstrated that this alkylating agent also has the capacity to partially restore wt p53 function in ovarian tumor cells. The independent mode of actions of these drugs suggested the potential for combining VAL-083 with cisplatin or oxaliplatin. These combinations in wt (H460 and A549) and mutant (H1975 and H157) p53 NSCLC models demonstrated significant super-additivity (p<0.05) and/or synergy (CI < 1). Taken together, these results demonstrate the antitumor activity of VAL-083 against both wt and mutant p53 cancers and raise the clinical potential for treatment in a combination setting with platinum drugs. Citation Format: Anne Steino, Guanghan He, Michelle Martinez-Rivera, Jeffrey A. Bacha, Dennis M. Brown, Zahid H. Siddik. Enhanced in vitro activity of dianhydrogalactitol (VAL-083) in combination with platinum drugs: Impact of p53 and platinum-resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2157.
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 ».