Abstract 5101: Defining exposure-PD and efficacy relationships with the novel liver-targeting nucleotide prodrug MIV-818 for the treatment of liver cancers
Notice bibliographique
Résumé
Abstract Background: Many systemic chemotherapeutics have failed to show efficacy in hepatocellular carcinoma (HCC), often because systemic toxicity prevents efficacious liver levels of the drug from being reached. MIV-818, a nucleotide prodrug of troxacitabine-monophosphate (TRX-MP) has been designed as a novel approach to deliver high levels of the chain-terminating nucleotide troxacitabine-triphosphate (TRX-TP) to the liver after oral dosing while minimizing systemic exposure. We investigated MIV-818 and troxacitabine using in vivo models in order to identify therapeutic levels of TRX-TP required in the tumors. Methods: MIV-818 or troxacitabine were administered to nude mice with subcutaneous Hep3B or Huh7 xenografts. LC-MS/MS was used to assess MIV-818 and its metabolites. Effects on tumor growth, plasma AFP, inhibition of proliferation and induction of DNA damage were examined and correlated with exposures to TRX-TP in the tumor. Quantitative immuno-fluorescent histology was used to assess DNA damage (pH2AX) proliferation (BrdU), and hypoxia (pimonidazole). Results: Compared to the parent nucleoside troxacitabine, MIV-818 has increased potency of inhibition of HCC cell line growth, increased conversion to its active metabolite TRX-TP and in vitro properties optimized for oral bioavailability and liver targeting, including permeability and intestinal stability. MIV-818 also shows strong synergistic anti-proliferative activity with sorafenib in a number of HCC cell lines in vitro. Pronounced tumor growth inhibition of 70-100% and extensive tumor growth delays of up to 26 days were observed in the Hep3B xenograft model following a five day period of dosing. 12-32-fold induction of DNA damage was seen throughout the tumor sections, consistent with the expected mechanism of action, and with associated inhibition of proliferation. Clear PD responses were apparent even in hypoxic regions of the tumor, indicating effective distribution of TRX-TP even far from blood vessels. DNA damage persisted for up to 7 days after the final dose, demonstrating long-lasting effects and indicating that intermittent dosing is likely to be effective. Similar dosing regimens given to Huh7 xenograft models resulted in significant tumor growth inhibition and induction of DNA damage. Intratumoral TRX-TP exposures across both models were correlated with anti-tumor effects including DNA damage induction, proliferation inhibition and tumor growth inhibition. Conclusions: We have identified TRX-TP exposures required for pronounced anti-tumor effects to give a comprehensive understanding of PK-PD-efficacy relationships for the active metabolite of MIV-818. These data could be used to guide dosing and dose selection in clinical studies. MIV-818 is currently in preclinical development in preparation for the initiation of clinical trials in patients with advanced HCC and other liver cancers. Citation Format: Mark Albertella, Biljana Rizoska, Alastair Kyle, Andrew Minchinton, Annelie Linqvist, Sanja Juric, Susanne Sedig, Karin Tunblad, Fredrik Öberg, Björn Classon, Anders Eneroth, John Öhd, Richard Bethell. Defining exposure-PD and efficacy relationships with the novel liver-targeting nucleotide prodrug MIV-818 for the treatment of liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5101. doi:10.1158/1538-7445.AM2017-5101
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 ».