Combination of a New Oral Demethylating Agent, OR2100, and Venetoclax for Treatment of Acute Myeloid Leukemia.
Cancer Res Commun
; 3(2): 297-308, 2023 02.
Article
de En
| MEDLINE
| ID: mdl-36860654
ABSTRACT
The standard treatment for elderly patients with acute myeloid leukemia (AML) is venetoclax (Ven), a BCL-2-selective inhibitor, combined with hypomethylating agents (HMA) such as azacitidine or decitabine. This regimen results in low toxicity, high response rates, and potentially durable remission; however, because of low oral bioavailability, these conventional HMAs must be administered intravenously or subcutaneously. A combination of oral HMAs and Ven would provide a therapeutic advantage over parenteral administration of drugs and improve quality of life by reducing the number of hospital visits. Previously, we showed the promising oral bioavailability and antileukemia effects of a new HMA, OR2100 (OR21). Here, we investigated the efficacy and underlying mechanism of OR21 when used in combination with Ven to treat AML. OR21/Ven showed synergistic antileukemia effects in vitro, and significantly prolonged survival without increasing toxicity in a human leukemia xenograft mice model. RNA sequencing following combination therapy revealed downregulation of VAMP7, which is involved in autophagic maintenance of mitochondrial homeostasis. Combination therapy led to accumulation of reactive oxygen species, leading to increased apoptosis. The data suggest that the combination of OR21 plus Ven is a promising candidate oral therapy for AML. Significance:
The standard treatment for elderly patients with AML is Ven combined with HMAs. OR21, a new oral HMA plus Ven showed synergistic antileukemia effects in vitro and vivo, suggesting that the combination of OR2100 plus Ven is a promising candidate oral therapy for AML.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Leucémie aigüe myéloïde
/
Antinéoplasiques
Aspects:
Patient_preference
Limites:
Aged
/
Animals
/
Humans
Langue:
En
Journal:
Cancer Res Commun
Année:
2023
Type de document:
Article
Pays d'affiliation:
Japon