Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer.
Aged
Animals
Antineoplastic Agents
/ pharmacology
Autophagy
/ drug effects
Cell Cycle Proteins
/ biosynthesis
Cell Line, Tumor
Cell Proliferation
/ drug effects
Clinical Trials, Phase I as Topic
Clinical Trials, Phase II as Topic
Endometrial Neoplasms
/ drug therapy
Female
Humans
Mice
Middle Aged
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
RNA, Messenger
/ genetics
Repressor Proteins
/ biosynthesis
Small Molecule Libraries
/ pharmacology
Up-Regulation
/ drug effects
ABTL0812
Endometrial cancer
PI3K/AKT/mTOR1 pathway
Small molecule inhibitor
TRIB3
Journal
Gynecologic oncology
ISSN: 1095-6859
Titre abrégé: Gynecol Oncol
Pays: United States
ID NLM: 0365304
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
07
01
2019
revised:
01
03
2019
accepted:
01
03
2019
pubmed:
12
3
2019
medline:
2
7
2019
entrez:
12
3
2019
Statut:
ppublish
Résumé
The PI3K/AKT/mTOR pathway is frequently overactivated in endometrial cancer (EC). We assessed the efficacy of ABTL0812, a novel first-in-class molecule presenting a unique mechanism of action inhibiting this pathway. We investigated the effects of ABTL0812 on proliferation, cell death and modulation of intracellular signaling pathways in a wide panel of endometrioid and non-endometrioid cell lines, an inducible PTEN knock-out murine model, and two patient-derived xenograft murine models of EC. Then, TRIB3 expression was evaluated as potential ABTL0812 pharmacodynamic biomarker in a Phase 1b/2a clinical trial. ABTL0812 induced an upregulation of TRIB3 expression, resulting in the PI3K/AKT/mTOR axis inhibition and autophagy cell death induction on EC cells but not in healthy endometrial cells. ABTL0812 treatment also impaired PTEN knock-out cells to progress from hyperplasia to cancer. The therapeutic effects of ABTL0812 were demonstrated in vivo. ABTL0812 increased TRIB3 mRNA levels in whole blood samples of eight EC patients, demonstrating that TRIB3 mRNA could be used as a pharmacodynamic biomarker to monitor the ABTL0812 treatment. ABTL0812 may represent a novel and highly effective therapeutic agent by inducing TRIB3 expression and autophagy in EC patients, including those with poorer prognosis.
Identifiants
pubmed: 30853360
pii: S0090-8258(19)30150-7
doi: 10.1016/j.ygyno.2019.03.002
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Cell Cycle Proteins
0
RNA, Messenger
0
Repressor Proteins
0
Small Molecule Libraries
0
TRIB3 protein, human
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
425-435Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.