Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors.
Aged
Animals
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Aurora Kinase A
/ antagonists & inhibitors
Azepines
/ administration & dosage
Benzoxazoles
/ administration & dosage
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Female
Humans
Male
Maximum Tolerated Dose
Mechanistic Target of Rapamycin Complex 1
/ antagonists & inhibitors
Mechanistic Target of Rapamycin Complex 2
/ antagonists & inhibitors
Mice
Middle Aged
Neoplasms
/ drug therapy
Protein Kinase Inhibitors
/ administration & dosage
Pyrimidines
/ administration & dosage
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
24
10
2019
revised:
23
02
2020
accepted:
11
05
2020
pubmed:
18
5
2020
medline:
26
11
2021
entrez:
17
5
2020
Statut:
ppublish
Résumé
The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors. TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD). The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia. The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib
Identifiants
pubmed: 32414750
pii: 1078-0432.CCR-19-3498
doi: 10.1158/1078-0432.CCR-19-3498
pmc: PMC7864382
mid: NIHMS1655339
doi:
Substances chimiques
Azepines
0
Benzoxazoles
0
MLN 8237
0
Protein Kinase Inhibitors
0
Pyrimidines
0
AURKA protein, human
EC 2.7.11.1
Aurora Kinase A
EC 2.7.11.1
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Mechanistic Target of Rapamycin Complex 2
EC 2.7.11.1
sapanisertib
JGH0DF1U03
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4633-4642Subventions
Organisme : NCI NIH HHS
ID : K23 CA172691
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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