In vivo activity of the second-generation proteasome inhibitor ixazomib against pediatric T-cell acute lymphoblastic leukemia xenografts.
Document Type
Article
Publication Date
4-1-2024
Original Citation
Randall J,
Evans K,
Watts B,
Kosasih H,
Smith C,
Earley E,
Erickson S,
Jocoy E,
Bult C,
Teicher B,
de Bock C,
Smith M,
Lock R.
In vivo activity of the second-generation proteasome inhibitor ixazomib against pediatric T-cell acute lymphoblastic leukemia xenografts. Exp Hematol. 2024;132:104176.
Keywords
JCA, JMG, Humans, Child, Animals, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Heterografts, Proteasome Inhibitors, Mice, Inbred NOD, T-Lymphocytes, Mice, SCID, Boron Compounds, Glycine
JAX Source
Exp Hematol. 2024;132:104176.
ISSN
1873-2399
PMID
38320689
DOI
https://doi.org/10.1016/j.exphem.2024.104176
Abstract
The overall survival rate of patients with T-cell acute lymphoblastic leukemia (T-ALL) is now 90%, although patients with relapsed T-ALL face poor prognosis. The ubiquitin−proteasome system maintains normal pro- tein homeostasis, and aberrations in this pathway are associated with T-ALL. Here we demonstrate the in vitro and in vivo activity of ixazomib, a second-generation orally available, reversible, and selective protea- some inhibitor against pediatric T-ALL cell lines and patient-derived xenografts (PDXs) grown orthotopically in immunodeficient NOD.Cg-Prkdc scid IL2rg tm1Wjl/SzJAusb (NSG) mice. Ixazomib was highly potent in vitro, with half-maximal inhibitory concentration (IC50 ) values in the low nanomolar range. As a monotherapy, ixa- zomib significantly extended mouse event-free survival of five out of eight T-ALL PDXs in vivo. © 2024 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.