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In vivo activity of the second-generation proteasome inhibitor ixazomib against pediatric t-cell acute lymphoblastic leukemia xenografts
Randall, J., Evans, K., Watts, B., Kosasih, H. J., Smith, C. M., Earley, E. J., Erickson, S. W., Jocoy, E. L., Bult, C. J., Teicher, B. A., de Bock, C. E., Smith, M. A., & Lock, R. B. (2024). In vivo activity of the second-generation proteasome inhibitor ixazomib against pediatric t-cell acute lymphoblastic leukemia xenografts. Experimental Hematology, 132, Article 104176. https://doi.org/10.1016/j.exphem.2024.104176
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 protein 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 proteasome inhibitor against pediatric T-ALL cell lines and patient-derived xenografts (PDXs) grown orthotopically in immunodeficient NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJAusb (NSG) mice. Ixazomib was highly potent in vitro, with half-maximal inhibitory concentration (IC50) values in the low nanomolar range. As a monotherapy, ixazomib significantly extended mouse event-free survival of five out of eight T-ALL PDXs in vivo. (c) 2024 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.