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Updated: Jul 4, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
In vivo activity of the second-generation proteasome inhibitor ixazomib against pediatric T-cell acute lymphoblastic
Joanna Randall1, Kathryn Evans1, Ben Watts1
1Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, University of New South Wales Medicine & Health, Centre for Childhood Cancer Research, University of New South Wales Sydney, Sydney, NSW, Australia.
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 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.
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