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Chronic myelogenous leukemia (CML)

b-Catenin (CTNNB1); interferon regulatory factor 8 (IRF8)

In vitro and mouse studies suggest simultaneously increasing IRF8 expression and inhibiting CTNNB1 could help treat CML. In Irf8-/- mice, which develop CML, enhanced activation of Ctnnb1 caused disease progression to fatal blast crisis. In a BCR-ABL tyrosine kinase mouse model of CML, combined Irf8 knockout and Ctnnb1 activation increased Gleevec imatinib resistance compared with wild-type Irf8 expression and normal Ctnnb1 activation. Next steps include testing Gleevec in combination with Irf8 activation and Ctnnb1 inhibition as a triple therapy at the initiation of blast crisis in models of CML.
Novartis AG markets Gleevec, a BCR-ABL tyrosine kinase inhibitor, to treat gastrointestinal stromal tumors (GISTs), acute lymphoblastic leukemia (ALL) and CML.
Prism Pharma Co. Ltd. and Eisai Co. Ltd. have the CTNNB1 inhibitor PRI-724 in Phase I/II testing to treat CML and other cancers.
Marina Biotech Inc.'s CEQ508, an oral RNAi targeting CTNNB1, is in Phase I/II testing to treat colorectal cancer.

SciBX 6(43); doi:10.1038/scibx.2013.1220
Published online Nov. 7, 2013

Patent and licensing status not applicable

Scheller, M. et al. J. Exp. Med.; published online Oct. 7, 2013;
Contact: Achim Leutz, Max Delbrueck Center for Molecular Medicine,
Berlin, Germany
Contact: Marina Scheller, same affiliation as above