ChemGenex Investigators Report Omacetaxine Effective in Killing CML Stem Cells in Animal Model Studies
News Dec 14, 2007
ChemGenex Pharmaceuticals has announced that pre-clinical data characterizing the mechanism of action of omacetaxine mepesuccinate (formerly known as Ceflatonin®) were presented at the American Society of Hematology (ASH) Annual Meeting in Atlanta, Georgia.
Study results demonstrate that omacetaxine, down-regulating the key protein Mcl-1, had a direct anticancer effect on leukemic stem cells that was not exhibited by the tyrosine kinase inhibitor imatinib.
The poster presentation was authored by Dr. Shaoguang Li and colleagues from the Jackson Laboratory in Maine, USA, as well as ChemGenex scientists.
The authors reported that omacetaxine reduced the number of leukemic stem cells in the bone marrow by more than 80% in an animal model of CML (mice with BCR-ABL-induced CML disease).
In contrast, the tyrosine kinase inhibitor imatinib mesylate (Gleevec®) did not reduce the number of leukemic stem cells in the bone marrow. Previous research by Dr. Li and his colleagues found that the second generation tyrosine kinase inhibitor dasatinib (Sprycel®) did not eradicate CML stem cells in the same model system (Hu et al., 2006).
Consistent with the killing of CML stem cells, the authors reported that omacetaxine provided a significant survival benefit to mice with two different types of leukemia; BCR-ABL-induced CML and B cell acute lymphoblastic leukemia (B-ALL).
Scientists now believe that some cancers arise from a small number of aberrant cells that, like adult stem cells, have the ability to self-renew and differentiate into multiple cell types. These cells often persist in cancer patients in low numbers even following therapy, and can cause disease relapse. Therapies that effectively kill cancer stem cells as well as differentiated cancer cells may thus hold promise for improving the treatment of cancer and increasing survival from the disease.
The authors also reported that omacetaxine inhibited cell proliferation and markedly reduced the expression of the anti-apoptotic protein Mcl-1 in leukemic cell lines. Mcl-1 is a key target protein in several types of leukemias and other cancers, and is believed to be one of the major targets through which omacetaxine causes clinical responses.
The spatial and temporal dynamics of proteins or organelles plays a crucial role in controlling various cellular processes and in development of diseases. However, acute control of activity at distinct locations within a cell cannot be achieved. A new chemo-optogenetic method enables tunable, reversible, and rapid control of activity at multiple subcellular compartments within a living cell.