AsianScientist (Jun. 4, 2013) – A research team in Singapore has identified ways to inhibit the function of a key protein linked to stem cell-like behavior in terminal-stage chronic myeloid leukemia (CML). The discovery makes it possible to develop drugs that may extend the survival of patients suffering from this deadly form of leukemia.
CML is a blood cancer that has seen tremendous improvement in treatment outcomes following the introduction of tyrosine kinase inhibitor (TKI) drugs that specifically target the BCR-ABL fusion gene, a genetic abnormality that is characteristic of CML. However, when CML progresses to its terminal stage, known as the blast crisis phase, TKI drugs become ineffective and patients with blast crisis CML rapidly succumb to the disease.
“TKI therapy is highly effective in chronic phase CML, and enables most patients to survive many years,” said principal investigator Ong Sin Tiong, an associate professor at the Duke-NUS Graduate Medical School in Singapore.
“In contrast, patients with blast crisis CML usually succumb to their disease within one year, with most patients dying because they develop drug resistance to TKI therapy”
A subset of cells associated with blast crisis CML exhibit characteristics of self-renewing stem cells, suggesting that targeting this particularly malignant and drug-resistant population would be effective in treating blast crisis CML. The team therefore searched for novel targets that will specifically eliminate these cancer stem cells.
In their study, published online in the Proceedings of the National Academy of Sciences, the team identified a protein enzyme, the MNK kinase, that was abnormally activated in clinical samples taken from patients with blast crisis CML.
Experiments conducted in the lab further unraveled details of the biochemical pathway in which the MNK protein functions and showed that activation of this pathway is a critical step in the progression of CML to the blast crisis phase. Furthermore, the researchers found that activation of MNK is responsible for the stem cell-like behavior of leukemia stem cells.
The team tested a panel of drugs that inhibit MNK kinase activity and found that these MNK inhibitors were effective in preventing blast crisis cells from behaving like cancer stem cells in both in vitro laboratory tests and animal studies.
“Our studies identify the MNK kinases as an important therapeutic target in blast crisis CML, and suggest that drug inhibition of MNK kinase will be useful in overcoming TKI resistance, and improving the survival of patients with blast crisis CML,” said Professor Ong.
Importantly, the MNK inhibitor drugs do not appear to be toxic to normal blood stem cells, indicating that drugs targeting MNK kinases may not cause harmful side effects. Ong said he hopes the findings from this study will open new research directions in the treatment of blast crisis CML.
“The development of dual MNK and BCR-ABL kinase inhibitors to treat patients with blast crisis CML may enhance the survival of patients with this deadly disease,” said Professor Ong, whose team is now working on developing such drugs.
The article can be found at: Lim et al. (2013) Targeting Of The MNK–eIF4E Axis In Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia stem Cell Function.
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Source: Duke-NUS.
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