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Novel target for cancer therapy

13 Aug 2013

First author of the study and Research Fellow at Duke-NUS, Dr Sharon Lim, with Assoc Prof Ong

Photo: Tang Yew Chung/Duke-NUS
A Singapore-led research team has identified ways to inhibit the function of a key protein linked to stem cell-like behaviour in terminal-stage chronic myeloid leukaemia (CML). Their study, spearheaded by medical oncologist and clinician scientist Associate Professor Ong Sin Tiong at the Duke-NUS Graduate Medical School Singapore (Duke-NUS), makes possible the development of drugs that may extend the survival of patients suffering from this deadly form of cancer.

Published in the Proceedings of the National Academy of Sciences international journal on 3 June, the team’s findings resulted from a long-standing collaboration between Duke-NUS, the Experimental Therapeutics Centre (ETC) and the Singapore General Hospital (SGH) that is focused on developing effective therapies for CML.

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 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.

Since a subset of cells associated with blast crisis CML exhibit characteristics of self-renewing stem cells, it was proposed that targeting this particularly malignant and drug-resistant population would be effective in treating blast crisis CML. The team thus searched for novel targets that will specifically eliminate these cancer stem cells.

They eventually 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 unravelled how MNK kinase activation plays a critical role in the progression of CML to the blast crisis phase.

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 Assoc Prof Ong.

Hoping that their findings will open new research directions in the treatment of blast crisis CML, Assoc Prof Ong disclosed that they are currently collaborating with the ETC and SGH to develop new drugs to simultaneously target both the MNK and BCR-ABL kinases, which may further enhance the survival of patients with this disease.