01 Nov 2010
Imatinib is one of the first drugs to identify and destroy leukaemia cells. However, one problem with this otherwise successful targeted therapy to treat blood cancers soon became evident:
Leukaemia stem cells grow resistant to the drug, especially in patients with more advanced phases of the disease.
When treatment stops, the leukaemia often recurs.
For Dr Charles Chuah, Senior Consultant, Department of Haematology, Singapore General Hospital (SGH), the problem of drug resistance has long been a fascination and a challenge. At the turn of this millennium, working as a registrar beginning to specialise in haematology, Dr Chuah witnessed “the remarkable clinical responses” imatinib achieved in patients suffering from chronic myeloid leukaemia.
But he also realised resistance to the drug was “a significant problem” which needed to be overcome. Years – and many research projects – later, Dr Chuah is leading a team of researchers from Duke-NUS Graduate Medical School and the Cancer Science Institute of Singapore to investigate how cancerous stem cells, the smallest units in the body that are capable of renewing themselves, can be eradicated in types of leukaemia such as chronic myeloid leukaemia.
“We will investigate if a combination of novel and existing targeted therapies using drugs like imatinib will be effective in killing leukaemia stem cells,” said Dr Chuah.
“One strategy is to combine drugs that are effective against different targets or pathways required for the survival of the leukaemia stem cells. This is the premise of our research.” The $675,000 study will take three years, with funding coming from the money that Dr Chuah receives as one of this year’s National Medical Research Council Clinician Scientist Award winners.
Among the compounds that Dr Chuah will study is one that was discovered by Professor Patrick Casey, Senior Vice Dean of Research at Duke-NUS Graduate Medical School, and which was shown to be effective in slowing the growth of cancer cells.
“My lab also showed that it was effective against leukaemia cells. We believe that the compound inhibits an important pathway that is involved in the survival of leukaemia stem cells,” said Dr Chuah. To study leukaemia stem cell function, the project will use a mouse model developed by Professor Daniel Tenen, Director, Cancer Science Institute of Singapore, and that was engineered to have similar characteristics as human chronic myeloid leukaemia. The study also involves the use of cord blood cells which will be used to determine if the drug therapy spares the normal stem cells while eliminating leukaemia stem cells, said Dr Chuah, adding that the cord blood cells will be provided by Singapore Cord Blood Bank.
A breakthrough in the findings will have wider implications. “Chronic myeloid leukaemia is a model disease for understanding cancer stem cell biology and therapeutics. If we are able to show that drug therapy eradicates chronic myeloid leukaemia stem cells through a certain pathway (or a sequence of reactions by which one substance is converted into another), we can adopt a similar strategy for other types of leukaemia stem cells which are dependent on that pathway for survival,” said Dr Chuah.
As recently as a decade ago, someone diagnosed with leukaemia might have felt that he had been handed the death sentence, but advances in medicine have significantly improved their prospects, said Dr Chuah. “I have been fortunate to witness this revolution as a haematologist, but a lot more still needs to be done for an alternative and effective treatment method to be implemented.”
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Dept of Haematology
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