Discovery 'significant step' in understanding leukaemia drug resistance

Cancer Research UK

Scientists have pinpointed an enzyme responsible for breaking down and inactivating a key childhood leukaemia drug, which could help to explain why around 20 per cent of patients do not respond to therapy. Their findings are published in the Journal of Clinical Investigation* today (Monday).

The researchers, funded by Cancer Research UK and Leukaemia Research, also discovered that the enzyme - called AEP - was not found in healthy white blood cells, which are the cells affected by leukaemia.

So production of AEP and resistance to the drug is the result of a genetic fault in some leukaemia cells**.

Over 80 per cent of children with acute lymphoblastic leukaemia (ALL) are successfully treated, but for some patients the treatment does not work. So it is crucial that new treatments are found to help ensure all children with this type of cancer are cured.

Asnase is a form of a drug called Asparaginase and is used to treat all children with ALL in the UK. It is produced commercially using the bacteria E. coli.

Around 20 per cent of ALL patients become resistant to the drug or have an allergic reaction.

The scientists found that AEP breaks down Asnase and so stops the drug from working. They think that the presence of AEP could determine whether patients respond to Asnase treatment, and whether they have an allergic reaction to it.

If these results are confirmed in patients, a test could one day be developed to help doctors predict whether children with ALL will benefit from Asnase before treatment starts and hopefully prevent some patients undergoing unnecessary chemotherapy.

Professor Vaskar Saha, Cancer Research UK's paediatric oncologist, based at the Paterson Institute in Manchester, said: "Although our results are at an early stage, our study is an important development in understanding the science behind why some patients don’t respond to leukaemia drugs.

"If our findings in leukaemia cells are confirmed in patients, we could be able to test if this drug is the best option before treatment starts - we're currently recruiting patients from 18 childhood cancer centres in the UK to help us discover if this is the case."

Dr Paul Bates, study co-author based at Cancer Research UK's London Research Institute, said: "We are now looking at how to modify the drug to make it more potent and resistant to AEP's actions."

ALL is the most common type of childhood cancer, and accounts for one in four of all cancers in children in the UK - around 450 cases are diagnosed each year.

Around 20 per cent of ALL patients are thought to have cancer cells that produce AEP, and so will not respond to Asnase.

Dr David Grant, Scientific Director of Leukaemia Research, said: "Asparaginase has been in use for over 40 years and it continues to be an essential element of treatment of ALL in adults and children. Almost as soon as it entered use, asparaginase resistance was recognized as a problem; this tremendously exciting work offers both an explanation of how that resistance may arise and a possibility of modifying the drug to overcome resistance.

"Researchers and clinicians have transformed childhood ALL from a virtual death sentence to an illness curable in over 80 per cent of cases. This still means that about one in five will not survive and many children who do survive have long-term side effects. This research is still at the laboratory stage and there is a long process ahead to translate this into clinical benefit but it offers hope of overcoming one of the obstacles to curing all children with ALL."

Professor Sir David Lane, chief scientist at Cancer Research UK, said: "These encouraging results are a significant step forward in developing 'personalised treatment' - where therapy is tailored to the requirements of an individual patient.

"This concept is now becoming a reality and we look forward to seeing if this discovery can be translated to benefit children with cancer. Our goal is to control or cure cancer in all children."

ENDS

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Notes to Editor

* A Dyad of Lymphoblastic Lysosomal Cysteine Proteases Degrades the Key Anti-Leukemic Drug L-Asparaginase. Patel et al. Journal of Clinical Investigation. 8 June 2009.

** The cells used in this study were acute lymphoblastic leukaemia (ALL) cells.