Scientists identify drugs to target ‘Achilles heel’ of Chronic Myeloid Leukaemia cells

Published: 8 June 2016

New research, by the Universities of Glasgow and Manchester, has revealed an ‘Achilles heel’ of Chronic Myeloid Leukaemia (CML) and found drugs to successfully target this weakness and eradicate the disease in mice.

New research, by the Universities of Glasgow and Manchester, has revealed an ‘Achilles heel’ of Chronic Myeloid Leukaemia (CML) and found drugs to successfully target this weakness and eradicate the disease in mice.

Video on the Chronic Myeloid Leukaemia research

The study, which is published in Nature today, analysed both CML and normal blood stem cells and found two proteins that were key to the survival of CML stem cells. The group, which has been working on this research for more than six years, then developed a drug combination to simultaneously target these critical proteins and kill the cancer stem cells, while largely sparing normal cells.

The interdisciplinary research team, led by Professor Tessa Holyoake from the University of Glasgow and Professor Tony Whetton from the University of Manchester, used a range of techniques to show that these two proteins (p53 and c-Myc) act as ‘gateway controllers’ in CML.

Guided by the concept of precision medicine (the right drug, at the right time, for the right effect in the patient), the team designed a new treatment to exploit this critical weakness in the cancer. Using CML cells transplanted into mice, the authors demonstrated that drugs targeting these two proteins killed the cells that cause the leukaemia, effectively eradicating the disease.

The results have potential implications for other cancers including acute myeloid leukaemia and brain tumours. The researchers are now keen to build on their work by beginning human trials in patients with drug-resistant CML.
Professor Holyoake, who led the team from the Paul O'Gorman Leukaemia Research Centre, said: “We are certainly excited by the results shown in the study. The research – a fantastic example of precision medicine in action – is at an early stage, but the data we collected has revealed two weaknesses in CML and a potential drug approach to eradicating these key stem cells.

“We also could not have achieved such an excellent result without all the generous stem cell donations from both CML patients and other members of the public, so it is important to say thank you to them.”Tile-Staff12-TessaHolyoake

The team used a range of techniques in their research including proteomics (the large scale study of quantities, structures and functions of proteins).

Professor Whetton said: “We have found a way to kill leukaemia stem cells which could lead to a cure of chronic myeloid leukaemia instead of managing the disease. We are really excited that our new proteomics approaches helped to achieve this.

“There are so many other diseases where we can use the same proteomics approach to find precision medicine solutions for patients. We have the largest clinical proteomics centre in Europe in Manchester so we really look forward to contributing to this work.”

Current therapy for CML is with tyrosine kinase inhibitors (TKIs) which effectively hold back the disease, but do not cure it. If the therapy is stopped, the leukaemia relapses in the majority of patients, requiring CML patients to remain on treatment for their lifetime. These drugs, as well as being costly to administer, can cause a number of side effects including diabetes and vascular problems. It is the dual issues of cost and toxicity in current CML treatment that has driven this particular piece of research.

Dr Matt Kaiser, Head of Research at Bloodwise, said: “Advances made in treatment for this type of leukaemia have, thanks to research, been one of the great medical success stories of recent years, with the transformation of a usually fatal cancer into a lifelong manageable condition for most patients. The only hope of a permanent cure at the moment is a gruelling stem cell transplant, which doesn’t always work and would not be suitable for many patients to even consider. Although it’s early days, these hugely significant findings suggest that targeted drugs could be developed to cut the cancer off at its roots while sparing healthy cells, providing hope of more effective and kinder treatments.”  

Dr Áine McCarthy, senior science information officer at Cancer Research UK, said: “By recognising the important roles p53 and MYC play in helping chronic myeloid leukaemia stem cells to survive, this study has identified two new ways to target and kill these cells. Excitingly, this early-stage laboratory work also showed that two experimental drugs which target the effects of these molecules can kill CML stem cells in mice. The next step will be to test if this combination works the same way in people, and if it is safe to use.”  

The study, ‘Dual targeting of p53 and c-Myc selectively eliminates leukaemic stem cells’ is published in Nature. The research was funded by Bloodwise, Cancer Research UK, The Howat Foundation, Roche, Constellation Pharmaceuticals, the Medical Research Council (MRC), the Scottish Government Chief Scientist Office, Friends of Paul O’Gorman, and the British Society for Haematology start-up fund.

About the Research
The research team used an unbiased approach to their work, which involved a series of laboratory tests complemented with computational analyses and proteomics. Human stem cell samples were collected from CML donors and tested against donated stem cells from healthy individuals.

After gathering protein and RNA data from CML and healthy cell types, they used computational analyses to identify the likely protein interactions controlling CML stem cells. The proteins p53 and c-Myc were revealed as controllers in cancer but not in the normal stem cells. Using CML cells transplanted into mice they demonstrated that drugs targeting this dual hub killed the CML stem cells.

About CML
CML is a blood cancer affecting less than 1% of the population with more than 700 new patients diagnosed in the UK each year. It causes the body to make too many white blood cells, which over time fill the bone marrow and reduce the number of healthy white blood cells.

As a result of CML sufferers surviving longer (85% live for more than five years after being diagnosed) there is a growing economic cost associated with current therapy costing between 40,000 and 70,000 Euros for one patient per year in Europe.

CML was also the first cancer found to have a genetic mutation. As a result science has used CML as a learning model to understand how other cancers work, and importantly how patients become resistant to drug therapy.

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First published: 8 June 2016

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