Researchers at The University of Manchester have discovered that a protein (5T4) found on the surface of cells contributes to chemotherapy resistance in the most common type of childhood leukaemia. Using a novel approach, early testing shows that targeting the protein with an antibody drug conjugate (ADC) could hold promise in improving treatment.
The research, which was funded by the blood cancer charity, Bloodwise, is published in Haematologica.
Survival rates for childhood acute lymphoblastic leukaemia (ALL) have improved substantially over the years. Now, around nine in 10 children can look forward to being cured, but current treatment – usually an intense course of chemotherapy – is gruelling and can leave children with life-long side effects such as infertility and even secondary cancers. There is also a chance of the blood cancer returning if high levels of leukaemia initiating cells remain after the first rounds of intensive treatment. If the cancer comes back, it is more difficult to treat.
In a study led by Professors Vaskar Saha and Peter Stern, researchers analysed samples from children who were determined to be at either low or high risk of relapse based on the numbers of leukaemic cells remaining after their first round of chemotherapy.
The researchers found a high proportion of 5T4 positive leukaemia cells in patients with a high risk of relapse, while this marker was not detected in samples taken from children who responded well to initial treatment.
5T4 positive leukaemia cells are significantly more clonogenic. This means that the disease can recur from very few residual cells. The researchers discovered that the 5T4 protein helps leukaemia stem cells migrate from the blood vessels to the safety of the bone marrow during treatment, which offers protection from chemotherapy and makes these cells much harder to eradicate.
Using a model system of human leukaemia engrafted in mice, an ADC developed by Pfizer Inc., A1mcMMAF, which targets cells with 5T4 molecules on the surface and delivers a drug which is toxic for the cells, was shown to be very effective in treatment. In addition, when used in combination with dexamethasone, a standard component of induction therapy, there was a significantly improved survival of the mice.
Professor Vaskar Saha, who led the research with Professor Peter Stern at The University of Manchester, said: “Although this is early work, our findings suggest that leukaemic initiating cells that have 5T4 are better at entering sites in the body that will protect them from standard chemotherapy, causing drug resistance and relapse. By targeting 5T4 in mice, we have shown that we can selectively attack the treatment-resistant leukaemia cells.”
Dr Alasdair Rankin, Director of Research at Bloodwise, said: “The chemotherapy currently used to treat childhood ALL is not always effective, and can cause life-long side effects. Using targeted therapies – alone or in combination – that hone in on specific characteristics of the cancer cells, could eventually make therapies gentler and more effective. These early findings are promising, and have opened up the future possibility of a new targeted treatment for childhood ALL.”
For further information, please contact Henry Winter at the Bloodwise Press Office on 020 7269 9019, press mobile 07824 375880, or email: [email protected]
NOTES TO EDITORS
The findings are published online in the journal Haematologica under the title ‘Targeting the 5T4 oncofoetal glycoprotein with an antibody drug conjugate (A1mcmmaf) improves survival in patient derived xenograft models of acute lymphoblastic leukemia’. Corresponding authors: Professor Peter Stern and Professor Vaskar Saha, University of Manchester
About childhood leukaemia
Leukaemia is the most common form of childhood cancer. It occurs when healthy white blood cells in the bone marrow develop DNA faults early in their development. These abnormal cells then multiply uncontrollably and live for longer than they should, crowding out normal blood cells.
There are two main types of childhood leukaemia. Acute lymphoblastic leukaemia (ALL), which starts in white blood cells called lymphocytes, is the most common and is diagnosed in around 400 children each year. Acute myeloid leukaemia (AML), which affects white blood cells called myeloid cells, is diagnosed in around 60 children each year.
Symptoms vary from child to child, but common signs include tiredness, breathlessness, frequent infections, fever, bone pain or unexplained bruising. Treatment for ALL normally consists of a combination of different chemotherapy drugs and can last up to three years.
Bloodwise is the UK’s specialist blood cancer research charity dedicated to improving the lives of patients. The charity, which was formed in 1960, changed its name from Leukaemia & Lymphoma Research in September 2015.
Around 38,000 people of all ages, from children to adults, are diagnosed with blood cancers and related disorders every year in the UK. It is a complex disease area made up of 137 individual diseases. Some affect thousands of people, such as common forms of leukaemia, lymphoma and myeloma. Others affect only a handful. But together, blood cancers are the fifth most common form of cancer and the third biggest cause of cancer death.
The charity’s research is targeted at understanding more about blood cancer, finding causes, improving diagnosis and treatments, and running groundbreaking clinical trials for patients. The charity champions patients’ needs by influencing relevant decision makers and influencers, and seeking to raise awareness of the issues faced by patients. Their patient services provide information, support and assistance to patients at every stage of their journey. For more information visit www.bloodwise.org.uk
About The University of Manchester
The University of Manchester, a member of the prestigious Russell Group, is the UK’s largest single-site university with 38,600 students and is consistently ranked among the world’s elite for graduate employability.
The University is also one of the country’s major research institutions, rated fifth in the UK in terms of ‘research power’ (REF 2014). World class research is carried out across a diverse range of fields including cancer, advanced materials, addressing global inequalities, energy and industrial biotechnology.
No fewer than 25 Nobel laureates have either worked or studied here.
It is the only UK university to have social responsibility among its core strategic objectives, with staff and students alike dedicated to making a positive difference in communities around the world.
Manchester is ranked 35th in the world in the Academic Ranking of World Universities 2016 and 5th in the UK. The University had an annual income of almost £1 billion in 2015/16.
Visit www.manchester.ac.uk for further information.
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