Scientists develop new strategy to overcome drug-resistant childhood cancer
Wednesday 11 July 2012
A new drug combination could offer hope to children with neuroblastoma – one of the deadliest forms of childhood cancer – by boosting the effectiveness of a promising new gene-targeted treatment.
Researchers at The Institute of Cancer Research in London have found a way to overcome the resistance of cancer cells to a drug called crizotinib, which recently showed positive early results in its first trial in children with cancer.
Crizotinib has already been licensed by the US Food and Drug Administration for use in adult cancers, but early experience suggests tumours eventually stop responding to treatment, after developing additional mutations in the ALK gene targeted by the drug.
The paper, led by The Institute of Cancer Research in collaboration with the Dana-Farber Cancer Institute and Children’s Hospital in Boston, publishes this week in the prestigious journal Cancer Cell. The study received funding from a variety of sources including The Neuroblastoma Society, Cancer Research UK, Sparks, the children’s medical research charity and The Rooney Foundation.
In the study, scientists detailed their new strategy of combining crizotinib with a second class of drugs – mTOR inhibitors – to knock out the resistance of cancer cells.
Scientists identified the strategy after revealing for the first time the role played by the ALK cancer-causing gene in driving neuroblastoma, which accounts for 15 per cent of all the UK’s childhood cancer deaths.
Neuroblastomas are cancers of the developing nervous system, and new drug combinations are desperately needed as aggressive forms of the disease are very difficult to treat with conventional chemotherapy.
Senior author Dr Louis Chesler, leader of the neuroblastoma drug development team at The Institute of Cancer Research and honorary consultant at The Royal Marsden NHS Foundation Trust, said: “With the first paediatric clinical trial reporting substantial responses to crizotinib in patients with ALK driven tumours, we are looking for ways to increase the effectiveness of ALK inhibitors in general. We have identified a very promising way to overcome crizotinib resistance in neuroblastoma, by adding a second drug called an mTOR inhibitor. Many mTOR inhibitors are already in adult clinical trials.”
“We hope that our work will benefit children with neuroblastoma by increasing the effectiveness of crizotinib. Our study may also have relevance for adult patients with ALK-driven lung cancer and lymphoma who develop resistance to crizotinib, because loss of treatment response in these patients correlates with the development of point mutations in the tyrosine kinase domain of ALK. In children with neuroblastoma these point mutations are in fact the most common primary somatic changes that we see in ALK, so we hope our work with a paediatric cancer will in this case help to unravel resistance mechanisms in adult cancer as well.”
Neuroblastoma patients with ALK mutations frequently have alterations to the MYCN gene, which is closely linked to the development of aggressive neuroblastoma but is difficult to target directly with drugs.
The team therefore set out to investigate how a common ALK mutation, ALKF1174L,and alterations in MYCN interact to drive the onset of neuroblastomas, and also to attempt to find a way to overcome resistance to crizotinib.
They found that the ALKF1174L mutation and changes in MYCN cause more aggressive, crizotinib-resistant neuroblastoma, by turning on the PI3K/AKT/mTOR pathway. This pathway has been implicated in the development of neuroblastoma and many adult cancer types, and has been an intense focus of drug-development in adult cancer.
The team found that combining an mTOR inhibitor with crizotinib prevented the growth of neuroblastoma by simultaneously inhibiting MYCN and ALK, overcoming the resistance of these tumours to treatment with crizotinib alone. As well as delivering a strategy to overcome crizotinib resistance in general, this work highlights a treatment approach that may be effective for patients with aggressive neuroblastoma who carry both genetic changes at diagnosis.
Media Contact: ICR Science Communications Manager Jane Bunce on 0207 153 5106
Notes to editors:
"The ALKF1174L mutation potentiates the oncogenic activity of MYCN in neuroblastoma" with corresponding authors Louis Chesler and Rani E. George, published in Cancer Cel Volume 22, Issue 1, 117-130, 10 July 2012
Around 100 children are diagnosed with neuroblastoma every year in the UK, usually before the age of five. Neuroblastoma starts in the child's developing nerves and often appears as a tumour in the abdomen, adrenal glands or the nerve tissue at the back of the abdomen.
Overall six out of ten children are successfully treated, often with a combination of surgery, radiotherapy and chemotherapy. However, the high-risk form of the disease remains one of the main causes of cancer relapse and death in children.
The Institute of Cancer Research (ICR) is one of the world’s most influential cancer research institutes.
Scientists and clinicians at the ICR are working every day to make a real impact on cancer patients’ lives. Through its unique partnership with The Royal Marsden Hospital and ‘bench-to-bedside’ approach, the ICR is able to create and deliver results in a way that other institutions cannot. Together the two organisations are rated in the top four cancer centres globally.
The ICR has an outstanding record of achievement dating back more than 100 years. It provided the first convincing evidence that DNA damage is the basic cause of cancer, laying the foundation for the now universally accepted idea that cancer is a genetic disease. Today it leads the world at isolating cancer-related genes and discovering new targeted drugs for personalised cancer treatment.
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The Royal Marsden NHS Foundation Trust
The Royal Marsden opened its doors in 1851 as the world’s first hospital dedicated to cancer diagnosis, treatment, research and education.
Today, together with its academic partner, The Institute of Cancer Research (ICR), it is the largest and most comprehensive cancer centre in Europe treating over 44,000 patients every year. It is a centre of excellence with an international reputation for groundbreaking research and pioneering the very latest in cancer treatments and technologies. The Royal Marsden also provides community services in the London boroughs of Sutton and Merton and in June 2010, along with the ICR, the Trust launched a new academic partnership with Mount Vernon Cancer Centre in Middlesex.
Since 2004, the hospital’s charity, The Royal Marsden Cancer Charity, has helped raise over £50 million to build theatres, diagnostic centres, and drug development units.
Prince William became President of The Royal Marsden in 2007, following a long royal connection with the hospital.
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As a leading children’s medical research charity we are dedicated to funding and championing pioneering research into a range of conditions affecting babies, children and mums-to-be.
Since 1991, we have now committed over £23 million into pioneering research projects across a wide spectrum of medical conditions including childhood cancers, cerebral palsy, premature birth and spina bifida.
Through the research we fund, we aim to improve the quality of life for children and families affected by serious illness or disability today, whilst seeking ways to better diagnose, treat and prevent these conditions in the future.
The medical breakthroughs we make possible, make a difference not only across the UK but for thousands of children and families around the world.
For more information, visit: http://www.sparks.org.uk/
The Neuroblastoma Society was formed in October 1982 by a group of parents whose children were suffering from or had died from Neuroblastoma. The Trust Deed formally creating the charity was signed on 20 May 1983. The Society is registered as a national charity 326385 with the Charity Commission for England and Wales.
The charity's sole purpose is the relief of children suffering from Neuroblastoma, and to achieve this it raises funds for medical research into improving both diagnosis and treatment of the disease. The Society also offers an opportunity for parents to give each other mutual help, support and comfort.
The Society is administered by a Board of Trustees made up of lay members who are parents or close relatives of children who have Neuroblastoma, and senior medical staff who treat the disease. The whole administration is carried out by voluntary effort so costs are kept to a minimum, with well over 90% of funds raised being spent directly on helping to fight the disease.
For more information, visit: www.nsoc.co.uk
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