Scientists find new drug target for hard-to-treat leukaemia

Thursday 29 March 2012

Cancer Research UK Press Release

Cancer Research UK scientists have discovered a promising new approach to treat a type of myeloid leukaemia – a cancer with limited treatment options and relatively poor survival, according to research published in Cancer Cell today.

The team at the Paterson Institute for Cancer Research at The University of Manchester have identified a new drug target – an enzyme called LSD1 – for an aggressive form of acute myeloid leukaemia called mixed lineage leukaemia (MLL).  LSD1 helps control whether certain cancer-causing genes are turned on or off. Blocking the enzyme prevents the production of proteins that drive the cancer.   

Scientists at Cancer Research UK’s Paterson Drug Discovery Unit synthesised molecules to block this enzyme, and lead author Dr Tim Somervaille, group leader at Cancer Research UK’s Leukaemia Biology Laboratory, showed that they could stop the growth of leukaemia cells – taken from patients with the disease, and also from mice.

Every year in the UK around 2,380 people are diagnosed with acute myeloid leukaemia and of these it is estimated that around five percent – around 120 patients – have the MLL subtype.

Survival for acute myeloid leukaemia remains low although it has improved. Currently, around forty percent of people aged under 60 with the MLL-AF9 subtype survive the disease for five years or more.

Dr Somervaille said: “It’s difficult to successfully treat patients with this type of leukaemia. There aren’t any targeted drugs available and many patients can’t be cured with current treatments, such as intensive chemotherapy and bone marrow transplantation.  So there’s an urgent need for new drugs.

“We’re very pleased to have tested molecules that homes in on an enzyme called LSD1 in a completely new approach to stop the growth of this disease. And we also believe this target may be important in a range of other types of cancer, but more research is needed.  

“The next stage is to develop molecules like this one further, and run clinical trials to see if they could be used to treat patients in the future.”

Dr Julie Sharp, Cancer Research UK’s senior science information manager, said: “It’s great news that this molecule could provide a new targeted way to treat an aggressive type of leukaemia, for which treatment options are limited.

“Our scientists have been at the heart of progress that has seen great improvements in the treatment of leukaemia. For example, we developed some of the first important drugs for blood cancers and pioneered treatment with radiotherapy. And we’ve revealed many of the gene changes that fuel the development and growth of blood cancers, paving the way for future treatments.

“But there is much more to be done and, only with continued public support, can our scientists around the UK continue their groundbreaking research into leukaemia to learn more about the biology of the disease – and improve survival.”

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Cancer Research UK launches trial of new drug to treat acute childhood leukaemia

Friday 27 January 2012

Cancer Research UK Press Release

Cancer Research UK’s Drug Development Office has opened the first trial of a new type of drug to treat children aged from six months to 18 years with acute leukaemia, who are no longer responding to treatment.

In this first-in-child study, 15 children with acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) will receive a treatment called AT9283. AT9283 belongs to a new class of drugs called aurora kinase inhibitors.

The trial is led by Great North Children’s Hospital, Newcastle upon Tyne and is also running at four other clinical centres.

Despite great progress in the treatment of childhood leukaemia, approximately 100 children with leukaemia under the age of 15 die each year in the UK. Leukaemia that has returned or is resistant to current treatments remains one of the key causes of death from childhood cancer. Cancer is the second most common cause of death in childhood.

AT9283 looks promising in laboratory studies and has been tested in a small number of adults (solid tumours and haematological malignancies) and children and adolescents with solid tumours. This trial will assist in establishing the correct drug dose and investigate if it can treat children and adolescents with leukaemia.

Chief investigator Professor Josef Vormoor, said: “It’s devastating to have to tell parents of a child with leukaemia that the disease has returned. Or that it’s unlikely their child can be treated with existing drugs.

“So I’m incredibly excited about the launch of this trial, to see if a new drug can treat the disease, when a child has stopped responding to current treatments."  

AT9283 blocks the activity of a group of proteins called aurora kinases which control cell growth. Blocking these proteins can stop cancer cells’ ability to grow.
Around 1,500 children are diagnosed with cancer each year in the UK, with leukaemia, the most common childhood cancer accounting for around a third (31 per cent) of all cases.
The trial is funded, managed and sponsored by the charity’s Drug Development Office (DDO) and the drug is provided by Astex Pharmaceuticals.
Dr Nigel Blackburn, director of drug development at Cancer Research UK’s Drug Development Office, said: “We’ve made amazing progress in the treatment of childhood cancers: In the 1960s, only around a quarter of children with cancer survived. Today, three quarters survive. But there is much more to do.
“There’s an urgent need to develop new treatments for young people with leukaemia. The launch of this first trial of a completely new treatment for childhood leukaemia is incredible news and we’ll be watching the results with great interest.”
Cancer Research UK spent nearly £9 million last year on research into children’s cancers.

For more information on the trial, please visit www.cancerhelp.org.uk or call the Cancer Research UK cancer information nurses on 0808 800 4040.

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Faulty enzyme linked to certain brain tumours

Monday 23 November 2009

US scientists have discovered that a faulty enzyme may contribute to the formation of some malignant brain tumours.

Around 70 per cent of people with a type of brain tumour - called a low-grade glioma - have a faulty version of an enzyme called IDH1. The mutation is also found in a significant proportion of patients with acute myeloid leukaemia.

Research led by Agios Pharmaceuticals has now shown that mutations in this enzyme result in unusually high levels of a metabolite called 2-hydroxyglutarate (2HG) in the brain, which has previously been linked to the development of brain cancer.

This study is the first evidence of a role for IDH1 in the development of cancer.

Although the enzyme was known to be faulty in gliomas, scientists did not understand exactly how it could contribute to the disease.

The team, whose findings are published in the journal Nature, analysed samples of tissue taken from malignant gliomas and found that those with faults in the IDH1 enzyme typically had 100 times more 2HG than those with the normal IDH1 enzyme.

It may now be possible to develop a diagnostic test that identifies patients with gliomas that harbour the IDH1 mutation by measuring the levels of 2HG in their brain. Evidence suggests that patients with the mutation tend to do better than those without.

The research could also lead to treatments that block the production of 2HG, which in turn could delay the progression of this kind of brain tumour.

Professor Lew Cantley, director of the Cancer Centre at the Beth Israel Deaconess Medical Centre and founder of Agios Pharmaceuticals, described the work as "groundbreaking".

"The team at Agios has demonstrated that what was previously considered an inactive enzyme is in reality an active oncogene and a potential therapeutic target," he confirmed.

"This has fundamentally changed our understanding of the field. Additionally, there is an easily measured metabolic biomarker, 2HG, that will help in the diagnosis and treatment of any related therapeutics that arise from this work."

Dr Laura Bell, science information officer at Cancer Research UK, said: "This study has brought exciting new information to light which could eventually help doctors understand more about how certain brain tumours are likely to progress - and how best to treat them.

"But there is still some way to go before this new information could be used to help treat people with cancer."

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Cardiff scientists take on leukaemia with drugs personalised to individual patients

Tuesday 6 October 2009

Cancer Research UK Press Release

Cardiff scientists are treating leukaemia by trialling new drugs tailored to individual patients’ genetic make-up according to a presentation at the NCRI Cancer Conference in Birmingham today (Wednesday).

The team is running a Cancer Research UK-funded trial supported by the Cardiff Experimental Cancer Medicine Centre to develop new ways to treat Acute Myeloid Leukaemia (AML).

AML can vary from person to person because of slightly different faults in different genes.

The Cardiff group is working to identify potential drugs which could treat the different variations of the disease.

The second part of the teamss research is to code the genes of the people with AML entering the trials - and measure how well people with different faults in their genes respond to specific new treatments.

Cancer Research UK's Professor Alan Burnett, head of the Cardiff ECMC based at the School of Medicine, Cardiff University, said: "Our team identifies the different faults in genes which are likely to cause acute myeloid leukaemia and we develop new drugs to treat the varying forms of the disease.

"When a patient with acute myeloid leukaemia is given the new experimental treatments they are monitored to see how effective the drug is and how the patient’s genetic variations impact a treatment’s success."

There are 19 specialist Experimental Cancer Medicine Centres in the UK. The aim of these centres is to bring together cancer doctors, research nurses and lab scientists to make clinical trials of new treatments quicker and easier.

Dr Sally Burtles, director of centres at Cancer Research UK, said: "This cutting edge research will enable us to find more targeted and effective ways to treat people with leukaemia.

"Leukaemia can be difficult to treat because the disease spreads widely through the body – as it is not a solid tumour it cannot be treated with surgery and so it is even more crucial to develop the right drugs to treat this disease. This trial allows us to enter into an exciting new era of tailored drug development to manage and treat the disease.

"Making the leap from something that looks promising in the laboratory to testing it in patients is one of the most challenging and expensive steps in drug development – and this is the key reason why we’ve committed to establishing these Experimental Cancer Medicine Centres – to speed up this process and bridge that gap.

"The 19 Experimental Cancer Medicine Centres across the UK give cancer patients new opportunities to participate in early trials for the latest, most innovative and exciting anti-cancer treatments in development."

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Scientists sequence genome of second patient with AML

Thursday 6 August 2009

US scientists have decoded the complete DNA sequence - or 'genome' - of a second patient with acute myeloid leukaemia (AML), following on from the first such achievement last year.

The advance has revealed a number of genetic changes in the patient's cancer cells, including one 'fault' that is also known to be involved in a form of brain tumour called a glioma, and another 'fault' - not previously linked to AML - that has now been found in two patients with this type of leukaemia.

Scientists at the Washington University School of Medicine in St Louis believe that their findings show that sequencing cancer genomes could have enormous potential in developing new treatments.

Senior author Dr Timothy Ley, haematologist and professor of medicine, commented: "Only by sequencing complete genomes of cancer patients are we going to find unexpected, recurring genetic mutations that are highly likely to be important for cancer to develop and grow.

"Gaining a genome-wide understanding of cancer lays the foundation for developing more powerful ways to diagnose, classify and treat patients."

In the latest study, researchers sequenced the genome of a man who was diagnosed with AML at 38 years of age who has been in remission for more than three years.

They used a sample of his healthy skin cells to sequence his genome, as well as a sample of tumour cells taken from his bone marrow.

This allowed them to look for genetic alterations that were present in tumour cells but not in his healthy cells.

Dr Ley explained that little is known about how and why different people respond to different treatments, so most people with AML are given similar cancer therapy.

"By defining the mutations that cause AML in different people, we hope to determine which patients need aggressive treatment, like a stem cell transplant, and which can be treated effectively with less intense therapies," he revealed.

The researchers identified around 750 mutations in the patient's tumour genome, including 64 that were thought to be related to his AML. The others are believed to be random, background mutations that were not related to the disease.

Twelve of the 64 mutations were found in genes that instruct cells how to make specific proteins, while the remainder were in the stretches of DNA between genes. Previously known as 'junk' DNA, these regions are now thought to influence the way in which genes work and are not yet properly understood.

Co-author Dr Richard Wilson, director of Washington University's Genome Centre, said the discovery of so many new mutations came as a "huge" surprise.

"That so many of the mutations were found outside of protein-coding genes also underscores the need to sequence whole genomes to find all the mutations that occur in cancer," he observed.

"If we only look at genes with known or suspected links to cancer, we'll miss many mutations that are potentially relevant."

The researchers then tested 187 DNA samples from other AML patients and discovered that one of the 64 mutations, which affects a gene called IDH1, was present in 15 of the samples, indicating that it is likely to be important in the disease's progress.

Dr Jodie Moffat, Cancer Research UK's senior health information officer, said: "It's exciting that these detailed studies to understand the genetic basis of cancer are now possible due to advances in technology.

"The genetic factors involved in leukaemia are particularly complex, so anything new we can learn is very welcome. But further research will be needed before scientists can reveal which parts of the genetic puzzle can actually be used to improve the lives of cancer patients."

The team is now sequencing more DNA samples from AML patients, as well as samples from people with breast, lung and ovarian cancers and glioblastomas.

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Gene network study sheds light on leukaemia

Friday 24 April 2009

New insights into the way that genes are controlled could help scientists understand more about the development of blood cancers such as leukaemia, a new study published in Nature Genetics suggests.

Scientists at the Roslin Institute at the University of Edinburgh, working alongside an international team of researchers, investigated how genes interact with each other.

They focused on white blood cells involved in the immune system, and found that their growth and development is regulated by hundreds of interrelating genes.

It had previously been thought that cell growth was managed by a smaller group of "master" genes that switched other genes on or off.

By gaining a greater insight into this complex process and pinpointing the gene network's areas of weakness, scientists hope they will be able to shed more light on the process behind the development of leukaemia, which affects the immune system.

According to Professor David Hume, director of the Roslin Institute at the University of Edinburgh, the findings could lead to better treatments for diseases involving the immune system, including myeloid leukaemia and arthritis.

"This study has effectively shown us where the brakes are that could stop or slow down diseases like cancer and multiple sclerosis," he commented.

"We genuinely believe this could lead to treatments and cures for many diseases of the immune system."

Dr Lesley Walker, director of cancer information at Cancer Research UK, said: "This exciting research reveals just how complex the development of our immune system is. It may eventually help to explain why some people respond to immunotherapies to fight cancer and others don't."

Reference

The transcriptional network that controls growth arrest and differentiation in a human myeloid leukaemia cell line. Nature Genetics. April 2009. doi:10.1038/ng.375

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DNA sequence of cancer patient decoded for first time

Monday 10 November 2008

Scientists at the University of Washington have sequenced the genome of a 50-year-old woman with acute myeloid leukaemia (AML) as part of an effort to identify the genetic mutations unique to her type of cancer. 

It is the first time that the complete DNA sequence of a cancer patient has been decoded and the research paves the way for the development of a genome-wide approach for deciphering cancer's genetic make-up and ultimately new types of cancer treatment. 

It is also the first time the complete DNA sequence of a woman has been published.

Analysis of tumour DNA uncovered ten genetic mutations linked to AML in the patient. Eight of the mutations occurred in genes which had hitherto lacked known association with AML and nine of the mutations were found to be present in almost every single tumour sample. 

While it is known that AML is caused by the build up of mutations in people's DNA, the precise mechanism which prompts uncontrolled cell growth has yet to be uncovered. 

However, Dr Timothy Ley, the study's lead author and Alan A and Edith L Wolff Professor of Medicine, believes genome sequencing holds the key to this discovery. "Until now, no one has sequenced a patient's genome to find all the mutations that are unique to that person's disease," he commented. 

"We didn't know what we would find, but we felt that the answers to why this patient had AML had to be embedded in her DNA." 

The decoding technique, which is described in the November 6th issue of the journal Nature, can now be applied to other forms of cancer. 

Kat Arney, senior science information officer, Cancer Research UK, said: "This is a very important piece of research, not only for our understanding of leukaemia but for many other types of cancer. Thanks to advances in technology it is now possible to unlock the genetic secrets within cancer cells, which will be the key to better diagnostic tools and treatments in the future."

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Scientists solve arsenic's cancer paradox

Sunday 13 April 2008

Cancer Research UK Press Release

Cancer Research UK scientists have discovered how arsenic works as an effective treatment for leukaemia - according to a report in Nature Cell Biology* today.

Patients with a certain kind of leukaemia - acute promyelocytic leukaemia - can be successfully treated with arsenic**, but scientists didn't know how the process worked.

Now scientists have solved the mystery of how arsenic can treat cancer, more targeted treatments with fewer side effects are likely to be developed.

Lead author, Cancer Research UK's Professor Ronald Hay based at the University of Dundee, said: "Our discovery is key to understanding how we can enhance the anti-cancer properties of this poison.

"Knowing the specific molecules involved allows us to now work on creating more targeted and effective cancer drugs with fewer side effects."

The scientists watched the drug at work in animal cells. They modified some cells to remove certain proteins and discovered the drug had different effects.

They found that arsenic helps molecules called SUMO stick onto proteins involved in leukaemia. An enzyme called RNF4 hunts down SUMO and breaks down the cancer-causing proteins.

Cancer Research UK's director of cancer information, Dr Lesley Walker, said: "Discovering which molecules are involved in this process is an exciting step forward in understanding this complex paradox - how can a chemical that causes cancer also cure it?

"It's a great piece of science that will hopefully lead to the development of drugs that home in on specific cancer-causing proteins to beat the disease."

For media enquiries please contact the Cancer Research UK press office on 020 7061 8300 or, out-of-hours, the duty press officer on 07050 264 059.

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Study shows that mutation can cause leukaemia

Thursday 10 April 2008

Scientists have found proof for the first time that a particular mutation found in some patients with acute myeloid leukaemia is linked to the disease.

But their study gave surprising insights into how the mutation causes cancer to develop.

The researchers, from the European Molecular Biology Laboratory (EMBL) in Italy, the UK's EMBL-European Bioinformatics Institute, and the Universities of Lund, Sweden, and Harvard, introduced the mutation, which affects a protein called C/EBPa, into mice to try and mimic its effects in patients.

They found that, rather than triggering the growth of malignant blood stem cells, widely assumed to be the cause of leukaemia, the mutation instead programmed normal white blood cells that were ready to stop dividing to do a U-turn and start multiplying out of control.

This means that, rather than maturing and losing the ability to keep on multiplying, the cells can carry on dividing and multiplying, eventually leading to an abundance of faulty cells and a shortage of normal, healthy blood cells.

According to the team, whose findings are published in the journal Cancer Cell, the findings may have implications for the treatment of AML as ten per cent of patients have this particular mutation.

But because they also found that the reprogramming process is shared with similar leukaemias caused by other mutations, it raises the exciting possibility of developing treatments that are more generally effective for leukaemia by targeting these common cellular changes.

Dr Nerlov, group leader at EMBL, commented: "This is the first time that non-stem cell myeloid leukaemia has been generated within a healthy blood system.

"The findings will have profound implications for our understanding of the development and treatment of leukaemias."

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