From developing a new, “off-the-shelf” therapy, to mapping a detailed genetic atlas of cancer, meet the teams who are hoping to improve our understanding of children’s and young people’s cancers.
Understanding why some children inherit a greater risk of developing cancer
Understanding why children and young people get cancer is a huge task and extremely complex. But the more we know about the possible genetic causes of these types of cancer, the easier they are to treat. One research team is taking it back to basics.
Generally, the cause of for DNA changes (mutations) that can result in cancer in children and young people are unknown, but many are likely to arise as a random, one-off event that takes place inside a developing cell. And because of this, there’s sadly no way to prevent many children’s and young people’s cancers from happening.
Some mutations in genes can be inherited – known as germline mutations – which can increase the risk of cancer. These genes are specifically known as cancer predisposing genes.
Professor Richard Houlston and his team at The Institute of Cancer Research are aiming to analyse the contribution of inherited mutations in a number of solid childhood cancers, in particular Wilms tumour, Ewing sarcoma, rhabdomyosarcoma, glioma, medulloblastoma and neuroblastoma. Collectively, these account for almost half of all solid cancers in children.
While mutations in some genes are a known cause of children’s and young people’s cancers, the number caused by inherited mutations as opposed to DNA changes that arise randomly at fertilisation or in early embryonic development, remains unknown.
With the funding, Houlston plans to analyse a biobank that includes DNA samples and family histories from over 7,000 children diagnosed with a solid cancer. Using state of the art technology and cutting-edge analysis, Houlston aims to not only identify new cancer predisposing genes, but understand how these mutations can contribute to the risk of developing cancer during childhood.
The results of Houlston’s work will deepen our understanding the role of inherited mutations in children’s and young people’s cancers and could help scientists detect cancers earlier and develop new personalised medicine for patients with these types of cancers.
Targeting to create new treatments
Today, more children and young people are surviving cancer than ever before, with around 8 in 10 children living for 10 years or more following a cancer diagnosis. The high survival rate is a great example of the power of modern medicine.
This is driven in part by an understanding of how cancer cells differ from normal cells, including their DNA. But we need more information, so our scientists are focusing on a change in the DNA often seen in the cancer cells of children and young people with cancer, known as aneuploidy.
What is aneuploidy?
Most DNA in our cells is packaged into tiny structures called chromosomes. Most people have 23 pairs of chromosomes in each of their cells, bringing it to a total of 46 chromosomes.
Aneuploidy is when a cell has one or more extra or missing chromosomes. For example, having 45 or 47 chromosomes, as opposed to the usual 46.
Aneuploidies are often found in the cancer cells of children and young people with different types of cancer, and although they can be used as markers to identify some cancer types, how and why aneuploidy occurs is not well understood. This is where Professor Christine Harrison and her team come in.
Harrison, along with Professor Jonathan Higgins and Professor Steve Clifford, all based at Newcastle University, will be harnessing their expertise in chromosome biology and cell division to understand how aneuploidy can drive cancer development, and in turn, identify targets that can be exploited by new therapeutics.
The results from this study also have the potential to improve our understanding of cancer in a way that may eventually help scientists identify children at greater risk of developing aneuploidy, allowing for better monitoring of those individuals. They may lead to us finding new ways to treat these types of cancer and potentially prevent certain cancers from developing in the first place.
Developing novel targeted immunotherapy for infant leukaemia
Some teams are zooming in their research to focus on one particular type of cancer, which is what Dr Anindita Roy and Professor Anastasios Karadimitris at Imperial College London plan to do with their award.
Childhood acute lymphoblastic leukaemia (ALL) is the most common type of leukaemia diagnosed in children, with around 440 children diagnosed every year in the UK.
One type of ALL has a particularly poor prognosis, with less than 40% of patients surviving for 6 years without specific a ‘event’ or symptom. These cancers have a signature genetic change called an MLL rearrangement, and the poor survival rates for children with this type of cancer point to the need for new treatment options.
Although there have been advancements in the treatment of ALL in recent years, particularly with the development of the ground-breaking CAR T–cell therapy, this type of treatment is not suitable with for children and young people with MLL rearranged ALL.
What is CAR T–cell therapy?
T cells are a type of immune cell that help our bodies fight infection. But it can be difficult for them to tell the difference between a cancer cell and a normal cell, which means the cancer cells can often hide and not be recognised.
Scientists are trying to find new ways to help T cells to recognise cancer cells. One possible way to do this is through CAR T–cell therapy.
CAR T–cell therapy is a type of immunotherapy that takes somebody’s own immune cells – specifically T cells – and modifies them by adding a small molecule known as a chimeric antigen receptor (CAR).
Having this specific receptor means that the T cells are more able to recognise and kill cancer cells.
A major drawback of CAR T–cell therapy is that it requires T cells to be taken from the patient through a blood sample. Obtaining these cells from young children can be a challenge, especially after they have already gone through intensive chemotherapy to treat their cancer. A better alternative is needed.
Roy, based at the University of Oxford and Karadimitris, from Imperial College London hope to tackle this challenge head on.
Roy and Karadimitris aim to develop a new approach for treating MLL rearranged ALL in infants. They plan to take the idea behind CAR T–cell therapy but remove the need for a person’s own immune cells, creating an “off-the–shelf” version.
What’s more, the team hope that the drug will be ready for clinical trials by the time the project ends in 3 years, and be available for children with this type of cancer as soon as possible.
Improving outcomes for children and young people whose leukaemia has returned after treatment
Like Roy and Karadimitris, a second team is also focusing on ALL.
Whilst the survival for children and young people with ALL is high overall, this isn’t the case for everyone. For children whose cancer comes back after treatment or doesn’t respond to treatment, survival remains poor.
Developing new, targeted treatments for relapsed ALL is notoriously difficult. This is mainly because relapse is rare, so coordinating studies can be challenging. As a result, children with the disease don’t have many effective treatments options if their initial treatment doesn’t work.
Dr David O’Connor, Dr Marc Mansour, Dr Jack Bartram and Professor Owen Williams based at University College London (UCL) and Great Ormond Street Hospital, hope to address this gap in the research by establishing a nationwide study analysing samples from children and young people with ALL.
“Whilst childhood ALL is usually curable with chemotherapy, the fact it is by far the commonest paediatric cancer means relapsed ALL remains one of the leading causes of cancer mortality in the UK. We are hoping that personalised treatments for these children will change this.” – Professor Marc Mansour
A real-time, comprehensive analysis of leukaemia samples will allow the team to analyse the genetic makeup of the cancers in unprecedented detail and uncover sensitivities to different treatments. This type of precision approach will guide which treatments patients receive, giving them the best chance of survival.
What’s more, the team hope to use the samples to identify clues called biomarkers that will help identify future children and young people with ALL who are likely to respond to particular treatments, while also potentially uncovering new targets for future treatments for ALL.
“The project will deliver a precision medicine approach for children with relapsed leukaemia, identifying effective drugs on an individual basis.
On a wider level, the study will characterise paediatric leukaemia in unprecedented detail, enhancing our understanding, identifying targets for new therapies and providing a resource for the entire paediatric leukaemia research community” – Dr David O’Connor
Mapping an atlas of rhabdomyosarcoma to better guide research
In the 70s and 80s, research made great strides in the treatment of a cancer that starts in the muscle cells, called rhabdomyosarcoma. But despite extensive clinical and biological research since then, progress has stalled, and new approaches are needed to improve the lives of children and young people with this type of cancer.
Dr Sam Behjati, based at the Wellcome Trust Sanger Institute, and Dr Karin Straathof at UCL are looking to revive progress by stripping the science back to the fundamental biology of the disease.
Which means going back to the very beginning. Rhabdomyosarcoma is believed to originate from cells that are play an important role in a developing embryo. These cells don’t usually exist after the child is born, but they somehow persist in children with rhabdomyosarcoma.
Behjati and his team want to know more. They’ll be building an ‘atlas’ – a detailed guide to the genetic landscape of the cells that make up rhabdomyosarcoma tumours – using 250,000 rhabdomyosarcoma cells from 50 tumour samples.
By analysing the tumour samples gathered at the time of diagnosis, and again if patients relapse, the team plan to identify developmental targets that could be used to help develop new treatments.
“Although treatments have dramatically improved over the past few decades, children continue to suffer from rhabdomyosarcoma, with very few novel treatment approaches in sight. Moreover, survivors often experience lifelong adverse effects from treatment. We’re looking forward to the insights the research provides, which has the potential to show us the previously hidden Achilles’ heels of rhabdomyosarcoma” – Dr Sam Behjati
Behjati and the team plan to make all the data they gather freely available so others in the rhabdomyosarcoma research community and beyond can build on their findings to drive momentum in the field.
The starting line
Our chief executive, Michelle Mitchell commented, “we’ve listened to both parents and researchers and their concerns about lack of progress for children’s and young people’s cancers. That’s why we made a commitment to change this through our Cancer Research UK for Children & Young People research strategy.
“We hope this funding boost will build momentum in the field to improve our understanding of these types of cancer and ultimately lead to fewer children and young people losing their lives to this disease.”
This is just the beginning for our 5 teams. And they’re raring to go. We’ll have our eyes peeled as results begin to emerge.