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Chris Lucas Trust the Research

Chris Lucas Trust

The Story so far:

2000 – Receiving information that only limited research was taking place for Rhabdomyosarcoma, The Chris Lucas Trust was established to begin to fundraise to begin research into this type of rare cancer.

2005 – The Research- It all began in 2005 when we approached Professor of Childhood Cancer Biology & Honorary Consultant in Paediatric Oncology Kathy Pritchard Jones, with an idea to begin childhood cancer research for Rhabdomyosarcoma. The Royal Marsden and the ICR (Institute of Cancer Research) We appointed senior post- doctoral researcher.

Edoardo Missiaglia from Italy.

2005 – Samples from Europe of Children and Young Adults suffering from Rhabdomyosarcoma were collected and analysis began.

2010 - Potential to Reduce Children’s Side-effects from Cancer Treatment

The research was funded by Chris Lucas Trust, Cancer Research UK, La Ligue Nationale Contre le Cancer, Institut National du Cancer and Enfants et Sante Association.

• Currently, treatment is based on whether a patient’s cancer is classified as alveolar or embryonal, which is determined by the appearance of a tumour sample under the microscope. Alveolar rhabdomyosarcoma is considered more aggressive, so these patients are given a more intense combination of chemotherapy, radiotherapy and sometimes surgery

• When the ICR scientists examined samples from 210 rhabdomyosarcoma patients, they identified 39 cancers that looked like aggressive alveolar type but behaved more like the milder embryonal type. This group of patients had less cancer spread and higher survival rates. Genetic testing revealed that the cancers from these patients lacked a genetic abnormality, known as a PAX/FOX01 fusion gene, which has previously been linked to the alveolar subtype.

• ICR scientist Dr Janet Shipley says subsequent analysis of thousands of genes confirmed alveolar rhabdomyosarcomas without a fusion gene are biologically similar to the embryonal subtype but very different from alveolar cancers with a fusion gene.

• “We have shown that presence of a fusion gene – not tumour appearance – is a key factor in predicting cancer aggressiveness,” Dr Shipley says. “This study should lead to a re-think in the management of children with the fusion gene-negative alveolar cancer in order to minimise side-effects for these patients. There is no longer any evidence to support treating all alveolar cases the same.”

• Dr Shipley says the next step is to hold a clinical trial to see if reducing treatment intensity can improve these patients’ quality of life while maintaining survival rates.

2012 - Test for single genetic fault can predict child cancer patient survival

• In this study, which was funded by the Chris Lucas Trust, Cancer Research UK and La Ligue Nationale Contre le Cancer,

• A study led by The Institute of Cancer Research (ICR) has shown that a simple genetic test could help predict the aggressiveness of rhabdomyosarcomas in children and should be introduced into clinical practice. The test would lead to changes in treatment for many patients, allowing some children to escape potentially long-term side-effects whilst giving others the intense treatments they need to increase their chances of survival.

• In a paper published online today in the Journal of Clinical Oncology, Dr Janet Shipley and collaborators in the UK, Switzerland and France found that children who have a tumour called rhabdomyosarcoma with a particular genetic fault, known as the PAX3/FOXO1 fusion gene, have significantly poorer survival rates than other rhabdomyosarcoma patients.

• Children diagnosed with rhabdomyosarcoma are treated with a combination of chemotherapy and surgery and sometimes radiotherapy. These treatments have helped improve survival rates, but can cause serious and long-term side-effects including the potential to develop another cancer later in life. Having better information about how aggressively the tumour is likely to behave can help doctors to tailor treatment for each patient that balances the need for effective treatment with the side-effects of such treatment.

• Dr Shipley says: “Our previous studies have raised issues with the current system of predicting patients’ risk, which is based on the appearance of patients’ tumours. Our new study finds that a simple genetic test should be incorporated into standard clinical practice as it significantly improves our ability to predict tumour aggressiveness. This fusion gene test could be used alongside other standard clinical measures to divide patients into one of four risk-groups, so that treatment can be tailored accordingly. Importantly, this will mean some patients who were previously categorised as high-risk could be able to avoid the side-effects associated with intense treatment, while others should receive the intense treatment they need to increase their chance of survival.”

• Using the new system, 31 per cent of patients in the study who would previously have been classified as intermediate risk would be reassigned to a lower risk group, while a further 29 per cent of intermediate-risk patients would be moved to a higher risk group.

• In this study, which was funded by the Chris Lucas Trust, Cancer Research UK and La Ligue Nationale Contre le Cancer, Dr Shipley’s team analysed data for thousands of genes from 225 rhabdomyosarcoma samples. This identified a panel of 15 gene alterations that could be used to predict how patients responded to treatment. However, these gene changes were mostly linked to the presence of the PAX3/FOXO1 fusion gene, which is much simpler and cheaper to test for than the other alterations. The test would involve scanning for the presence of the fusion gene in a sample of the patient’s tumour.

• Combining the fusion gene test with two existing standard measures of risk for rhabdomyosarcomas – the patient’s age at diagnosis and the tumour’s stage of development – gave a simple but highly effective prognostic test.

• Lynn Lucas, whose son passed away in July 2000 after a three year battle with rhabdomyosarcoma, says the Chris Lucas Trust helped fund the team’s important research in the hope that other children and parents would be spared their ordeal.

• Treatments for the cancer left Chris with serious side-effects including weight loss, difficulty walking and a painful mouth.

• “Rhabdomyosarcoma is a cruel disease since children can go into remission thinking they have won the battle then find out months later it has returned even more aggressive,” she says. “The current treatments have some dreadful side-effects, which children have no choice at present but to tolerate. This test could help some children avoid this suffering, making sure only those who really need it receive intense treatment.”

2013 - Double-pronged attack could treat common children’s cancer

• In this study, scientists at the ICR targeted the PI3 Kinase pathway and a second pathway called MAP Kinase, to assess any compensatory signalling and determine if blocking both pathways could effectively inhibit rhabdomyosarcoma cell growth.

• The researchers found that the PI3 Kinase pathway was active in 83% of rhabdomyosarcoma samples from patients, and that 43% of these also showed activation of the MAP Kinase pathway. In experiments on rhabdomyosarcoma cells to block either pathway alone, they saw compensatory signalling through the alternative pathway, suggesting that inhibiting both pathways is an essential approach to treatment, irrespective of whether MAP kinase signalling was initially activated.

• The researchers tested rhabdomyosarcomas with drugs known to be effective against the PI3 Kinase and MAP Kinase pathways. When they tried the drugs AZD8055 and AZD6244 separately they saw reduced cell growth and a decrease in levels of markers showing the activity of the signalling pathways. However, compensatory activity was clearly evident.

• But when they combined the two drugs they found a synergistic effect, with cell growth reduced to a greater extent than with either treatment alone. They saw similar synergistic results when AZD8055 and AZD6244 were used together in mice with rhabdomyosarcoma tumours, with tumour marker levels reduced to less than 30% of those in controls.

2014 - Cause of rare childhood cancer discovered

• Scientists have made a breakthrough in understanding the cause of a rare childhood muscle cancer, called Rhabdomyosarcoma (RMS).

• The discovery could lead to the development of improved therapies to treat the disease and other types of cancer in the future.

• Around 60 and 350 new cases of RMS are diagnosed in the UK and Europe/US respectively, each year. Most RMS tumours occur in children younger than 10 years old.

• A collaborative study led by scientists from Harvard University and involving experts from the University of Aberdeen, The Institute of Cancer Research, London, and the Swiss Institute of Bioinformatics has revealed for the first time the key role a protein called Yap plays in triggering RMS.

• “The current therapies for RMS, although relatively efficient, are very aggressive and drastically alter the quality-of-life of the children who survive. Indeed, most of the survivors will suffer life-altering consequences such as loss of mobility or vision, growth impairment and developmental problems, or the need for life-long hormone replacement therapies.

• “We discovered that in cases of the disease, excessive activity of a protein called Yap causes muscle stem cells to permanently divide instead of stopping and becoming normal muscle tissue.

• “Yap does that by inhibiting the activity of muscle determination proteins, which are key to the formation of muscle tissue.

• “In contrast to normal muscle stem cells, the high Yap muscle stem cells fail to develop into normal muscle tissue and RMS develops as a consequence.”

• The Yap protein is fundamental to this process, with the myoblasts experiencing a marked increase in its activity during the division stage. Once enough myoblasts are present, Yap gets turned off which allows them to stop dividing and fuse together to form functional muscles.

• Findings from the study show that in instances of RMS cancer, the Yap protein remains active – like the accelerator of a car being stuck.

• By combining the results from animal models with histological and bioinformatics approaches using human RMS samples, researchers at the University of Aberdeen, the Swiss Institute of Bioinformatics and the ICR additionally showed that Yap is actually hyper-active in a large proportion of human RMS cases.

• “Our work will now focus on how the Yap protein works in cancer and how its activity can be controlled.

• “If we can achieve the inhibition of Yap locally in the tumours, we could cause the cancer to stop and regress by turning the RMS into normal muscle instead. This would most likely produce significantly less side effects than the current therapies.”

• “Other research has shown that Yap is active in several other types of cancer including liver and skin cancers. These results could therefore be of wider significance in also enhancing our global understanding of the role of Yap in cancer.”

• Dr Janet Shipley, leader of the Sarcoma Molecular Pathology team at the ICR, said: "This study has promising therapeutic implications for targeting YAP1-driven pathways for the treatment of children with RMS. Through our analyses of human tumour samples, we were able to demonstrate that the findings in the mouse model are highly relevant to these cancers in humans."

The three-year study was supported by funding from Aberdeen charity, Friends of Anchor, Sarcoma UK, the Medical Research Council, Cancer Research UK, the Chris Lucas Trust, and Stand Up to Cancer-AACR innovative research programs and the Canadian Institutes of Health Research.

2015 - Chris Lucas Trust donates £300,000 to rhabdomyosarcoma research

The Chris Lucas Trust has made another generous pledge of £300,000 to support rhabdomyosarcoma research at The Institute of Cancer Research, London. The charity, which was set up after teenager Chris’s tragic death from the disease in July 2000, has so far raised over £1m for research into rhabdomyosarcoma and continues to fundraise through flagship events such as the Great North Bike Ride.

• Donations from the trust have already contributed to studies that found combining two separate molecularly targeted therapies could block processes driving growth in rhabdomyosarcoma, a major cause of cancer death in children.

• This latest award from the Chris Lucas Trust will enable us to employ two scientists to exclusively work on rhabdomyosarcoma for the next three years, under the supervision of Professor Janet Shipley – one of the world’s leading authorities on research into soft tissue sarcomas. Rhabdomyosarcoma is a tumour that resembles muscle tissue, and at present there are no effective targeted treatments for the aggressive forms of the disease.

2015 - New test could help personalise treatment

for common childhood cancer - The work was supported in the UK by the Chris Lucas Trust

• A new gene test can identify which patients are likely to suffer more aggressive forms of the childhood cancer rhabdomyosarcoma, new research reports.

• Examining the activity of only five genes in a sample of the tumour was enough to identify high-risk children who might benefit from more intensive treatment or from new therapies in clinical trials.

• The findings, published today (Thursday) in the journal Clinical Cancer Research, could open up the opportunity for doctors to prescribe personalised treatment for children with cancer depending on the gene activity of their tumours.

• This five-gene signature, known as MG5, was developed by researchers at The Institute of Cancer Research, London.

• It has now been validated in tests of samples from 68 patients

• The test for gene activity – known scientifically as gene ‘expression’ – is the first to be able to predict accurately which children with a type of rhabdomyosarcoma called ‘fusion-negative’ will have more aggressive forms of the disease.

• Children with fusion-negative tumours lack a particular genetic defect often found in rhabdomyosarcoma that results in two genes, called PAX3 and FOXO1, becoming fused together.

• UK study leader Professor Janet Shipley, Professor of Cancer Molecular Pathology at The Institute of Cancer Research, London, whose laboratory originally developed the test, said:

• “Our research showed a significant link between a particular gene signature from tumour samples and higher-risk, aggressive rhabdomyosarcoma. This study is an important step towards introducing an approach that identifies children who are unlikely to benefit from current, standard treatments and can be offered more intensive or new treatment strategies that will improve their outcome.”

• “We now hope to bring our test for this gene signature to the clinic as soon as possible. Our aim is to identify these high-risk cases of rhabdomyosarcoma more quickly in the clinic, and ultimately improve treatment for these children.”

• Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

• “We’re determined to bring the same kind of molecular advances that are starting to transform treatment for adult cancer patients to children too. A key step is to begin dividing up children’s cancers depending on their genetics and gene activity, so that we can adjust their treatment according to the aggressiveness of the disease. That should help us to increase the chances of survival in those with aggressive cancer, while easing the side-effects from treatment in less deadly forms.”

• Another study showed that combining two targeted therapies could block processes driving the growth of rhabdomyosarcoma cancer more effectively than either alone.

• A recent pledge by the Chris Lucas Trust enabled the ICR to employ two scientists to work exclusively on rhabdomyosarcoma. These researchers are being supervised by Professor Janet Shipley, who is a world leader in researching these kinds of sarcomas.

• 2017 – NHS Hero Award Lynn received the NHS Hero Award for Fundraiser of the Year for her continued support for the ICR. She was also recognised by Prime Minister Theresa May when she was chosen for a Points of Light Award.

2017 - Fundraiser recognised by Prime Minister with Points of Light Award after raising millions for ICR research millions for ICR research

• Prime Minister Theresa May has celebrated the dedicated fundraising of Lynn Lucas, who set up a trust to fund research into a rare form of cancer in memory of her son Chris.

• Chris’s parents, both called Lynn, lost him to a rare sarcoma called rhabdomyosarcoma in 2000. Since then they set up the Chris Lucas Trust and have raised more than £2 million towards research into the disease at The Institute of Cancer Research, London.

• Recognising volunteers who make change

• In recognition of their incredible efforts Lynn, who lives in North Tyneside, was chosen for a Points of Light Award, which recognises outstanding individual volunteers who are making a change in their community.

• The importance of the Chris Lucas Trust to ICR research

• The Trust has already contributed to some important research at the ICR. One study showed that incorporating a genetic test into assessment of the cancer is superior to a visual microscopic approach in deciding what treatment intensity to give patients – an approach now being introduced into an international clinical trial for rhabdomyosarcoma.

2018 - ICR thanks star fundraisers for their significant contributions to our research

• The Chris Lucas Trust, Lynn Lucas, were thanked at the October meeting of the ICR's Discovery Club for their phenomenal fundraising efforts to support our research.

• Lynn Lucas, joint founder of The Chris Lucas Trust, has worked tirelessly with her husband Lynn to support our research into rhabdomyosarcoma, a rare childhood cancer which took their son Chris in 2000.

• The Chris Lucas Trust has raised over £1 million for research into rhabdomyosarcoma at the ICR, and continue to fundraise through flagship events such as the Great North Bike Ride.

• Their support has helped Professor Janet Shipley's lab develop a genetic test to better classify rhabdomyosarcoma patients into low and high risk groups that decide treatment intensity.

• In 2017 Lynn received the NHS Hero Award for Fundraiser of the Year for her continued support for the ICR. She was also recognised by Prime Minister Theresa May when she was chosen for a Points of Light Award.

2021 - Genetic discovery could help guide treatment for aggressive childhood cancer

A new study could lead to improved decision making in assigning treatments for children with the aggressive cancer rhabdomyosarcoma after revealing key genetic changes underlying development of the disease.

• In the largest and most comprehensive study of rhabdomyosarcoma to date, scientists found that specific genetic changes in tumours are linked to aggressiveness, early age of onset and location in the body.

• All these factors affect the chances that children will survive their disease – and understanding how they are driven by a cancer’s genetics could lead to new ways of tailoring treatment for each patient.

• Rhabdomyosarcoma is a rare type of cancer that resembles muscle tissue and mostly affects children. Less than 30 per cent of children with rhabdomyosarcoma who have relapsed or whose cancer has spread will survive.

'Could be spared the most severe side effects'

• It could also identify other children who could benefit from less aggressive therapy and could be spared some of the most severe side effects of treatment.

• The researchers are already planning to incorporate the new insights into the design of upcoming clinical trials aiming to improve the management of the disease.

• Two main sub-types of rhabdomyosarcoma exist – fusion gene-positive and fusion gene-negative, depending on the presence of a ‘fusion gene’. A fusion gene is a hybrid gene formed from two previously separate genes – in this case, a PAX gene and a gene called FOXO1.

Looking at MYOD1 and TP53 mutations

• When looking at children with fusion-negative rhabdomyosarcoma, researchers found that children whose tumours had faults in the genes MYOD1 and TP53 had significantly poorer response to treatment and worse survival outcomes. TP53 was altered in 69 out of 515 children and was linked to worse survival outcomes.

• Approximately half the children whose cancers had TP53 mutations succumbed to their disease compared with one in four children with cancers that were not TP53 mutant – indicating that those without the mutation had a better chance of survival.

• The researchers found mutations in MYOD1 in 17 out of 515 children and linked these to both worse outcomes and rapid progression of the disease. The findings suggest that children with these mutations could benefit from more aggressive treatment.

• A small number of children with fusion-positive rhabdomyosarcoma – five out of 126 – also had changes in TP53. None of these children survived their cancer and, as a consequence, researchers have identified TP53 as a ‘high risk’ indicator in this sub-group too.

CDK4, MYCN and RAS mutations

• Researchers believe having too many copies of the genes CDK4 or MYCN may also be linked to a poorer outcome in fusion-positive rhabdomyosarcoma, with 16 and 13 cases, respectively, showing these genetic changes. However, as the number of cases in the study was small this needs to be explored further in future research.

• The new study challenges previous findings that the presence of a fault in the RAS gene is linked to poor outcomes. Researchers did however find that some RAS mutations seemed to be correlated with particular ages of onset – with HRAS mutations arising in babies, KRAS mutations in toddlers and NRAS mutations in adolescence.

• Babies have previously been shown to have lower survival than older children, which may be because clinicians avoid using more aggressive treatments like radiation in the youngest patients.

• Taking into account findings from this study, researchers believe that using targeted drugs such as tipifarnib, which blocks HRAS, may be particularly beneficial for these young, vulnerable and high-risk patients.

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