CCLG supports the Little Princess Trust to fund world-class research, by managing their research funding programme.
CCLG manages the entire grants process on behalf of the Little Princess Trust, including advertising, receiving applications, reviewing and assessing applications to the highest standards, and making recommendations to the Trustees of the Little Princess Trust about funding projects. We then manage grant payments and progess reports, feeding back the outcomes of research to the funder.
We made our first round of grant awards in November 2016, and the following projects were funded:
Defining the cellular origins of neonatal and paediatric brain tumours
Dr Anestis Tsakiridis, The University of Sheffield
A striking feature of many early childhood brain and spinal cord tumours is the presence of non-brain “mesodermal” cell types alongside the neural (brain) cells. These ‘mixed neuromesodermal’ (NM) tumours are often aggressive, are associated with poor prognosis and require radical surgery combined with radio- and chemotherapy. They are also difficult to diagnose using conventional detection methods, which rely on the identification of neural markers and therefore they may be more common than previously thought.
An attractive strategy for investigating the causes of NM tumours involves the isolation and culture of the cancer stem cells which drive their formation, and are thus ideal targets for drug development. Currently, brain cancer cell lines (sources of brain cancer cells used in laboratory studies) are not suitable for studying these cells. This study aims to establish new sources of brain cancer cells for laboratory studies which would enable the investigation of these types of tumours. The results of this pilot study will serve as the basis for a larger follow-up study aiming to give insight into the cellular causes of NM brain tumours and open new avenues for their effective treatment.
In vitro evaluation of the potential of glucose restriction as an adjuvant therapy for paediatric brain tumours
Dr Lisa Storer, The University of Nottingham
Brain tumours are the leading cause of cancer related death in children and are one of the most challenging childhood cancers to diagnose and to treat. Only 50-60-% of children diagnosed with a brain tumour are cured and 60% of those cured are left with a disability affecting quality of survival.
Ependymoma and high grade glioma account for up to a quarter of all children diagnosed with a brain tumour. Compared to other childhood brain tumours 5-year survival rates are relatively poor. It has been reported that 39-64% of those diagnosed with an ependymoma will still be alive 5 years after diagnosis and that 15-35% of those diagnosed with a high grade glioma will survive this length of time. In addition, tumour recurrences are common with treatment options becoming more limited and many children dying from the disease. We therefore would like to investigate other treatment options which could be used in conjunction with standard therapies.
Normal cells in the body get the energy they require to grow and divide from glucose, a sugar derived from carbohydrates in our diet. If the body doesn’t have enough glucose, normal cells can instead use ‘ketone bodies’ which are produced from fatty acids by the liver. Cancer cells have defects which mean that they are dependent on glucose as an energy source and cannot use ketone bodies. We are therefore interested in investigating whether a carbohydrate restricted diet (e.g. the ketogenic diet) would starve the brain tumour cells whilst still providing ketone bodies for normal brain cells to survive. If this is the case then a ketogenic diet would provide a useful way of attacking cancer cells. We have already shown that approximately 85% of ependymoma and 75% of paediatric high grade gliomas have an amenable enzyme profile and therefore may benefit from the diet.
In order to do this we would like to grow brain tumour cells and normal brain cells as 3-dimensional balls of cells (spheroids) in different amounts of glucose. We intend to grow the cells in a glucose range that includes the amount known to be in the body when a person is following the ketogenic diet, and glucose amounts above and below this. Two different ketone body drugs will be added to see if these help the cells to survive the low glucose conditions. We will then measure the size of the spheroids after seven days, and see whether the cells are still alive and whether the enzymes needed to survive the ketogenic diet are present.
The James Lind Alliance priority setting partnerships were created to identify clinical research questions of greatest importance to the patients and families actually affected by brain tumours. One of the top 10 questions raised was the effect of lifestyle factors including diet and sleep on tumour growth, therefore indicating a need for diet therapy options and possible interest from families to the ketogenic diet. We therefore feel that it is timely to perform this research which will give us vital information to support a clinical trial into the ketogenic diet in paediatric brain tumours.
Identifying the metabolic ‘Achilles Heel’ of childhood brain cancers
Dr Ruman Rahman, The University of Nottingham
Brain tumours are the second most common tumour in children with a low survival rate. Although paediatric high grade glioma (pHGG) accounts for 8-12% of central nervous system tumours, this results in a significant clinical challenge with only 19.2% of children surviving 5 years after diagnosis.
Paediatric and adult high grade glioma (aHGG) have very different molecular biology and genetics, suggesting that the way paediatric high grade gliomas form is very different to those in adults. It is therefore important that the next generation of treatments be based on paediatric data, rather than repurposing drugs approved for adults.
The growth of cancer cells is dependent on the building blocks of cells being available, and while some of these are made by the cancer cells themselves, some are taken from external sources in the body. This study will look and metabolic changes inside and outside of pHGG cells when grown under laboratory conditions in the absence of some of these building blocks. The aim of the study is to identify metabolic ‘biomarkers’ in pHGG that may be suitable for targeting with next-generation therapies.
Pre-clinical efficacy and biomarker studies of ALK, MAPK and MDM2-p53 inhibitor combinations in neuroblastoma
Prof Deb Tweddle, Newcastle University
Curing children with high-risk neuroblastoma remains extremely difficult, with those that do survive often suffering from long-term toxicities as a result of current treatment protocols, which use intensive high-dose chemotherapy and radiotherapy. There is an urgent need to identify and develop new treatment options not only to improve survival but also with fewer long-term side-effects.
New drugs known as ‘targeted therapies’ are designed to specifically target genetic abnormalities present in tumours but not normal cells, and are less likely to cause the side-effects associated with the non-tumour specific action of current therapies. When drugs are used in optimal combinations, this can lead to more effective tumour-specific killing, than using any of the drugs alone, which reduces the chances of tumour cells becoming resistant to the drugs.
MDM2-p53, ALK and MAPK inhibitors are targeted drugs that are currently being developed for clinical use. Although they work in different ways, they all aim to cause cancer cells to die. This study will investigate different combinations of these drugs in a laboratory setting, to evaluate the best combinations to use in future clinical trials for children with neuroblastoma.
Screening for novel drug combinations in childhood B-cell acute lymphoblastic leukaemia
Prof Josef Vormoor, Newcastle University
Despite a high cure rate, treatment of children’s leukaemia is associated with significant acute and long-term morbidity. Hence much focus is directed towards replacing current toxic chemotherapy with more targeted therapies (“chemo-free” therapy) that specifically targets the leukaemia cells but spares normal tissues.
Similar to current chemotherapy protocols, several novel agents will need to be combined to avoid the development of resistance to the drugs (combination therapy).
This study will look at different combinations of novel agents and assess which drugs act best with each other and are most efficient at the lowest dose. The objective is to develop better and safer medicines for children with leukaemia.
One major barrier to developing novel combination therapies has been our inability to cultivate leukemic cells in the laboratory. This is even a bigger problem in the context of a very limited number of patients available for clinical trials. Hence pre-clinical prioritisation of new drugs and drug combinations is key but up to now has been virtually impossible. We have managed to improve the culture conditions for human leukaemia and can now grow cells from individual leukaemia patients. We have shown that the cancer cells preserve their initial leukemic characteristics meaning they behave in our laboratory in a very similar way as they would behave in the patient.
We will now use this technology to establish a platform of leukaemia samples to test novel drug combinations. Selection of the different novel agents will be informed by our molecular studies and aimed at specifically targeting pathways that promote survival and growth of the leukemic cells. The ultimate aim is to generate data for novel clinical trials with the ultimate goal to develop more efficient and less toxic therapies for children with leukaemia.
Identification of new drug targets to improve treatment options and reduce treatment-related toxicity for children diagnosed with aggressive B-cell non-Hodgkin lymphoma (B-NHL)
Dr Vikki Rand, Newcastle University
Understanding the biology of paediatric B-cell non-Hodgkin lymphoma (B-NHL) will enable us to improve the lives of children diagnosed in the UK and Africa. Current treatment is associated with distressing and dangerous side effects and for those children who do not respond to treatment outcome remains poor. More effective and safer treatments are urgently required.
Knowledge of the key defects in the cancer cells is fundamental to the development of such treatment strategies. Recent advances in understanding the biology of B-NHL has identified recurrent abnormalities in genes which may offer alternative treatment options to both reduce treatment-related toxicity and improve outcome for patients with chemotherapy resistant disease.
Our current knowledge, however, is predominately based on adult disease and the value of these new discoveries in paediatric lymphoma is unknown. Moreover, analysis of published data has revealed key differences between adult and paediatric B-NHL.
To this end, we have established the largest cohort of childhood B-NHL samples from the UK and Malawi. Using a combination of cutting-edge techniques we will identify the full spectrum of mutations in 50 paediatric patient samples. Recurrent mutations which alter gene expression and the associated pathways will be assessed to determine which are immediately actionable with existing and approved drugs.
Their incidence will then be determined in a further 178 UK and 98 Malawi B-NHL patient samples. The therapeutic value of the strongest target and sensitivity to drugs will be assessed and findings from this study will significantly enhance our understanding of the genomic complexity underlying childhood B-NHL and provide potential targets for new and safer treatments.
Brain distribution models to select polymer-delivered drugs for the treatment of childhood brain cancers
Dr Ruman Rahman, The University of Nottingham
Central nervous system (CNS) tumours are the major cause of cancer related death in children, with high grade invasive brain tumours showing a poor response and frequent high local recurrence rates despite multiple modes of therapy.
Conventional oral or intravenous chemotherapy distributes drugs to the whole body whereby systemic toxicity to healthy parts of the body (e.g. bone marrow failure) limits the maximum dose that can be achieved in the brain. This presents a particular concern for CNS tumours where the blood-brain-barrier (BBB) restricts drug influx from the circulation. The ability to deliver chemotherapy locally at the tumour site offers the opportunity to target residual cancer cells post-surgery whilst minimising systemic toxicity.
Our laboratory has developed a biodegradable polymer paste called PLGA/PEG, which several chemotherapy drugs can be mixed into, prior to the paste being moulded to the tumour cavity lining after surgery. It is important that we can observe whether the drugs released from PLGA/PEG actually get to where any remaining brain cancer cells are. Currently the only way to measure the distribution of drugs in the body is to inject radioactive drugs into an animal. The animal is then killed and the location of the drug in the body is worked out by measuring radiation. This unfortunately requires a high number of animals, is a method that cannot measure different drugs at the same time and the radioactive labelling of a drug may mean that the movement of the drug (pharmacokinetics) differs compared to the non-labelled drug that a patient may receive.
This study aims to develop a model in the laboratory to measure how far chemotherapy drugs released from PLGA/PEG paste can move through slices of brain. As we can use several slices of brain from just one animal, this will dramatically reduce the amount of animals needed for this type of research. At different time-points we will measure how far the drugs released from PLGA/PEG have moved across the brain slice.
By taking measurements of six chemotherapy drugs across a number of time-points, we hope to develop a mathematical model that can predict the movement of other drugs through brain tissue. The model could also quickly identify drugs that do not penetrate into brain tissue very well and which therefore should not be taken forward for clinical trials in children.
Completion of a successful project will allow the developed methods to be used to retrospectively measure drug distribution in animals with brain tumours. Ultimately the work will enable the selection of drugs released locally from PLGA/PEG at the site of resected childhood brain tumours, which have the greatest chance of effectively targeting residual cancer cells in the patient and likely inform drug delivery considerations via other methods e.g. convection enhanced delivery techniques.
Understanding neuroblastoma heterogeneity: genetic studies of circulating neuroblastoma tumour cells
Prof Deb Tweddle, Newcastle University
Neuroblastoma (NB) is the most common childhood solid tumour outside of the brain. New treatments and a better understanding of drug resistance are needed to improve survival. Circulating tumour cells (CTCs) may provide a source of tumour cells for genetic studies, give insights into tumour load and serve as biomarkers for the effectiveness of new treatments.
Over the past 18 months we have detected NB CTCs and Disseminated Tumour Cells (DTCs) from bone marrow. Use of CTCs & DTCs for genetic characterisation may obviate the need for tumour biopsy especially in cases where this is hazardous.
This study aims to undertake genetic studies on CTCs from blood and disseminated tumour cells (DTC) from bone marrow) from NB patients to isolate single CTCs and DTCs for in depth genetic characterisation including next generation sequencing.
These studies will extend our knowledge of genetic heterogeneity in tumour cells by comparing primary tumour genetics with CTCs and DTCs, since the latter may be important in determining response to treatment and may shed light on why patients relapse. In depth genetic characterisation of DTCs and especially CTCs provides a non-invasive method of tumour biopsy, so called “liquid biopsy” particularly in patients in whom biopsy of the main tumour or even bone marrow may be hazardous.