Our Funded Research
Neuroblastoma
Developing new treatments for high-risk neuroblastoma
With Professor Deb Tweddle
High-risk neuroblastoma is very difficult to treat, and what treatments there are often come with unpleasant long term side effects. Medicines known as ‘targeted therapies’ can specifically attack tumour cells, based on the cells’ genetic code, and leave healthy cells relatively unharmed.
Professor Deb Tweddle at Newcastle University is investigating three new targeted therapies that work in different ways. She wants to see which combinations of these medicines could be the best treatment for neuroblastoma, and hopes to find evidence to progress the best treatment into a clinical trial.
Project title: Pre-clinical efficacy and biomarker studies of ALK, MAPK and MDM2-p53 inhibitor combinations in neuroblastoma
Lead investigator: Professor Deb Tweddle, Newcastle University
Funded by: The Little Princess Trust
Funded: November 2016
Award: £93,074.38
Improving our understanding of neuroblastoma genetics
With Professor Deb Tweddle
Neuroblastoma is one of the most common types of childhood tumours. Doctors often need to take biopsies, small pieces of the tumour taken surgically, to diagnose or assess the cancer. This can be risky for patients and is invasive.
Professor Deb Tweddle and her team at Newcastle University are researching circulating tumours cells. Neuroblastoma tumours can release tumour cells and pieces of neuroblastoma DNA into the blood stream and bone marrow. The researchers will be investigating the genetics of the cells and DNA fragments, which will increase our understanding of neuroblastoma and why it relapses. Deb also hopes that assessing circulating tumour cells could be an alternative to surgical biopsies.
Project title: Understanding neuroblastoma heterogeneity: genetic studies of circulating neuroblastoma tumour cells
Lead investigator: Professor Deb Tweddle, Newcastle University
Funded by: The Little Princess Trust
Funded: November 2016
Award: £99,991.60
Understanding genetic changes in neuroblastoma cells to pave the way for targeted treatments
With Professor Deb Tweddle
Some children with neuroblastoma have ‘high-risk’ cancer, which is especially difficult to treat. About half of these children will have changes to the genetic code inside the cancer cells which stop the cell from carrying out its normal repairs to damaged DNA.
Professor Deb Tweddle and her team at Newcastle University believe that neuroblastoma c ells with these genetic changes might be more sensitive to specific medicines. In this project, the researchers will be investigating the genetic changes more and testing the medicines. They also hope to create a test that will show whether patients have these changes so that they can benefit from the medicines.
Project title: Investigation of the effects of DNA repair inhibitors in pre-clinical models of neuroblastomas with ATM, MYCN and TP53 abnormalities
Lead investigator: Prof Deb Tweddle, Newcastle University
Funded by: The Little Princess Trust
Funded: July 2017
Award: £99,999
Using genetics to find targets for new medicines to treat relapsed neuroblastoma
With Professor Deb Tweddle
Neuroblastoma is a common type of children’s cancer. Around a quarter of children with neuroblastoma’s cancer will come back after treatment, where it becomes very difficult to treat. To improve care for these children, we urgently need new medicines and treatment options.
Professor Deb Tweddle’s team at Newcastle University have been studying the genetics of neuroblastoma from samples of a patients tumour taken at diagnosis and at relapse (when the cancer comes back). The team believe that they have found some genes that are mutated when the cancer relapses that weren’t mutated when the child was diagnosed. In this project, they will investigate these genes to see when these mutations happen and what they are doing.
Project title: Characterisation and validation of recurrently mutated genes in relapsed neuroblastoma as targets for novel therapies
Lead investigator: Prof Deb Tweddle, Newcastle University
Funded by: The Little Princess Trust
Funded: December 2017
Award: £99.956.80
Using existing medicines to target genetic errors
With Dr Kyle Matchett
Leukaemia is the most common type of childhood cancer, and acute myeloid leukaemia is a difficult to treat form of this cancer. There are also a lot of side effects for the treatments used, so new medicines are urgently needed.
Dr Kyle Matchett and his team at Ulster University are working on a gene called NRAS. Experts have found that, if it has errors, it is a common problem for children with acute myeloid leukaemia, and the researchers want to find a way to target this gene with existing medicines. Using existing medicines means that any found to fight NRAS errors can be used to help children sooner, as they have already been approved.
Project title: Targeting mutant NRAS in paediatric AML
Lead investigator: Dr Kyle Matchett, Ulster University
Funded by: The Little Princess Trust
Funded: January 2019
Award: £74,933
Understanding why some neuroblastoma doesn’t respond to treatment
With Dr Karim Malik
Cancer coming back after treatment is a big problem for childhood cancer specialists. When cancer returns it often can’t be treated by the same medicines, or the medicines need to be at such high doses that they are too harmful to patients. This is an especially important issue for neuroblastoma, because it is very variable so it can be difficult to pinpoint why it has come back.
Dr Karim Malik and his team at the University of Bristol have found that different subtypes of neuroblastoma cells have different sets of proteins to each other, leading the researchers to think that personalised treatments are vital to treating relapsed neuroblastoma. In this project, Karim is investigating whether the different sets of proteins could be targeted with medicines to kill different types of neuroblastoma.
Project title: Overcoming drug resistance for efficacious neuroblastoma therapeutics
Lead investigator: Dr Karim Malik, University of Bristol
Funded by: The Little Princess Trust
Funded: July 2018
Award: £99,986
Understanding different groups of neuroblastoma
With Professor Deb Tweddle
Neuroblastoma is a common type of childhood cancer, and it can be classed as high, low, or intermediate risk. Intermediate risk neuroblastoma is very different in each patient and, whilst some children can be treated successfully, there is a subgroup of patients whose treatment does not go well.
Professor Deb Tweddle at Newcastle University plans to look at the genetic code of neuroblastoma cancer cells that fall into this subgroup to see how similar their DNA is to that of high-risk neuroblastoma cells. Her team want to find out whether the subgroup of intermediate risk patients should actually be considered as high-risk. This would mean that they would get stronger treatments right from the start which could mean more children get treated successfully.
Project title: A genome wide study of unresectable, MYCN non-amplied, unfavourable histology neuroblastomas in patients older than 18 months of age
Lead investigator: Professor Deb Tweddle, Newcastle University
Funded by: The Little Princess Trust
Funded: July 2018
Award: £123,947.50
Understanding why some children with neuroblastoma respond badly to treatment
With Dr Helen Bryant
Neuroblastoma is a particularly difficult to treat type of childhood cancer, and we desperately need new and less harmful treatments. Sometimes neuroblastoma cells use a special process called the ‘Fanconi anaemia pathway’, which is linked to the cancer being especially difficult to treat.
Dr Helen Bryant and her team at the University of Sheffield want to investigate this pathway to see how it is making neuroblastoma harder to treat. The researchers will also test whether medicines blocking the pathway could help kill the cancer cells. Helen hopes that this will lead to specialised treatments for hard-to-treat neuroblastoma.
Project title: Targeting the Fanconi Anaemia pathyway in neuroblastoma
Lead investigator: Dr Helen Bryant, University of Sheffield
Funded by: The Little Princess Trust
Funded: July 2018
Award: £98,111
Improving our understanding of immunotherapy in high-risk neuroblastoma
With Dr Juliet Gray
Neuroblastoma mostly affects babies and younger children. Often intensive treatment is required, involving combinations of chemotherapy, radiotherapy and surgery. More recently a new treatment option called ‘immunotherapy’ is starting to become routinely used. Whilst it has promising results, more research is needed to know how best to combine this newer therapy with other treatments.
Dr Juliet Gray and her team at the University of Southampton will be playing a part in international clinical trials for combining immunotherapy with standard treatments. The researchers will look at blood samples from children with neuroblastoma to look how well the immune system can fight the cancer after each type of combination therapy. This research will help inform the best combinations of treatments, and which children could benefit most from them.
Project title: Understanding and improving the mechanism of action of anti-GD2 monoclonal antibody therapy in neuroblastoma.
Lead investigator: Dr Juliet Gray, University of Southampton
Funded by: The Little Princess Trust
Funded: August 2019
Awarded: £111,236
How can we tell whether neuroblastoma will come back after treatment?
With Professor Deborah Tweddle
There have been a lot of advancements in neuroblastoma treatments, but some children with ‘high-risk’ neuroblastoma have their cancer return after treatment. This is then very difficult to treat, so we urgently need more understanding of why and how neuroblastoma comes back after treatment.
Professor Deborah Tweddle at Newcastle University will look at over 20 years’ worth of data from relapsed neuroblastoma patients. The research team will look at genetic and biological factors to see if they can find a factor that predicts whether the neuroblastoma will relapse or not. The new information collected through this research will be used to help guide new treatment plans.
Project title: Clinical and biological factors associated with relapse and length of survival following relapse in UK neuroblastomas
Lead investigator: Professor Deborah Tweddle, Northern Institute for Cancer Research, Newcastle University
Funded by Little Princess Trust
Funded December 2019
Award: £149,104
How does neuroblastoma begin and can we use this knowledge to develop new treatments?
With Dr Helen Bryant
Scientists think that neuroblastoma starts in embryos in the womb when some cells have errors in their genetic code. This can be because of high levels of a gene called MYCN. It is a lot more difficult to treat children with high levels of MYCN because there aren’t any effective treatments.
Dr Helen Bryant at the University of Sheffield wants to find out more about how the MYCN gene and neuroblastoma cells interact. The researchers will artificially increase the level of MYCN in healthy cells in the lab. This will allow them to study how MYCN would affect embryos in the womb and see if there are medicines that can stop MYCN from working.
Project title: Dissecting the role of MYCN in neuroblastoma initiation
Lead investigator: Dr Helen Bryant, University of Sheffield
Funded by: The Little Princess Trust
Funded: December 2020
Award: £196,341
Understanding changes in neuroblastoma to improve treatment
With Dr Alejandra Bruna
Neuroblastoma is the most common solid tumour outside the brain in children. Most children respond well to treatment, but for children with high-risk neuroblastoma it is more difficult. There aren’t that many treatments for neuroblastoma and they are normally quite harmful, leading to long term side effects. One of the barriers to developing new treatments is that neuroblastoma can vary both between children and within a single tumour.
Dr Alejandra Bruna and her team at the Institute of Cancer Research plan to study the makeup of tumours and what leads to them becoming resistant to treatment. They will use cutting-edge technology to look at tumours at the molecular level, and see what changes happen as neuroblastoma progresses. They hope to use their new knowledge to develop better treatment strategies.
Project title: Single-cell transcriptomics linked to lineage tracing to interrogate the role of intra-tumour heterogeneity in shaping therapeutic susceptibility and resistance in paediatric cancer
Lead investigator: Dr Alejandra Bruna, The Institute of Cancer Research
Funded by: The Little Princess Trust
Funded: June 2021
Award: £499,912
Combining medicines to treat neuroblastoma
With Dr Karim Malik
Cancer cells are very different from healthy cells. They will often have too many proteins that promote cancer growth, and not enough of the proteins that help protect our cells from becoming cancerous.
Dr Karim Malik and his team at the University of Bristol have found a new protein that could be promoting neuroblastoma. It is called CARM1 and, in some neuroblastoma cells, it helps the cell cope with the rapid growth of tumours. When the researchers removed CARM1 artificially, the neuroblastoma cells could not grow as fast and did not survive as well. Dr Karim Malik hopes to show that existing medicines that work against CARM1 and, in combination with other medicines, could be a new treatment option for neuroblastoma.
Project title: Combined inhibition of autophagy and epigenetics as a novel therapeutic strategy for poor prognosis neuroblastoma
Lead investigator: Dr Karim Malik, University of Bristol
Funded by: The Little Princess Trust
Funded: July 2021
Award: £198,991.57
Making antibody immunotherapy for neuroblastoma safer
With Dr Alexander Davies
Children whose neuroblastoma cancer can’t be treated by chemotherapy or radiotherapy have the option of using antibody immunotherapy. This type of treatment helps your body’s own immune system to fight the cancer cells. Unfortunately, it also has serious side effects, such as pain and nerve damage, that can lead to the treatment being reduced or stopped all together.
Dr Alexander Davies and his team at the University of Oxford are looking into why the antibody proteins used in immunotherapy are causing these nerve related side-effects. They plan to change parts of the structure of antibodies to see whether it reduces the effects of antibodies on nerves whilst still killing cancer cells. Dr Alexander Davies hopes that a better understanding how the structure of antibodies will lead to safer and more effective treatments for neuroblastoma.
Project title: Reducing neurotoxicity of immunotherapies by glycan modification of monoclonal antibodies
Lead investigator: Dr Alexander Davies, University of Oxford
Funded by: The Little Princess Trust
Funded: April 2022
Award: £33,854
Testing existing drugs in new combinations for high-risk neuroblastoma
With Dr Karim Malik
During normal growth of the body, our cells are constantly being replaced. Older cells that are no longer needed, or are damaged, are triggered to die. Whether this programmed cell death is triggered or not is due to the amount of different proteins in the cell, which can either push for cell death or prevent it. Normal cells can’t prevent this, but cancer cells can resist programmed cell death and continue to survive and multiply, in part because they have more pro-survival proteins.
There are medicines that can stop pro-survival proteins from working, but there can be side effects and cells can become resistant to the medicine. Dr Karim Malik and his team work at the University of Bristol. His studies have shown that using a second medicine in combination with medicines that stop pro-survival proteins from working can kill neuroblastoma cells with much lower dosages. Dr Karim Malik hopes to prove the usefulness of this type of combination treatment for high-risk neuroblastoma patients who do not have many treatment options.
Project title: Targeted inhibition of methyltransferases and anti-apoptotic Bcl2 proteins to synergistically induce apoptosis in neuroblastoma
Lead investigator: Dr Karim Malik, University of Bristol
Funded by: The Little Princess Trust
Funded: July 2022
Award: £209,363
Using anti-depressants to improve immunotherapy for neuroblastoma
With Professor Arturo Sala
Every year, around 100 children are diagnosed with a type of childhood cancer called neuroblastoma. There are a lot of treatment options, but these can be quite difficult for patients. Immunotherapy, a new type of treatment that uses a patients own immune system to fight their cancer, can be safer and more effective. However, immunotherapy doesn’t work for a lot of patients. This is because their immune system can make cells that stop the body’s normal ability to fight cancer.
Professor Arturo Sala and his team at Brunel University London want to improve immunotherapy for children with neuroblastoma. They think using anti-depressants alongside immunotherapy could counter the cells which stop the body from fighting cancer. The team will be looking at how anti-depressants fight both immune cells and neuroblastoma cells to gather enough evidence to support their new treatment. Professor Sala hopes that, if their project goes well, anti-depressants could become standard practice when using immunotherapy to treat neuroblastoma.
Project title: Suppressing neuroinflammation as a strategy to enhance childhood cancer immunotherapy
Lead investigator: Professor Arturo Sala, Brunel University London
Funded by: The Little Princess Trust
Funded: March 2023
Award: £207,156
Understanding why chemotherapy doesn’t work as well for some children with neuroblastoma
With Dr Sally George
Neuroblastoma is a type of cancer where cells grow out of control, ignoring the normal ‘rules’ for healthy cells that only let them multiply a certain number of times. To do this, they maintain an important part of their genetic code – the telomeres. Telomeres are bits of DNA that protect the main genetic code. In normal cells, telomeres get shorter every time a cell divides until there is not enough left for another go. Cancer cells have a few different methods can get around this problem. Some neuroblastoma tumours use a method called ALT that sticks extra bits of DNA to the telomeres, keeping them long.
In this project, Dr Sally George at the Institute of Cancer Research is making cancer models that behave like neuroblastoma with ALT. Her team will look at how ALT changes the behaviour of early nerve cells, which researchers believe is where neuroblastoma starts. They will also look at how early nerve cells with and without ALT respond differently to chemotherapy drugs, to understand the reason why ALT neuroblastoma is so hard to treat. Dr George hopes that they will increase their understanding the cause of neuroblastoma and how to treat it.
Project title: Linking telomere maintenance to neural differentiation to identify novel therapeutic strategies for ALT neuroblastoma
Lead investigator: Dr Sally George, Institute of Cancer Research
Funded by: The Little Princess Trust
Funded: March 2023
Award: £244,204
Developing a kinder and more effective immunotherapy for neuroblastoma
With Dr Juliet Gray
Immunotherapy for neuroblastoma uses antibodies, which are proteins made by the immune system to hunt down and fight harmful things in the body like viruses and bacteria, to find and kill cancer cells. Immunotherapy antibodies are made in the lab to target a molecule found on neuroblastoma cells, called GD2. However, these man-made antibodies also have significant side effects, such as nerve pain, because GD2 can be found on nerve cells too.
Dr Juliet Gray at the University of Southampton wants to develop a new type of immunotherapy that is safer and more effective by modifying the current anti-GD2 antibody. The new antibody will require an additional molecule, found on neuroblastoma cells but not on nerve cells, to be present before it would bind to a cell. To improve the effectiveness, she will also make the antibody attract immune cells that can kill the cancer cell. The researchers hope that their three-pronged approach to immunotherapy will be safer and more effective, leading to fewer side effects and more children being cured.
Project title: Tri-specific GD2/B7-H3 T cell engaging antibodies in neuroblastoma
Lead investigator: Dr Juliet Gray, University of Southampton
Funded by: The Little Princess Trust
Funded: July 2023
Award: £198,167.49
Understanding what the red flags are in aggressive neuroblastoma to improve and develop treatments
With Professor Suzanne Turner and Dr Perla Pucci
Neuroblastoma is the most common type of cancer seen in babies and unfortunately, is also one of the hardest to cure. Why and how childhood neuroblastoma develops is key research priority. Most cancer cells have changes in their genetic sequence, the instructions that tell our cells how to behave, but neuroblastoma cells have very few changes. Researchers believe that neuroblastoma is instead driven by the cell reading the genetic code in different ways, rather than changes to the sequence of the genetic code.
Professor Suzanne Turner and Dr Perla Pucci at the University of Cambridge want to find out more about the proteins which cause neuroblastoma cells to read the genetic code differently. In this project, she has two aims – to see whether these proteins could be stopped with medicines, and to find out which misreads can be linked to how the cancer behaves. Ultimately, the researchers hope to have developed a blood test to monitor how children respond to treatment and determine how aggressive their tumours are, as well as having identified potential new treatments.
Project title: Investigating the utility of histone post-translational modifications and the proteins that regulate them as therapeutic targets and biomarkers for high-risk neuroblastoma
Lead investigator: Professor Suzanne Turner, University of Cambridge
Funded by: The Little Princess Trust
Funded: July 2023
Award: £249,965
What happens in cells to make neuroblastoma develop and how can we stop this?
With Dr Anestis Tsakiridis
Healthy human cells are supposed to have 46 chromosomes in them, which store all of a person’s genetic code that forms the instructions for how cells should behave. However, children’s cancers like neuroblastoma often have extra bits of chromosomes. These extra bits of chromosomes can also lead to a lot of MYCN protein in cancer cells, which can make that cancer harder to treat or more aggressive.
In this project, Dr Anestis Tsakiridis will examine how the extra bits of chromosome and excess MYCN proteins work together to promote the 'conversion' of normal early cells into cancer cells in neuroblastoma and medulloblastoma. They also want to find out why cancer cells get extra bits of chromosomes, and whether they helps the cancer cell to survive.
In the final part of the project, the researchers will test potential treatments in neuroblastoma cancer cells in the lab. Dr Tsakiris hopes that this project will increase understanding of how these cancers grow in children and that it will lead to the development of new therapies.
Project title: Deciphering the role of chromosomal copy number variants in paediatric tumour initiation.
Lead investigator: Dr Anestis Tsakiridis, University of Sheffield
Funded by: The Little Princess Trust
Funded: July 2023
Award: £22,949
