Current research projects
2019 grant round
Neuroblastoma UK is supporting nine new research studies this year, with a total funding of £1.177 million. Research ranges from studies to understand the origin and development of neuroblastoma to research that aims to develop new therapeutic approaches or improve existing treatments.
Development of personalised therapeutics to prevent and treat ALK-positive neuroblastoma resistant to ALK inhibition
Project title: Development of personalised therapeutics to prevent and treat ALK-positive neuroblastoma resistant to ALK inhibition
Lead researcher: Dr Suzanne Turner – University of Cambridge
Duration of grant: Three years
Grant amount: £236,141
Overview: Personalised medicine determines a patient’s treatment based on the genetics of their tumour. In neuroblastoma, a change seen in approximately 10% of patients is overexpression or mutation of the gene anaplastic lymphoma kinase (ALK). The protein encoded by this gene can activate many other proteins in the tumour cell leading to uncontrolled growth.
Because ALK is also expressed in adult lung cancer, drug companies have developed many ALK inhibitors. These drugs are slowly making their way through to clinical trials involving children with neuroblastoma.
Through the adult use of these drugs in lung cancer, there is some understanding of how tumours respond to them. For example, it is known that many adults treated with ALK inhibitors relapse as their tumours become resistant to the drug. This is largely not due to the ALK protein changing its shape (therefore the drug can no longer bind) but more often due to activation of bypass tracks i.e. the tumour cells find different routes to proliferate in the presence of the ALK inhibitor.
Dr Turner has previously performed screens of neuroblastoma treated with ALK inhibitors and has identified several bypass pathways, some of which are unique to neuroblastoma and some common with lung cancer. These bypass pathways will be investigated in this project, with the aim of improving the effectiveness of ALK inhibitors.
Understanding and targeting proteins in neuroblastoma development and microenvironment via stem cell models
Project title: Understanding and targeting of B7-H3 in neuroblastoma development and microenvironment via stem cell models
Lead researcher: Prof Louis Chesler – The Institute of Cancer Research & Prof John Anderson – UCL Great Ormond Street
Duration of grant: Two year
Grant amount: £205,238
Overview: In high risk neuroblastoma, traditional chemotherapy has had limited success and can damage healthy organs throughout the body. Consequently, there is an urgent need to find therapeutic approaches that can successfully target only neuroblastoma cells to eradicate disease with no side effects.
B7-H3 is a protein on the surface of cancer cells involved in turning off the body’s immune response to cancer. In this project, they aim to understand how B7-H3 prevents the normal immune system from recognising neuroblastoma tumour cells, whilst also stimulating their growth. They are developing new treatments that cause killer cells of the immune system to recognise B7-H3 on tumour cells leading to their elimination. The ultimate goal is to test these newly developed antibody based drugs that target B7-H3, to see whether they are viable for clinical trial.
Understanding and improving antibody therapy
Project title: Understanding and improving the mechanisms of action of anti –GD2 monoclonal antibody therapy in neuroblastoma
Lead researcher: Dr Juliet Gray – University of Southampton
Duration of grant: Three years
Grant amount: £126,990 co funded with Niamh’s Next Step and Bradley Lowery Foundation
Overview: The first aim of the project is to design a better anti-GD2 antibody that will be more effective in killing the neuroblastoma cells and less toxic than those which are currently used, to reduce the serious side effects of treatment.
The project will also investigate if anti-GD2 therapy can be further improved by combining with two different agents (anti-PD-1 antibody and STING agonists) to stimulate the immune system and increase response to treatment.
Modelling neuroblastoma – immune cell interactions in a tissue-engineered 3D platform
Project title: Modelling neuroblastoma – immune cell interactions in a tissue-engineered 3D platform
Lead researcher: Dr Olga Piskareva – Royal College Of Surgeons in Ireland
Duration of grant: Three years
Grant amount: £116,400
Overview: A big challenge in the development of new therapies for neuroblastoma is the lack of adequate experimental models that can mimic the complexity of tumour tissues.
Immunotherapy is a promising treatment due to it specificity and reduced side effects in comparison to chemotherapy. Immunotherapy modifies the immune cells to recognise cancer cells to ;attack and eventually kill them.
In this project, Dr Piskareva aims to engineer a novel experimental model to study the biology and treatment of neuroblastoma. They will grow neuroblastoma cells together with immune cells in 3D scaffolds. They will use 3D printing technology, which allows for reproducible scaffolds, replicate the more realistic 3D architecture of tumour tissues. The new model system will then be used to screen for the effectiveness of different immunotherapies.
The knowledge gained from this will advance current immunotherapies and develop more effective treatments with more tolerable side-effects.
Characterising the Tumour Supporting Roles of HMMR in neuroblastoma
Project title: Characterising the Tumour Supporting Roles of HMMR in neuroblastoma
Lead researcher: Dr Andrew Stoker – University College London
Duration of grant: Two years
Grant amount: £143,648
Overview: Dr Stoker’s team have recently examined the functions of a group of enzymes called tyrosine phosphatases in tumour derived cell lines.
They have already demonstrated that the inhibition of phosphatases has anti cancer effects in neuroblastoma cells. They now they want to look at the molecular basis for these effects and how they may be exploited therapeutically in the future.
Their studies to date have highlighted a specific protein, HMMR, which they believe is part of a phosphate signalling machinery. HMMR is well defined as a tumour promoter in several other cancers and their preliminary data points to it being a cancer-causing protein in neuroblastoma too.
Their objectives for this grant are to understand how the HHMR protein works inside neuroblastoma cells at a molecular and cellular level and whether it is an important driver of the cancer. If they do confirm this, it will potentially open up a new area of therapeutic research for neuroblastoma.
Nanobody-based strategies to investigate and target the oncogenic transcription factor, N-Myc
Project title: Nanobody-based strategies to investigate and target the oncogenic transcription factor, N-Myc
Lead researcher: Dr Heike Laman – University of Cambridge
Duration of grant: Two years
Grant amount: £153,369 co funded with Bradley Lowery Foundation
Overview: The excessive expression of a protein called N-Myc is a well known cause of some of the worst neuroblastomas, yet there are still no therapies that specifically target its function.
It has been very hard to design molecules that bind to N-Myc , because the protein only takes its active shape when it binds to other proteins.
The Laman group are taking advantage of the curious fact that camelids (including camels and alpacas) make very small antibodies, known as nanobodies, as part of their normal immune response. Because of their small size, nanobodies could be delivered more easily into cancer cells, whilst being specific to particular gene targets. Having sifted through numerous possibilities to discover nanobodies that target N-Myc, the Laman group will use these specific nanobodies to track and investigate the function of N-Myc in neuroblastoma cells.
They aim to discover how N-Myc regulates particular sets of genes to convert cells from normal to cancerous. It is hoped that using nanobodies will be a successful new approach to targeting N-Myc in neuroblastoma patients.
Establishment of an in vitro model of neuroblastoma initiation using pluripotent stem cell differentiation
Project title: Establishment of an in vitro model of neuroblastoma initiation using pluripotent stem cell differentiation
Lead researcher: Dr Anestis Tsakiridis – University of Sheffield
Duration of grant: One year
Grant amount: £72,656
Overview: Neuroblastoma is thought to arise in utero when a group of normal embryonic cells called trunk neural crest become cancerous, involving changes in their DNA. One such change results in the presence of very high levels of the N-Myc gene, which is known to drive the change of normal trunk neural crest cells into neuroblastoma.
Current methods for examining this transition are limited as either they are based on the use of animals which fail to recreate the human disease or they involve the isolation of cancer cells from already established tumours and consequently miss out the ‘events’ which previously converted cells from normal neural crest to cancer.
At Sheffield, they are proposing to employ a method that will lead to the production of human trunk neural cells in the petri dish and then convert them into being cancerous by artificially raising their N-Myc levels.
They will carry out a series of tests to ascertain whether these cells become neuroblastoma, and how, using several different approaches. It is hoped that this grant will help us better understand the causes of neuroblastoma and therefore lead to further investigations to stop the proliferation of these cancerous cells.