Neuroblastoma is one of the most common solid tumours affecting children, and these days some forms of it are very treatable. But in high risk types, long-term survival rates are only 50%, particularly when a child has had chemotherapy treatment but their cancer has relapsed.
There is evidence to suggest that some chemotherapy treatments actually increase the likelihood of the tumour mutating and becoming more aggressive and resistant to further treatment, so in this research project, Dr Calton aims to find ways to overcome this resistance with new approaches to treatment.
She is examining a chemotherapy-resistant model to study how it becomes resistant, in order to identify genes suitable for new combination treatments.
Mutational dynamics and their effect on chemoresistance and metastasis in a genetically engineered mouse model of relapsed neuroblastoma
Dr Elizabeth Calton
The Institute of Cancer Research
6 March 2017
Neuroblastoma is the second most common solid tumour in children, and the five-year survival rates for high risk types of the disease is only 50%. Many high-risk neuroblastoma cases show amplification of what scientists call the MYCN oncogene.
Mutation or amplification of the gene called Anaplastic Lymphoma Kinase (ALK) also confers a particularly poor prognosis, and is this is most commonly seen in children who have already had treatment but have relapsed.
Doctors have found evidence to suggest that some relapsed tumours, having been treated with chemotherapy, are more likely to mutate into new subclones of tumours – and these mutations make them harder to treat again.
In this project, Dr Calton is looking at how chemotherapy resistance develops in these tumours – investigating the mutations which happen in relapsed tumours in order to identify which genes are suitable for therapeutic targeting effective in the complex cancers which affect children who have been treated but have relapsed.
This project will directly impact the testing of new molecular therapies for neuroblastoma.
By ensuring that the model environment Dr Calton studies more closely represents advanced tumours, she expects to increase the ability of neuroblastoma researchers to transfer new drug discoveries into tests in hospitals, and give more critically-ill children a better chance of survival.
Metastasis, the spread of a tumour to other parts of the body – in the case of neuroblastoma, particularly to bone and bone marrow – affects 40% of all children at diagnosis, and is responsible for the majority of childhood deaths from neuroblastoma.
Therapy which can effectively limit this would be major step forward, and this project will advance our understanding of this aspect of the disease. The project will also enable scientists to suggest new drug targets for relapsed and refractory neuroblastoma.
We will identify the specific mutation events in pre-treated tumours, and explore their effects on tumour aggression and metastasis, and by examining what makes them resistant to chemotherapy, suggest combinations of targeted drugs to overcome this resistance.
These suggestions can then be effectively translated into new drug candidates to give more children a chance to survive this disease.
Dr Calton has worked specifically in neuroblastoma research in Professor Louis Chesler’s laboratory as an Academic Clinical Fellow since 2014. To carry out the current project, Dr Calton has been awarded a Children with Cancer UK Clinical PhD Studentship.
The project will be supervised by Professor Chesler. His team combines in vitro experiments with established cell lines with in vivo work. Specialised equipment is available to support DNA and RNA studies, and tissue culture, and the laboratory has established protocols for testing targeted therapies, including pharmacokinetics, pharmacodynamics, and effects on tumour size and animal survival within a unique ‘mouse hospital’.
Extensive banked material is available to reduce new animal use. The laboratory also has close links with the ICR’s Centre for Cancer Imaging. There is access for all researchers to genome sequencing technology and bioinformatics expertise within the ICR’s Genetics Laboratory and Tumour Profiling Units.
Additional support will be provided by Professor Mel Greaves, who leads the ICR’s Centre for Evolution and Cancer (CEC). This collaboration of scientists across cancer types has already produced landmark studies into the diversity seen in human cancers.