Precision Oncology: A novel approach to modelling neuroblastoma and specific treatment as its underlying genetic abnormalities changes during a patients treatment

Neuroblastoma is the most common tumour of children (other than brain cancers) and is the commonest cancer in infants. Whilst it represents only 8% of all childhood cancers it is a serious disease, responsible for 15% of all childhood cancer deaths. The majority of children present with disease that has already spread, and in this situation fewer than half of them will survive despite aggressive surgery and complex chemotherapy treatments.

In fact the treatments we offer to children has changed very little in the past 20-years, and are rather brutal. The chemotherapy drugs are old fashioned and very toxic, and fails more often than not. Despite the fact this is a rare disease, dealing with it is a big burden on cancer services due to its poor outcome, and has a devastating impact on families and healthcare staff.

Currently there is very little research into this disease nationally and nothing in Wales, and hence our new initiative brings surgical expertise and basic biological scientists in Wales together to try and address the many unknown questions. Our ultimate ambition is to improve the poor survival outcomes in neuroblastoma.

Our proposal aims to understand some of the cellular and molecular changes that are important in dictating how dangerous the disease is. We have experience in measuring RNA- taken from the tumour to establish a “fingerprint” for the disease. We will identify which RNA-factors are different when comparing dangerous to non-dangerous Neuroblastoma.

Currently the presence of a specific genetic change (MYCN amplification) is the standard means of doing this- but this tells us little about the complexity of the tissue and other elements that are critical to promoting severe, difficult to treat disease.

We are also keen to understand how treatment forces the tumour to change, and adapt to treatment, so we can identify new opportunities for other drugs if/when the disease might return.

An exciting aspect of this, is the development of mini-tumours in the test tube. Such “organoids” are well established in Wales for other tumours, but not in this rare disease setting. Establishing organoids will be extremely valuable. Collaborators in Italy will help us achieve this. These test-tube tools will represent the individual and unique aspect of each child’s tumour- and allow us ultimately to explore the use of novel drugs for these tumours in a patient tailored fashion.

We have incorporated the Health and Care Research Wales funded Wales Gene Park and WCRC into the study, and plan to recruit two lay research partners (e.g. parents of children with neuroblastoma), to consult on communication strategies. They would help evaluate materials for patient information and consent, and for public engagement activities.

Our research findings will be shared to the research community through presentation at conferences and through publication at the conclusions of this project, as well as hosting a workshop which will be accessible to researchers and the public. We have already jointly given a talk at the Rare Cancer Forum (in September 2020) to highlight future intentions in this important and neglected research area, and will contribute to many such events as we proceed.