Anticipatory medicine: Can we identify, predict, and target mechanisms of disease relapse in childhood medulloblastoma?

Medulloblastoma is the most common malignant brain tumour of childhood. Approximately 80 children are diagnosed with the disease every year in the UK, and over 600 children across Europe per annum. Over the last 50 years, advances in treatment (surgical removal of tumour, radiotherapy and chemotherapy) have led to long-term survival rates of approximately 70%. Recently the scientific community has begun to understand the biology of medulloblastoma tumours at diagnosis and how this relates to clinical features and patient survival. Despite these discoveries however, survival rates have plateaued and remain at 70%.

Unfortunately, medulloblastoma comes back (disease relapse), in 30% of patients and is usually fatal, accounting for a very high proportion (10%) of childhood cancer deaths overall. Despite this clear unmet clinical need, the biology driving disease relapse has not been fully investigated, and there have been very few clinical trials aimed at treating children with relapsed medulloblastoma. This is likely due to the challenges of obtaining a tissue biopsy when the tumour returns, and the relative rarity of medulloblastoma relapse. However, a small number of key studies, undertaken by myself and others, have shown that tumour biology changes when a medulloblastoma tumour relapses. Until we understand the factors driving this changing biology and subsequent tumour return, the number of children dying from a relapsed medulloblastoma will remain the same.

This proposal will investigate the biology of medulloblastoma tumours sampled at relapse, and compare these findings to the biology of tumours sampled from the same patient at diagnosis. This will be achieved through the detailed investigation of an unprecedented collection of matched medulloblastoma tumour pairs. This cohort will be used to identify common and emerging biological factors, also known as genetic candidates, which are likely responsible for driving disease relapse. To investigate these...