Every year in the UK, 80 children are diagnosed with medulloblastoma, and 30% of them will see their tumour return—a relapse that is almost always fatal. Despite decades of progress, survival rates have stalled at 70%, and the biology of why these tumours come back remains largely unknown. This research tackles that gap head-on. The team has assembled an unprecedented collection of tumour pairs—samples taken from the same child at diagnosis and again at relapse. By comparing them, they aim to identify the genetic changes that drive the cancer’s return. They will test these candidate genes in lab-grown tumour cells and in mice, using models derived directly from human patient tissue. Drugs that hit the most promising targets will then move into pre-clinical trials. If successful, this work could lead to treatments given at diagnosis that prevent relapse altogether, or to life-prolonging therapies for children whose tumours do return. Because shifting tumour biology between diagnosis and relapse occurs in many cancers, the methods developed here could also apply to other childhood brain tumours. This is fundamental science with a clear, urgent clinical target.
View original technical description
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 genetic candidates, this Fellowship will use established, and new, medulloblastoma modelling systems which are derived from human tumour cells and therefore best represent the cell-to-cell variation observed in the disease. Medulloblastoma tumour cells will be grown in cell culture and in immunocompromised mice. These approaches have been designed to ensure experimental success, and will enable the direct assessment of genetic candidates to establish their role in relapsed disease biology. Drugs which target the most promising genetic candidates will be taken forward into pre-clinical drug trials in cell cultures and immunocompromised mice using the patient-derived models developed. These original experiments will advance our understanding of medulloblastoma biology at relapse and, in the future, enable us to offer life-prolonging treatment to children whose tumour returns. These findings will also enable us to develop treatments to be used at diagnosis, which have the potential to prevent disease relapse and improve overall survival. Furthermore, changing biology between diagnosis and relapse is seen in a variety of other cancers. Therefore, the approaches developed in this proposal could be applied to other childhood brain tumours. In summary, understanding the factors which drive medulloblastoma relapse provides real hope that these factors are predictable, therapeutically targetable and can therefore be exploited to improve cure rates.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know