UCL Research Domains


Tailoring treatments for childhood brain cancers

International collaborations will be essential if the potential of targeted therapies for childhood brain cancers is to be realised, says Professor Darren Hargrave, a UCL researcher and consultant paediatric oncologist at Great Ormond Street Hospital.

Brain cancers are thankfully rare in children, but they are still the biggest cause of cancer-related deaths. Moreover, even when treatments are a success, they often have side effects that can last a lifetime. Hence, there is an urgent need for better, kinder treatments.

Until recently, treatments for childhood cancers were typically adapted from those developed for adults. However, it is becoming clear that childhood cancers differ significantly from adult cancers, often being the result of developmental processes gone awry. Indeed, childhood and adult tumours that look alike in terms of pathology may have quite different underlying biological causes.

This insight has important implications for treatment, and in particular the use of agents targeting underlying molecular pathways. The mainstay of treatment has to date been surgery, radiotherapy and chemotherapy, all of which can have significant side effects and have had limited success against the brain cancers responsible for the greatest numbers of deaths, such as high-grade gliomas. Now, says Professor Hargrave, the hope is that a new wave of treatments - particularly targeted therapies and immunotherapies - may provide much-needed new options.

One exciting example is the repurposing of targeted therapies (BRAF and MEK inhibitors) initially developed for malignant melanoma. These were developed following the discovery (to which Professor Hargrave contributed) of a particular mutation, known as V600, in the BRAF gene in melanoma and some other adult cancers. It was subsequently discovered that nearly all paediatric low-grade gliomas (the most common type of childhood brain tumour) have an underlying activation of the MAPK pathway. This can be caused by several genetic aberrations, including the BRAF V600 mutation, but also by chromosomal rearrangements that generate BRAF-activating gene fusions or, in patients with the genetic condition neurofibromatosis type 1, by a mutation in the NF1 gene.

A phase I trial was therefore organised to test adult-licensed BRAF drugs in children with low-grade gliomas and rare brain tumours with BRAF V600 mutations. Although the trial was primarily designed to identify a suitable dose for paediatric use, several multiply relapsed patients showed excellent responses [1].

Given these promising findings, a global study has been organised randomising a combination of oral BRAF and MEK inhibitors against the current standard of care, intravenous chemotherapy, as a first-line therapy for low-grade gliomas with V600 mutations. Although such tumours can be effectively treated with radiotherapy, this type of treatment can have long-term complications that could be avoided by use of targeted therapies.

To treat low-grade glioma caused by either BRAF gene fusions or NF1 mutations, first-generation BRAF-specific inhibitors will not work, but MEK inhibitors that target later steps in the MAPK pathway have shown exciting preliminary results in early phase trials. Professor Hargrave has been involved in the steering group designing two international studies to compare targeted oral MEK inhibitors against standard intravenous chemotherapy for children with NF1 or BRAF fusion low-grade glioma.

Other targeted agents have been or are being explored in paediatric brain tumours, such as inhibitors targeting the hedgehog/smoothened pathway in relapsed medulloblastoma, which also achieved some success [2], with responses seen in some young patients with activated hedgehog signalling. However, not all patients responded and biological markers have been identified that are associated with resistance to therapy. In addition, some young patients experienced side effects on growth and the future role of this agent in the treatment of medullobastoma is being considered.

Global collaboration

Given the rarity of childhood brain tumours, stratification of patients according to underlying molecular defects will inevitably create very small patient populations. As well as innovative trial design, this emphasises the importance of global collaboration to generate the numbers needed for statistically valid clinical trials. The paediatric oncology community has led the way in global collaboration, and Professor Hargrave is involved in several national and international consortia investigating the biology of paediatric brain tumours and trials testing new therapies. In 2018, he will take up a position as chair of the SIOP-European Paediatric Brain Tumour Group, an umbrella body coordinating trials across Europe.

Professor Hargrave is also extensively networked across UCL, working with groups developing innovative technologies that could be applied to paediatric brain tumours. With Dr Karin Straathof, he is involved in work to identify brain tumour antigens that could be targeted by CAR-T cell therapy (chimeric antigen receptor T cell therapy), while a joint project with Professor Giuseppe Battaglia is examining the use of nanoparticle carriers to deliver drugs across the blood-brain barrier to tumours.

His close links to research also enable Professor Hargrave to rapidly introduce innovations into clinical practice at Great Ormond Street Hospital. As a member of the Children and Young Adult Cancer Services Clinical Reference Group, he has been advising the Department of Health on the potential implementation of molecular diagnostics for paediatric cancers within the NHS. And with colleagues at the Institute of Cancer Research, he is also leading a national programme undertaking multi-omic profiling of relapsed brain cancers funded by CRUK (SMPaeds). A key aspect of this work is to consider how technologies could be implemented within a clinical delivery environment to support enhanced patient care.

  1. Kieran MW et al. The first study of dabrafenib in pediatric patients with BRAF V600-mutant relapsed or refractory low-grade gliomas. Abstract LBA19_PR, European Society of Molecular Oncology, Copenhagen, Denmark, 7-11 October 2016
  2. Kieran MW et al. Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro Oncol. 2017;19(11):1542-1552.


Professor Darren Hargrave