Diffuse intrinsic pontine glioma (DIPG) develops in the brain stem, mainly presenting in children aged 5 to 10 years. There is no cure and most children die within 18 months of diagnosis.
Professor Chris Jones is building on previous work that has found that a gene called ACVR1 is mutated in some DIPG tumours. Finding a drug that targets this mutation could be an effective way to treat DIPG, and we hope that this project will lead into a clinical trial of new drugs.
Following rigorous assessment as part of our competitive project grant round, this project was selected because the members of our Scientific Advisory Panel felt that it would make an important contribution to knowledge in an important area of high unmet need. Whilst DIPG is rare tumour, its impact is devastating. Professor Jones is building on a solid body of previous work, and is very well-placed to succeed in delivering an effective treatment for DIPG.
DIPG is a high grade childhood brain tumour. It is the second most common primary high grade brain tumour in children, affecting 20 to 30 children a year in the UK. It has no cure.
DIPG develops in a part of the brain stem known as the pons, which controls essential bodily functions including heartbeat, breathing, swallowing, eyesight and balance.
The pons is inaccessible surgically. Chemotherapy is ineffective. Radiotherapy can temporarily slow growth of the tumour, but is not curative. Ninety per cent of children die within 18 months of diagnosis, and survival beyond two years is almost unheard of.
Effective treatments are desperately needed.
Professor Chris Jones is focused on the genetics of childhood brain tumours, especially DIPG. His aim is to find the genes that are driving the development of these tumours, and to find ways to translate his team's discoveries into new treatments for young patients.
His team was part of an international collaborative effort to sequence the genome of DIPG, in work that was published in 2014. One of their most notable findings was a mutation in a gene called ACVR1, a mutation not seen in any other type of cancer. The same mutation is, however, found in a disease known as stone man syndrome, a debilitating genetic condition in which muscles can turn to bone. The unexpected discovery, linking these two drastically different diseases, meant that research into drugs to treat stone man syndrome might also be important in the search for treatments for DIPG.
Professor Jones has developed a thorough understanding of the role of ACVR1 in the biology of DIPG and believes that finding a drug that can target the mutation could represent an effective treatment for DIPG.
This new project, funded by Brain Research UK in collaboration with the DIPG Collaborative, builds on previous work showing that drugs that inhibit ACVR1 can modestly prolong survival in mice with human DIPG tumours. The next step is to see if the effect can be enhanced using combinations of different drugs.
The key is to find the right combination at the right dose. They also need to assess the interaction of candidate drugs with radiotherapy, as this is the current standard of care in DIPG.
An important step on the pathway to human trial is the development of a mouse model of DIPG, which can be used for advanced testing of potential therapies. Existing models involve grafting a tumour onto a mouse whose immune system has been disabled - a so-called xenograft. This is useful, and the best option currently available, however, a genetically engineered mouse model is more representative of a real tumour. It will enable the collection of important evidence about the safety and effectiveness of potential new therapies in a living system with a fully functioning immune system, as well as giving further insights into the role of ACVR1 in the development of DIPG.
In results published in September 2021, in the journal Cancer Discovery, the team reported a combination of two drugs that together extended survival in mice with DIPG. The targeted drug vandetanib acts against the ACVR1 gene but has difficulty getting past the blood-brain barrier (BBB). When combined with a drug called everolimus, however, its capacity to pass through the BBB is enhanced. Both drugs are already approved to treat children with DIPG and could be repurposed for use in combination to treat children with DIPG and an ACVR1 mutation. Read more.
DIPG is a rare but devastating childhood brain tumour. There is no effective treatment, meaning that it is considered fatal from the outset.
In the last five years, thanks to advances in genetic sequencing technology, new biological discoveries and worldwide collaborative research efforts, there is a glimmer of hope. Effective treatments may be within reach.
Professor Chris Jones is one of the world’s leading researchers in the field of DIPG. He has excellent collaborations, both internally at the Institute of Cancer Research, nationally, and internationally – especially important when working in such a rare tumour type.
Professor Jones has played a key role in the progress made to date, and continues to drive progress. The expectation is that – by the end of this project – he will have identified new therapies, tested in valid animal models, ready for translation through to clinical trial in young patients.
The applicant has laid out a well thought out, realistic and innovative proposal that has a real prospect of identifying an effective therapy for DIPG.
- External reviewer.
Brain tumours are one of our current research priorities, reflecting the large unmet need in this area. Our aim is to fund research to advance understanding of the causes and underlying mechanisms of brain tumours, and help us to diagnose and treat them more effectively.
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Find out about our other research in this area: