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.
In this project, Professor Chris Jones built on previous work that had 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 this work has identified a promising drug combination that is now going forward to clinical trial.
DIPG, also now known as diffuse midline glioma, DMG, is a high-grade childhood brain tumour. It is the second most common primary high grade brain tumour in children and 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 and swallowing.
The pons is inaccessible surgically. Chemotherapy is ineffective. Radiotherapy can temporarily slow growth of the tumour, but is not curative. Most children die within 18 months of diagnosis, and survival beyond two years is almost unheard of.
Effective treatments are desperately needed.
The Jones lab at the Institute of Cancer Research is one of the foremost labs in the world for research into DIPG. The team there were 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 other types of cancer but found in a quarter of children with DIPG.
Professor Jones was awarded a project grant in 2018 for research that aimed to understand the role of ACVR1 in DIPG, and how it can be targeted in treatment. With this funding, the team collaborated with a group at the Crick Institute in London to show how mutations in ACVR1 change its function in DIPG cells. They worked with multiple drug companies to evaluate existing ACVR1 inhibitors in their DIPG models in order to support future clinical trials, identifying a promising combination with a type of drug called an MEK inhibitor and radiotherapy as part of a worldwide collaboration across six labs as part of the CONNECT consortium of paediatric neuro-oncology centres.
As an alternative approach, the team also explored drug repurposing approaches for ACVR1 mutant DIPG, using an artificial intelligence drug discovery platform to search for compounds that may have inhibitory effects on ACVR1. This led to the identification of the drug vandetanib, which acts against ACVR1, and is approved for the treatment of thyroid cancer. Vandetanib has difficulty getting past the blood-brain barrier, however, and is pushed back out of the brain, meaning that it cannot build up to a high enough concentration in the brain to have a therapeutic effect.
In results published in September 2021, in the journal Cancer Discovery, the team reported on experiments that combined vandetanib with a drug called everolimus. They showed that combining the two drugs increased the amount of vandetanib reaching the brain. In their mouse model of DIPG, this drug combination reduced tumour burden (size) and extended survival. Based on the preclinical data, the drug combination was used on a compassionate basis in four children with ACVR1 mutant DIPG, including a seven year old patient from the Royal Marsden Hospital, who enjoyed an improved quality of life for 20 months post-diagnosis before eventually progressing and passing from the disease.
The vandetanib-everolimus combination has recently been approved for clinical trial and is seeking funding.
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 decade, advances in genetic sequencing technology, new biological discoveries and worldwide collaborative research efforts have opened up a glimmer of hope. Effective treatments may be within reach.
Professor Jones has played a key role in the progress made to date, and continues to drive progress. In this work, he has driven forward the development of a number of new therapeutic approaches, ready for translation through to clinical trial in young patients.
February 2024
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