Diffuse midline glioma is an aggressive and incurable brain tumour that most commonly presents in children. It has a dismal prognosis – most children die within 18 months.
Dr Pathania is studying genetic mutations commonly found in diffuse midline gliomas in order to determine their roles in tumour growth, and their potential as targets for treatment.
Following rigorous assessment as part of our competitive grant round, this project was recommended for its strong potential to advance knowledge of these devastating tumours, and to open up new treatment options. The work is based on a solid body of preliminary data and presented by a strong collaborative team that is well-placed to deliver the work.
Diffuse midline glioma (DMG) is a very aggressive and variable type of children's brain tumour.
Until recently, these tumours were thought to be mostly restricted to the brain stem, and were known as 'diffuse intrinsic pontine glioma' or 'DIPG'. Knowledge has advanced rapidly in recent years and we now know that this type of tumour can extend from the brainstem, up the middle part of the brain (the midline), and into the frontal lobes in some cases. This has given rise to the new name of diffuse midline glioma. Although the name is new, DIPG and DMG are the same type of tumour.
Whilst our understanding of these tumours continues to advance, we haven't yet reached the stage where we have effective treatments for DMG. The diffuse nature of DMGs, combined with their critical location, means that surgical removal is usually not possible. Chemotherapies used to treat other forms of glioma are ineffective in DMG. Radiotherapy is used to slow their growth but is not curative.
To improve the outlook for children with DMG it is essential that we develop new therapies that target the unique biology of these tumours.
Genetic sequencing has revealed that DMGs represent several distinct tumour types – based on the different constellations of mutations they carry and where they occur in the brain. However, the relevance of many of these extra mutations is unknown - they may be present in tumours, but what do they do? Are they required for tumour growth? And how important are they for treatment?
Dr Pathania has developed a way to produce brain tumours with different combinations of mutations in mice. He will use these mouse models to test the effects of the extra mutations found in DMGs, and to identify drugs that can be used to target these mutations.
In particular, he is focusing on one specific mutation very commonly found in DMGs, in a gene called ATRX. His project aims to identify how these mutations in ATRX co-operate with other mutations in brainstem tumours to allow tumour cells to grow and divide. He will test drugs designed to counteract the processes set in motion by the ATRX mutation, to assess whether tumours can be reduced by targeting these processes. The drugs will be tested together with treatments already in use in the clinic to evaluate whether the treatments can have a greater effect when used in combination.
The ultimate goal is the development of a ‘precision’ patient-matched approach to treating DMG.
DMG is a devastating form of brain cancer that has no effective treatment.
New treatments are desperately needed, and Dr Pathania’s work will open up a potential new avenue of treatment, offering new hope to those affected by this terrible tumour.
“Very interesting and important project with a high chance of success to generate new insights in this deadly disease and hopefully new directions for novel treatment strategies.” Reviewer
Dr Manav Pathania is a Junior Group Leader within the CRUK Children’s Brain Tumour Centre of Excellence at the University of Cambridge.
Awarded his PhD (Cell Biology, Yale) in 2011, Manav falls into our Early Career Researcher category, where we are targeting funding to help build capacity in our priority research areas.
Dr Pathania’s strong expertise in glioma modelling means he is well-placed to succeed in this work, which itself sits well with other work taking place at the Centre.
As well as having support and mentorship from his Department Head, Professor Richard Gilbertson, Dr Pathania brings in complementary expertise from Professor Chris Jones (Institute of Cancer Research), Professor Thomas Jacques (UCL Great Ormond Street Institute of Child Health), and Dr Pradeepa Madapura (Blizard Institute), who will each contribute unique technical and analytical expertise to ensure success of this work.
“The applicant is a very promising young researcher with a unique expertise and excellent track record in investigating DMG. The proposal is very exciting and supported by excellent collaborators.” 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.
Other research projects currently funded under this theme:
Find out about our other research in this area: