Centres of Excellence grants update
These are our biggest value grants that we think will really drive us into a world where brain tumours are defeated. Sometimes it’s a group of researchers in the same institution, but more often we’re seeing researchers from all over the globe join forces and expertise to excel in their areas of neuro-oncology.
Our Centres of Excellence grants cover a range of topics and tumour types, we’re excited to share the latest progress from a selection of those grants below. At the end of each progress update you’ll find the link to the grant’s own webpage where you’ll find more information.
The Everest Centre
Lead researcher: Dr David Jones
Where: German Cancer Research Centre (DKFZ), Germany
Cost: £5 million over 5 years, initially
The team funded by The Everest Centre grant is making great progress towards their objectives. Under the leadership of Dr David Jones, they’re advancing their work into the epidemiology, genetics and molecular biology of low grade paediatric brain tumours, and the clinical trial that’s supported by this grant, LOGGIC, is already gathering data.
Determining the origin of low grade brain tumour types
The team have defined two new subtypes of low grade brain tumour, which were previously only poorly characterised. Both new subtypes have unusual features in terms of their genetic alterations, making them somewhat different from other low grade tumours. This is interesting biologically and also important for developing targeted treatment strategies in the future.
Developing low grade brain tumour models and pre-clinical screening
Further progress on this aim has seen development of the tool that allows the researchers to track activity of key signalling molecules within the cells in real-time. They’re now using this system to screen large panels of drugs with the ultimate goal of finding combinations of treatments that more effectively switch off the main tumour-driving proteins in the cell.
Identifying factors that affect tumour growth
In London, the team has generated a large amount of data on two distinct types of low grade brain tumour, as well as normal brain tissue for comparison. In contrast to previous data on the DNA and RNA components of the tumour cell, they’re now examining the proteins and protein activity within the cell directly. This data will be extremely useful for detailing how key cancer pathways are activated within the cells and prioritising areas for further study in tumour models.
Enabling a pan-European clinical trial, called LOGGIC (LOw Grade Glioma In Children)
The first phase of the study, the LOGGIC Core BioClinical Database, is now open and collecting information on newly-diagnosed patients as well as providing detailed molecular analysis of their tumours. So far, more than 80 patients in Germany are registered, and the molecular screening has already revealed some unexpected findings that will help to provide more accurate diagnosis (as well as offering potential treatment options). This part of the study is currently being opened up in additional international hubs, including the UK, and we expect the full clinical trial to start in early 2020.
Pathologist Professor Thomas Jacques, along with other Everest researchers in the UK and Germany, examined the clinical value of performing routine molecular testing in childhood brain tumour patients to assist with diagnosis. They found that in cases with an unusual appearance under the microscope, or showing uncommon clinical behaviour, the use of these molecular tools (originally developed by Everest researchers in Heidelberg) could greatly help in providing an extra degree of diagnostic certainty. Sometimes even suggesting more effective treatments. Read more about this exciting clinical development.
ACP research and a clinical trial
Lead researcher: Dr Todd Hankinson
Where: University of Colorado, USA
Cost: £1.058 million over five years
Adamantinomatous craniopharyngioma (ACP) is a low grade brain tumour usually found in children. It has a profound effect on children’s quality of life due to the location of the tumour - near the pituitary gland, hypothalamus and optic nerve.
Previous research has shown that the different types of cells that make up ACPs communicate with each other using chemical messengers called cytokines. Cytokines are molecules released from cells that allow them to ‘talk’ to each other and promote survival and growth. Researchers suspect that in ACP these chemical messengers are promoting tumour growth but we need to know more.
Understanding how ACP cells communicate
Dr Hankinson and his team have refined the technique they will are using to separate out the individual cells within the tumours. They’re now using ethically-donated human ACP samples to find which cell types are producing different cytokines.
Identifying treatments for ACP
When the research team know which cytokines are involved they are able test the best potential drugs in pre-clinical models. The team are now analysing the experiments they did using the first of their candidate drugs.
Once the researchers confirm that one or more drugs are reaching the tumour in effective levels they will ask the questions, ‘Are the drugs killing the tumour?’ and ‘Which ones are doing it best?’
Doing research on uncommon tumours is very difficult to do and having multi-national and multi-institutional support is very hard to find. The support provided by The Charity is critical to accelerate progress.
Testing treatments in the clinic
From our perspective, this is the most exciting progress in the grant because it’s been accelerated beyond what we thought the grant would produce.
The researchers have been able to advance their timetable and we’re now funding their Phase II trial instead. (Phase I trials aren’t needed in this case because the drugs have already been tested for safety).
Phase II trial: A panel of experts from the CONNECT consortium assessed the data our researchers provided and accepted their proposal for treating children with an immunosuppressive drug alongside a type of drug called a MEK inhibitor. This shows how the work is racing towards the clinic.
Proteins as drug targets for glioblastoma
Lead researcher: Professor Steve Pollard
Where: University of Edinburgh
Cost: £1.48 million over 5 years
Chromatin regulators control gene expression. These proteins regulate the entire process of DNA being wrapped tightly into chromosomes. Chromatin regulators carry the important genetic information that controls how the cells in our body behave. If these regulators become mutated, it changes the way the DNA is wrapped, causing the cell to behave differently.
Professor Pollard’s team are paying particular attention to Trithorax group proteins (a chromatin regulator), aiming to identify which of the 1,000 chromatin regulators should be prioritised for drug development.
To study these proteins they’re testing drugs that have already been approved for use in other human diseases to see if they can target the chromatin regulators. These drugs have already been approved for use in humans, so if proven they’ll reach brain tumour patients much faster.
The research team are approaching this from two different directions.
- Firstly, using a candidate approach, harnessing existing knowledge of the most likely targets for drug development.
Existing small molecules (chemicals that could be used as drugs) are identified as candidates and are tested directly on normal and tumour cells.
- Secondly, exploiting the latest ‘genome editing’ technologies.
Genome editing enables the team to screen a large number of genes, and in parallel to identify those that would be priority for drug development.
In this second year of the project Professor Pollard and his team have optimised the methods needed to tackle the ambitious goals of this project. They have performed successful chemical and genetic screens, which have uncovered a wealth of potential new targets to follow up, including uncovering new gene switch regulators.
We have shifted attention to a specific target that might be expressed only in the brain stem cells - this would make it a better therapeutic target with less risks of toxicities in other tissues and organs.
Encouragingly, the chemical screening has shown that a family of molecules known as HDACs are important to maintaining the key features of GBM stem cells that underpin their growth. The next avenue of research for this investigation is to inhibit HDACs, in combination with other drugs, and determine if that slows or stops GBM models growing in the lab.
Targeting clinically challenging meningiomas
Lead researcher: Dr Gelareh Zadeh
Where: University Health Network, Toronto, Canada
Cost: £1.5 million over five years
This research aims to improve our understanding of aggressive meningiomas and provide a foundation for more accurate diagnoses and treatments. The collaborative research programme is assembling experts in pathology, neurosurgery, genetics, and molecular biology from Canada, the UK, and USA. In addition, this programme will enable researchers to establish an international meningioma consortium with 14 collaborating institutes.
Dr Zadeh’s team have now completed genetic and epigenetic sequencing of over 150 meningioma tumour samples making this the most richly annotated cohort of samples that exists to date.
Excitingly, this work has enabled the creation of a clinical tool that helps predict the risk of tumour re-growth, for individual patients, after surgical removal.
Patients are now able to find out their own personalized risk of tumor growing back within 5-years once their tumour is removed by surgery. This represents a major advance in prognostication for meningiomas, and will impact whether or not patients would consider receiving radiation therapy after surgery to reduce the risk of tumor regrowth.