(L-R) Prof Neil Carragher
Scientists will develop tiny “Russian doll-like” particles that carry, layer-by-layer, multiple drug therapies to treat glioblastoma – the most aggressive type of brain tumour.
The team are one of three to have been awarded a combined total of £18 million in funding as part of the Cancer Research UK Brain Tumour Awards.
Brain tumours represent one of the hardest types of cancer to treat because not enough is known about what starts and drives the disease, and current treatments are not effective enough.
Cancer Research UK, in partnership with The Brain Tumour Charity, established these awards to advance our understanding of the biology of brain tumours and tackle the challenge of translating discoveries into treatments for patients.
Two of the internationally funded teams are based at the University of Edinburgh, and one is led from the University of Cambridge. Teams will focus on the most aggressive type of brain tumour, called glioblastoma, as well as children’s brain tumours.
Russian doll-like particles
Professor Neil Carragher’s team, from the University of Edinburgh, aims to identify and target the best drug combinations against aggressive brain tumours. Working with a US team from the Koch Institute for Integrative Cancer Research at MIT, they will develop prototype nanoparticles, one thousand times smaller than a human hair, which are able to cross the blood-brain barrier. The nanoparticles can carry multiple drugs at once by holding them inside layers, similarly to the way Russian dolls fit inside one another.
They will test whether this way of configuring multiple drugs in particles will be more effective and safe at carrying combinations to cancer cells without being taken up by healthy cells, in the hope of minimising side-effects for future patients.
Professor Neil Carragher said: “For brain tumours, we need a completely different approach in terms of how we discover and test drugs. Brain tumours adapt very rapidly to any treatment, so it’s very unlikely that a single drug is going to do much: we really need drug combinations.”
The team will also work with other scientists at the University of Edinburgh and the University of Oxford to test numerous drug combinations on patient-derived stem cells, which accurately represent a patient’s disease. Their advanced imaging technique will allow them to not only identify which drug combinations work best on the most aggressive type of brain tumour, but also how they work and what they do to cancer cells. Using cells from many different patients, they hope to develop a sense of which drugs work best for whom, in order to design personalised treatments.
Sleep/wake cycles of cells
Professor Steven Pollard’s team who are also from the University of Edinburgh aim to control the sleep/wake cycle of cancer cells to stop tumours from growing back.
Glioblastoma, the most aggressive type of brain tumour, can grow by hijacking tools we use during embryonic development, reactivating them in the wrong place and time.
Professor Pollard will lead a team of researchers from the UK, US and Canada to find new strategies to target this process. For example, the researchers plan to degrade key tools that are used by cancer cells to turn on these embryonic gene programs.
Glioblastomas tend to grow back even after they are removed, because some cancer cells can evade treatment while in a ‘sleeping’ state and grow into new tumours when they ‘wake up’ later.
The team will also study the mechanisms that control this switch from dormancy to wakefulness, and how tumours respond to cues from their environment such as mechanical forces or signals from immune cells.
Professor Pollard said: “We want to quickly translate our findings into treatments for patients. We will focus on identifying biological weaknesses and searching for therapeutic strategies that target these. For instance, if we block pathways that are important in waking up the cancer cells, it may keep them under control and stop the tumour from growing back. We might also be able to improve the immune system’s ability to identify and destroy the cancer cells.”
Unpicking the biology of children’s brain tumours
Unlike most cancers that develop when healthy cells go haywire, most children’s brain tumours are ‘leftovers’ from embryonic tissue: cells that were meant to disappear, but didn’t, when a baby’s brain has been fully formed.
Professor Richard Gilbertson, from the University of Cambridge, and his collaborators in the US and Canada aim to build maps of developing human and mice brains to identify which parts of the embryonic brain turn into which type of brain tumour. They are hoping to use what we already know about embryonic brain development to discover new drug targets for the corresponding tumours.
The team will also explore the way children’s brain tumours behave, so that they may target some of their unique features. For example, a group of collaborators based in the US will investigate how we could stop brain tumour cells from ‘reaching out’ to healthy cells and taking nutrients from them.
Professor Richard Gilbertson said: “At the moment, all treatments we use for children’s brain tumours have been extrapolated from adults or from treatments we use against other cancers. In this project we’re going to develop a whole new generation of agents that will only be right for brain tumours, or children with brain tumours.”
Although relatively rare, with around 11,700 cases in the UK each year,* brain tumour survival remains tragically low. Only 14% of people diagnosed with brain cancer in England and Wales survive their disease for ten years or more,** and little has changed in over a generation. These are the first research projects to receive funding from the Brain Tumour Awards and represent a major investment by Cancer Research UK in this hard-to-treat disease.
Michelle Mitchell, chief executive of Cancer Research UK, said: “As some of the most difficult cancers to treat, brain tumours are a priority for Cancer Research UK’s research strategy and as part of our commitment, we are investing an extra £25 million in brain tumour research before 2022.
“We are excited to partner with The Brain Tumour Charity to support researchers across the globe, who will push the edge of our thinking on how to tackle brain cancer. We can’t approach brain tumours the same way we do most cancers because brain tumours develop differently. And the brain is such a complex structure that it’s an added challenge to even get treatments to where they need to go. Our common ambition for these awards is to plug the gaps in brain cancer research.
“Each of the winning teams has shown a commitment to innovative thinking that considers the specific challenges of working with the brain. These teams are multidisciplinary, and their projects are taking cues from neuroscience, computational biology and chemical engineering – to name a few – to unpick the biology of brain tumours.
“Our Awards promise to break new ground in the way we understand brain cancer and how it develops, so that we may overcome the unique challenges it presents to design more effective, kinder treatments and improve patient care.”
Sarah Lindsell, chief executive of The Brain Tumour Charity, said: “Brain tumours are indiscriminate. They strike people of all ages and they devastate too many lives around the world.
“Our investment in the Brain Tumour Awards is a key part of the research we’re funding globally to accelerate progress towards our twin goals: to double brain tumour survival and halve the harm caused by the disease.
“Our partnership with Cancer Research UK in creating and sustaining the Brain Tumour Awards underlines the commitment of both charities to bring about change for everyone diagnosed with brain cancer.”
* Based on the annual number of new cases of brain, other CNS and intracranial tumours (ICD10 C70-C72, C75.1-C75.3, D32-D33, D35.2-D35.4, D42-D43, D44.3-D44.5) diagnosed in the United Kingdom between 2014-2016.
** As shown by age-standardised net survival for patients diagnosed with brain cancer during 2010-2011 in England and Wales.