Our priorities for brain tumour research

Brain tumour researchBrain tumour survival remains low, and has changed little in over a generation, which is why we made them a strategic priority as one of our cancers of unmet need. We've identified the top problems which we believe need to be solved in order to transform the field.

Progress in brain tumour research has been hindered by huge gaps in our knowledge, in particular of the biology underpinning the diseases. In 2016, we convened a panel of brain tumour experts from around the world to identify the questions in brain tumour research which, if answered, could remove these barriers to progress. While not an exhaustive list of all the challenges faced by those researching brain tumours, we believe that tackling these ten areas will significantly accelerate progress for patients.

Our approach

We want to support the research that will make a real difference to people with brain tumours. To achieve our ambitions for brain tumour research, we are:

  • Spending around £25 million over the next five years on ring-fenced, targeted initiatives
  • Expanding our broad research portfolio across the discovery and translational research pipeline, and in all types of brain tumours, whether paediatric or adult, through our existing response-mode funding schemes
  • Building a dynamic, multidisciplinary research community in the UK through training, recruitment and by helping people in other fields shift their focus to brain tumour research
  • Developing the infrastructure required to facilitate innovation in the field, and create hubs of expertise

Our top 10 research priorities

Understand the biological basis for clinical trial outcomes, and drive a precision cancer medicine approach to managing brain tumours

Clinical trials for new brain tumour therapies are often based on limited preclinical data, they fail to appropriately select patients for molecularly targeted therapies, and in most cases are predicated on a lack of understanding of whether the therapeutic will be pharmacologically active in the tumour. Consequently the majority of potential brain tumour therapies fail in early-phase clinical trials. In addition there are few investigations into the biological basis for these failures.

There’s a real need to develop novel approaches to understand how to monitor efficient delivery of treatment to the tumour, such as functional imaging, and to monitor treatment response and the development of resistance using minimally invasive approaches, such as circulating tumour DNA and circulating tumour cells. This research theme focuses on the need for more innovative, biologically driven clinical trials that allow for the interrogation of individual responses to inform the underpinning biology of the disease.

Develop and use pre-clinical model systems that recapitulate human brain tumour biology and treatment approaches

Many clinical trials in brain tumours fail where the novel therapy has shown efficacy in the preclinical setting. This failure to translate is often due to the use of inaccurate brain tumour models and/or the failure to test novel therapies in the context of standard of care neurosurgery, radiotherapy and conventional chemotherapy.

There’s a real need to build confidence in preclinical brain tumour studies and the evidence required to progress treatments to clinical trials. This includes the development and validation of pre-clinical brain tumour models, the use of functional imaging to test drug delivery and response, and setting a minimum standard for pre-clinical trial design that recapitulates the clinical setting in which novel treatments will be tested.

Identify and characterise new molecular drivers of brain tumours

Next generation sequencing and other -omics technologies have unmasked the heterogeneity of brain tumours and have revealed some drivers of disease formation and progression. However, to better understand molecular subtypes there is a need to identify and functionally characterise novel molecular drivers of brain tumours including genomic, epigenetic or microenvironmental factors.

There’s a real need to leverage the considerable -omics data available in brain tumours alongside cutting edge neural stem cell and preclinical models to identify novel brain tumour drivers that may guide patient stratification in clinical trials or serve as potential therapeutic targets.

Understand the role of the immune system in brain tumour biology and the development of immunotherapeutic strategies

The brain represents a unique immune environment in the body. Protected from the peripheral immune system by the blood-brain barrier, it boasts its own dedicated defence system led by microglia – specialised immune cells tasked with preventing injury and inflammation. But very little is known about microglia, and how they interact with developing tumours during disease evolution. Moreover, we now know that tumours disrupt the blood-brain barrier leading to an influx of circulating immune cells, whose contribution to disease progression remains unclear. With immunotherapies now revolutionising treatments for many other types of solid tumours, understanding the immune landscape in brain tumours represents a real opportunity to develop similar approaches for people with brain tumours.

Understand the basis and clinical significance of brain tumour heterogeneity

While tumour heterogeneity has been shown to be a feature of brain tumours, we currently have a very incomplete picture of how it occurs, the extent to which it occurs, and crucially, its clinical significance This heterogeneity is likely to drive resistance to treatment and disease recurrence, but the mechanisms driving heterogeneity, and the contribution of treatment itself, need to be explored in detail.

There’s a real need to better understand the functional significance of brain tumour evolution and to consider how these insights might be used to design better treatment strategies. 

Understand the pathophysiology of the blood­–brain barrier (BBB) and its impact on treatment

Tasked with protecting the brain from toxins and other insults, the BBB actively blocks the movement of therapeutic agents and components of the peripheral immune system. But as tumours develop, interactions with the BBB lead to breaches in its integrity, although how this happens, and how it affects the delivery of therapies is unknown.

There’s a real need to characterise the structure, function and regulation of the BBB in brain tumours, and build our understanding of how this differs among brain tumour subtypes. This improved understanding could lead to the development of improved delivery mechanisms for systemic treatments to brain tumours.

Understand the role of the tumour microenvironment in brain tumour development and progression

Insights from other tumour types have shown that the tumour microenvironment can significantly influence tumour behaviour. But there are real gaps in our knowledge about the cellular populations that comprise the unique brain tumour microenvironment, and little understanding of how this ecosystem interacts with the tumour across space and time.

This theme is about understanding how the tumour microenvironment could be used as a basis for new treatment strategies for brain tumour patients.

Understand tumour initiation and progression within a developing brain

Studies aimed at surveying the molecular landscape of paediatric cancers have revealed a striking role for aberrations in neurodevelopmental pathways, particularly epigenetic mechanisms regulating stem cell self-renewal. These findings have led to the hypothesis that paediatric brain tumours are in essence developmental disorders.

While this theory provides a useful conceptual framework to study these disorders, we’re still a long way off from understanding the how the molecular interface between neurodevelopment and tumorigenesis might be weaponised in innovative therapeutic strategies.

Develop and employ state-of-the-art molecular diagnostics for brain tumours

The current classification system for brain tumours is largely based on histology which fails to provide meaningful functional information about the tumour. There’s a real opportunity to fully integrate the wealth of molecular pathology that has emerged from genomic studies into the diagnostic pipeline, allowing for tumours to be classified into biologically meaningful subtypes according to their genetic, epigenetic and transcriptomic features.

A revamped classification system would improve stratification of patients into clinical trials, and provide clinicians with upfront prognostic and/or predictive information to guide individualised treatment decisions. 

Establish whether there are sub-types of paediatric brain tumours that respond to less intensive treatment

Treatment for paediatric brain tumours tends to be aggressive, often leaving children with debilitating side-effects which last into adulthood. There’s a real opportunity to mine the wealth of genetic data from large-scale genomic, epigenetic and transcriptomic studies to identify the biological pathways that distinguish paediatric brain tumours that need to be treated aggressively from those that would respond well to gentler treatments. Pinpointing the molecular hallmarks that define and govern aggressive tumour behaviour will enrich our understanding of disease pathogenesis, reveal new opportunities for therapeutic intervention and significantly improve the quality of life for many survivors.

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