Brain tumours are among the most feared of all forms of cancer. More than two-thirds of adults diagnosed with glioblastoma — the most aggressive type of brain cancer — will die within 2 years of diagnosis.^. Brain cancers are also the most common and most lethal of all paediatric solid tumours. Furthermore, children with these tumours who survive and enter adulthood will often be affected by the long-term consequences of exposing the developing brain to medical interventions, including surgery, radiotherapy and/or chemotherapy. Brain tumours have proved challenging to treat, largely owing to the biological characteristics of these cancers, which often conspire to limit progress. First, by infiltrating one of the body’s most crucial organs, these tumours are often located beyond the reach of even the most skilled neurosurgeon. These tumours are also located behind the blood–brain barrier (BBB) — a system of tight junctions and transport proteins that protect delicate neural tissues from exposure to factors in the general circulation, thus also impeding exposure to systemic chemotherapy^. Furthermore, the unique developmental, genetic, epigenetic and microenvironmental features of the brain frequently render these cancers resistant to conventional and novel treatments alike. These challenges are compounded by the rarity of brain tumours relative to many other forms of cancer, which limits the level of funding and interest from the pharmaceutical industry and attracts a relatively small and fragmented research community.

To begin to address these issues and improve the outcomes of patients with brain tumours, Cancer Research UK (CRUK) convened an international panel of brain cancer researchers with interests in neurobiology, preclinical tumour modelling, genomics, pharmacology, drug discovery and/or development, neuropathology, neurosurgery, imaging, radiotherapy and medical oncology, with the task of identifying the most important challenges that must be overcome if we are to eventually be in the position to cure all patients with a brain tumour. In this Position Paper, we summarize seven key challenges identified by the panel that should serve as the foci for future research and investment. Each of these challenges is worthy of extensive discussion and review, which are beyond the scope of this manuscript. Therefore, we highlight these challenges as a ‘call-to-arms’, summarizing the nature and importance of each challenge rather than providing an exhaustive review of the current level of understanding.

Clinical trials have yet to reveal an effective therapy for most brain tumours. This harsh reality stems, in part, from an incomplete understanding of brain tumour biology and the existence of a disconnect between preclinical drug development and rigorous testing in the clinic. Each element of the brain tumour research pipeline, from basic neurobiology to clinical trials, requires careful scrutiny and increased investment, although the development of an overarching strategy that facilitates and promotes interdisciplinary research is equally important. This strategy would bring an end to the previous ‘siloed’ organization of working practices, in which basic and clinical researchers performed their studies independently and collaborated only when laboratory research was judged to be ready for the clinic or when the laboratory is engaged to understand the reasons why a promising drug failed to achieve the expected level of efficacy in clinical trials. Much deeper, longitudinal collaboration is essential in order to drive progress as rapidly as possible. The level of understanding of the cellular hierarchies and signals that generate and maintain brain activity in the absence of cancer15. Specialized glial cells serve as neural stem cells (NSCs) in both the embryonic and adult brain, in which they reside in neurogenic niches and produce daughter cells that differentiate into neurons, astrocytes and oligodendrocytes. These niches also include supporting cells and secreted factors that are critical for the close regulation of both NSC self-renewal and the early stages of daughter cell differentiation: an intimate relationship between NSCs and blood vessels seems to be especially important in the neurogenic niche16. Several lines of evidence suggest that brain tumours arise within, or are driven by, cells that recapitulate the neurogenic niche. Stem-like cells have been isolated from paediatric and adult brain tumours, and brain tumours have been shown to contain malignant niches that seem to recapitulate the micro-architectural features and signalling properties of the nonmalignant neurogenic niche. Over many decades, research groups studying neurodegeneration and other nonmalignant brain diseases have generated a considerable level of understanding of the biology of the extracellular matrix, of specific brain-resident cellular populations (such as microglia, astrocytes and neurons) and of blood vessels (including those forming the BBB) that comprise the TME. Regardless of the type of immunotherapy that is being developed, several key challenges must be addressed if we are to deploy these agents effectively in the treatment of brain tumours. Once again, a better understanding of tumour biology will be important to the selection of patients who are most likely to benefit from therapies and to improve the level of understanding of treatment-related toxicities. The limited progress made in the treatment of brain tumours relates, in part, to the inaccuracy of preclinical models that have thus far failed to consistently show responses to agents with therapeutic activity in patients. Preclinical drug development pipelines that enable the accurate prediction of effective drugs are especially important for rare cancers, including brain tumours, owing to the low numbers of patients available for participation in clinical research. The so-called omics revolution is providing a comprehensive view of the genomes, epigenomes and transcriptomes of brain tumours; this additional information has enabled the segregation of histologically similar subsets of tumours into clinically and molecularly distinct subgroups. The current classifications of brain tumours are based primarily on microscopic morphology and immunohistochemistry. This approach enables the broad characterization of tumour type and a certain level of prognostication, although it fails to capitalize on the wealth of clinically relevant insights produced by the genomic subtyping of brain tumours. This dilemma is exemplified by medulloblastoma and ependymoma, both of which consist of clinically relevant subtypes with discrete cells of origin, driver mutations and global transcriptomic and epigenomic patterns that are yet to be incorporated into the WHO classification of central nervous system tumours. The past 15 years have witnessed a revolution in our understanding of cancer. The integration of genomic and developmental biology has shown that morphologically similar cancers comprise discrete subtypes, driven by different genetic alterations, which likely arise from distinct cell lineages.