Seven Critical Challenges to Curing Brain Tumours: A Call to Arms from Cancer Research UK
核心洞察
Cancer Research UK convened an international panel identifying seven key challenges that must be overcome to cure brain tumours, published in Nature Reviews Clinical Oncology.
Brain tumours remain among the most lethal cancers, with over two-thirds of glioblastoma (搜索) patients dying within two years of diagnosis and no new effective therapies developed in the past 30 years.
The panel calls for deeper interdisciplinary collaboration, improved preclinical models, better understanding of the blood–brain barrier, and integration of genomic classification into routine diagnosis.
Despite decades of research, the treatment of most childhood and adult brain tumours remains at an impasse, with no new, more effective therapies developed in the past 30 years. More than two-thirds of adults diagnosed with glioblastoma (搜索) — 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, and children who survive often face lifelong neurocognitive and endocrine adverse effects from surgery, radiotherapy, and chemotherapy.
To address these stark realities, Cancer Research UK (CRUK) convened an international panel of brain cancer researchers with expertise spanning neurobiology, preclinical tumour modelling, genomics, pharmacology, drug discovery, neuropathology, neurosurgery, imaging, radiotherapy, and medical oncology. Their mission: to identify the most important challenges that must be overcome to eventually cure all patients with brain tumours. The resulting Position Paper, published in Nature Reviews Clinical Oncology, outlines seven critical challenges that should serve as the foci for future research and investment.
The Seven Challenges: A Framework for Progress
The panel identified challenges spanning the entire brain tumour research pipeline, from basic neurobiology to clinical trial design. Each challenge, the authors emphasize, is worthy of extensive discussion and review beyond the scope of their manuscript; the paper serves instead as a "call-to-arms."
The first challenge involves redesigning the brain tumour research pipeline itself. The panel argues that the current "siloed" organization — in which basic and clinical researchers perform studies independently and collaborate only when laboratory research is judged ready for the clinic — must end. "Much deeper, longitudinal collaboration is essential in order to drive progress as rapidly as possible," the authors write.
Second, the panel highlights the need to leverage insights from neuroscience more effectively. Evidence suggests 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 recurrent mutations can perturb signalling pathways that regulate brain development. Yet only approximately 1% ($260 million) of the $21 billion invested in neuroscience research by the US NIH in 2018 was aimed specifically at brain tumour research.
The Blood–Brain Barrier and the Tumour Microenvironment
The third challenge focuses on understanding the tumour microenvironment (TME). The immune and vascular components of the TME are likely to have particular relevance for improving treatment. Glioblastoma (搜索) cells stimulate tumour-associated macrophages (TAMs) to produce immunosuppressive, tumour-promoting cytokines and enhance apoptosis of T cells. Research conducted over the past decade suggests that "re-educating" TAMs to adopt phenotypes that prevent or inhibit tumour progression might be more effective than depleting all TAM populations.
The fourth challenge addresses the blood–brain barrier (BBB), described as "a major hurdle to the successful treatment of brain tumours." The WNT (搜索) subtype of medulloblastomas, which are highly sensitive to treatment, has been shown to secrete WNT antagonists that render the BBB highly permeable to systemic chemotherapy. Similarly, the therapeutic response of gliomas to temozolomide might be improved by combining this agent with small-molecule inhibitors of WNT signalling.
Preclinical Models and Drug Development
Challenge five concerns the inaccuracy of preclinical models. Current pipelines typically involve poorly characterized in vitro systems or subcutaneous tumour xenografts rather than more accurate orthotopic models. The panel recommends that the community maintains a centralized catalogue of all existing and newly developed preclinical models subjected to rigorous histological, genomic, and imaging evaluations. They also advocate for "mouse hospitals," in which potential new therapies are tested in combination with neurosurgery, fractionated radiotherapy, and conventional chemotherapy.
The sixth challenge involves embracing the complexity of brain tumour biology. The panel emphasizes that "the notion that brain tumours are monogenetic and monoclonal must be dispelled." Comprehensive mapping of genomic evolution before, during, and following treatment — including single-cell sequencing — should be used to better identify and prioritize treatment targets.
Diagnosis, Classification, and Treatment De-escalation
The seventh challenge calls for deploying genomic profiling in routine diagnosis. The successful large-scale methylome subtyping of formalin-fixed, paraffin-embedded tumours has dispelled concerns that genome-wide classification tools might prove impractical. The panel also urges investigation of advanced imaging techniques, such as 13C-hyperpolarized MRI, radiomics, and sequencing of cell-free DNA from plasma and cerebrospinal fluid.
A related priority is reducing treatment intensity where possible. Medulloblastomas provide a clear example: the recognition that almost all patients with the WNT (搜索) subtype are cured has led to ongoing studies testing reduced-intensity radiotherapy. Evidence that WNT-subtype tumours lack a BBB and are therefore remarkably vulnerable to systemic chemotherapy provides an explanation for their curability and opens further options for alternatives to radiation-based treatments.
Immunotherapy: Promise and Challenges
Immunotherapy holds great promise, with a range of approaches in development including vaccines, CAR T cells, and immune-checkpoint inhibitors. However, several key challenges remain. Even imprecise predictors of response to immune-checkpoint inhibition in other cancers, such as tumour mutational burden, remain to be proved in patients with brain tumours. The identity of optimal targets for CAR T cells also remains unclear. Other unanswered questions include the degree to which the BBB will impede access of cellular and molecular immunotherapies to tumours, and whether immunotherapies will synergize with or counteract existing treatments such as temozolomide, steroids, and radiotherapy.
A Call for Cultural Change
The panel emphasizes that greater integration of research disciplines will require a change in current research culture. "The principal metrics used to reward success in most academic environments are focused on competitive activities, such as publication in high-impact journals and the acquisition of grant funding," the authors note. They argue that new reward and promotion structures should be developed that inspire and encourage participation in collaborative academic brain tumour research, akin to the complex, multidisciplinary groups that operate in the pharmaceutical industry.
"The harsh reality is that the current efforts at various universities and aligned clinical environments around the world have failed to adequately improve the understanding and treatment of patients with brain tumours," the panel concludes. Their vision calls for a "much more substantial congregation of experts and infrastructure, focused on the task of curing brain tumours" — a fundamentally different approach from the predominantly poorly structured collaborations that currently exist in most academic centres.