Challenges to curing primary brain tumours

Abstract

Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment.

Fig. 1. Challenges to curing primary brain tumours at different stages of tumour development.

The nonmalignant cellular composition of the ventricular–subventricular zone includes neural stem cells that divide and produce transit-amplifying cells. Transit-amplifying cells give rise to migratory neuroblasts. Ependymal cells are also present in the neural stem cell niche. The niche is intimately associated with blood vessels and might also communicate with other cell types, including microglia and astrocytes. Malignant transformation of neural stem cells presumably leads to the premalignant expansion of transit-amplifying cells and migratory neuroblasts as the nonmalignant hierarchy begins to transform. This unregulated hierarchy generates the malignant brain tumour. As these lesions are treated, tumour cells are killed, with the ultimate goal of eventual cure. The blue panels below these cartoons denote the focus of key research questions at each stage, from nonmalignant brain tissue to the development of cancer and remission following successful treatment. The green panels depict how the seven challenges to progress relate to these specific stages of disease development.

Fig. 2. Suggested general outline of a platform approach to designing clinical trials for the assessment of brain tumour therapies.

Patients with different molecular subtypes of a specific type of brain tumour (represented as blue, red and green figures) are enrolled into the trial. Patients in the control group receive the optimal standard of care. New treatments can then be tested as comparators in groups A and B. Following a defined period of treatment, the responses of patients in these groups are compared with those of patients in the control group. Responding patients are represented by bold colours; nonresponding patients are coloured grey. In this example, new treatment B produced a biased favourable response in patients with a single disease subtype (blue figures) relative to the control treatment. No advantage of new treatment A is observed relative to the control treatment. Therefore, in the next phase of the study, the new treatment A group is discontinued, while the new treatment B arm proceeds, with enrichment for patients with tumours of the ‘blue’ subtype. The control group continues with randomized recruitment of patients with all disease subtypes. The success of this approach is dependent upon addressing the key challenges summarized in the thought bubbles emerging at each stage of the trial. Many of these challenges are yet to be addressed in patients with brain tumours.

Fig. 3. The cellular origins of brain tumours.

Brain tumours are thought to arise from a transformed and malignant brain tumour hierarchy generated from transformed neuronal stem cells. Nonmalignant and malignant stem cells in the brain are believed to reside in perivascular niches formed by the blood vessels of the brain. Unaddressed key research questions that could provide a better understanding of brain tumour development and treatment are shown in the thought bubbles.

Fig. 4. The brain tumour microenvironment and treatment.

Brain tumours typically comprise a complex mixture of malignant cells and a great variety of nonmalignant cells. These include immune, vascular and nonmalignant brain cells, all of which are able to communicate with malignant cells and contribute to the development and progression of cancer. These features also form a key part of the response of a tumour to treatment. Key research questions focused on understanding how these elements affect tumour biology and responses to treatment are shown in the thought bubbles. BBB, blood–brain barrier; TAM, tumour-associated macrophage.

Fig. 5. Stratified approaches to the development of new treatments for patients with brain tumours.

Schema depicting pathways for improvements in the preclinical development of new treatments for subsets of patients with brain tumours of distinct molecular and/or clinical subtypes (represented by different colours). This approach should include both patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs) that accurately reflect the principle molecular and/or clinical subtypes. In order to provide the optimal level of clinical relevance, these models must also involve an assessment of responses to conventional combination therapies. These existing treatments could be included in adaptive preclinical trials designed to test novel treatments and inform the ultimate clinical trial design.

Fig. 6. A precision medicine approach to the treatment and management of patients with brain tumours.

Serving as a ‘biological prism’, the use of artificial intelligence (AI) and machine learning (ML) approaches should enable the integration of separate data streams at critical points in the patient journey, providing an unprecedented level of comprehensive decision-making to guide the selection of the most appropriate treatment and support the management of patients with brain tumours. The knowledge gained through the management of each patient should be analysed iteratively over time, enabling constant refinement and improvements in clinical decision-making. ctDNA, circulating tumour DNA.