Still A Challenge For Efficient Therapy Of Primary Brain Tumors

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.

Primary brain tumors represent over 100 different tumor types with widely divergent biologies and clinical outcomes, but these neoplasms frequently pose similar challenges to neuro-oncologists. Malignant gliomas are the most common type of primary intrinsic brain tumor in adults and remain extremely lethal. Current standard-of-care therapies for these cancers include surgery, radiation and palliative cytotoxics, which have significant side-effects and limited efficacy.

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.

Malignant primary brain tumors remain an important area of clinical research. Most of these cancers remain incurable despite decades of laboratory and clinical investigation. These tumors are somewhat unique in that they rarely spread outside the central nervous system (CNS). Despite this finding, surgery is not curative even in low-grade (WHO grade 2) tumors because of their infiltrative nature. However, the extent of tumor resection is important as it has prognostic significance in many CNS cancers, and in some tumors, such as medulloblastoma and low-grade glioma, dictates subsequent therapies. Following surgery, radiotherapy remains the cornerstone of most brain tumor treatment regimens. Enhancing tumor targeting with new radiation modalities such as intensity-modulated radiotherapy or alternative radiation sources such as heavy particle therapy (i.e., proton, carbon ion) may improve the risk to benefit ratio in brain tumors.

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Challenge 1: Redesign Research Pipeline

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.

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. Recurrent mutations in brain tumours can also perturb the signalling pathways that regulate brain development, and subgroups of brain tumours have been shown to contain the transcriptomes and epigenomes of their originating parental NSCs that generated these tumours in the mouse brain.

Challenge 2 : Understand the TME

A thorough understanding of the properties and functions of the tumour microenvironment (TME) is required in order to obtain a complete understanding of brain tumour biology and treatment.. 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.

Challenge 3: Develop Preclinical Models

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. Current pipelines are limited in their ability to identify new, more effective treatments of brain tumours for several reasons: they typically involve poorly characterized in vitro systems or subcutaneous tumour xenografts, rather than more accurate orthotopic models of brain tumours; they do not enable the assessment of benefit from new treatments in terms of survival relative to that provided by the existing combinations of neurosurgery, radiotherapy and/or chemotherapy; and finally, they usually lack rigorous characterization of other clinically important features, such as those of the BBB.

Challenge 4: Drugging Complex Cancers

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. However, despite a few notable exceptions, such as inhibitors of mTOR or BRAF in selected patients, genomics has yet to deliver on the promise of identifying new therapeutic targets in patients with brain tumours. Discovering new treatments of brain tumours will require a much deeper level of understanding of the biology of potential drug targets, combined with the application of cutting-edge drug discovery approaches to inhibit these targets.

Challenge 5: Precision Medicine

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.

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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. These data help to explain why cancers once regarded as histologically homogeneous diseases have a discrepant range of characteristics. Improved understanding is also leading to the development of completely new treatment approaches for cancer, such as immunotherapies, and novel ways to test such therapies, such as adaptive trial designs.

British Bio Medicine.

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