Brain tumours kill more children and adults under the age of 40, than any other cancer. Despite all we have learnt about the biological nature of ‘cancer’, the incidence of primary brain tumours has risen at an alarming rate over the past few decades, generally bringing with them a poor prognosis.
The complex biology of a brain tumour, in comparison to other cancers, is a major obstacle in the development of new therapies. Unlike other cancers, a significant disadvantage is the vast array of cell types (cellular heterogeneity) present within the brain, hence the diversity of tumour types (there are around 130 different brain and intracranial tumour types). Although primary brain tumours rarely metastasise to distant organs, one of the major biological features of these tumours is diffuse local cellular invasion (aggressive movement of brain tumours into the normal, healthy adjacent brain).
Our Brain Tumour Research Centre dedicates its research to focusing on the cellular and molecular mechanisms of brain tumour development, and progression of response to therapy. With over five research programmes, it is the group’s goal to work with national and international collaborators to develop novel and multi-targeted therapies for patients diagnosed with brain cancers. While many brain tumour laboratories concentrate on a single tumour type or specific area of research it has been our goal to run programmes of research of a diverse nature. In this context we have formed five research sub-groups:
Paediatric Brain Tumours
In our paediatric brain tumour research group we focus on medulloblastoma and paediatric high grade glioma (DIPG and pGBM). We are currently gaining an understanding of the metabolic mechanisms that contribute to the growth of these cancers as well as testing gene therapy approaches targeting genes responsible for protecting tumour cells from chemotherapies. There is a great need to develop novel therapies that are less toxic and more specific to children with brain cancer. We are also investigating the mechanisms whereby some medulloblastomas spread – either directly along the neuro-axis via the leptomeninges, or via blood vascular channels – to the spine, thereby significantly worsening the prognosis. With recent medical advances in understanding the molecular pathology involved in driving childhood brain cancers, there is a renewed hope for improved stratification schemes that will help identify new therapeutic targets as well as reduce the debilitating toxicity in current treatment.
Normal cell function and metabolism is dependent on many thousand miniature energy-producing batteries known as mitochondria. Defective mitochondria are a hallmark of cancers, including brain tumours. The brain tumour research team at the University of Portsmouth has identified numerous, small defects (mutations) in the mitochondrial DNA of brain tumours, and are investigating how they contribute to altered cancer cell metabolism, tumour formation and sensitivity to anti-cancer drugs. This research will aid the development of new personalised therapies, improving patient outcomes. We have already identified functional mutations in sub-groups of GBM patients and are attempting to map drug response to some of our mitochondrially-acting novel and re-purposed therapeutics using protein modelling (in collaboration with our structural biology/X-ray crystallography colleagues at Portsmouth) and yeast studies (with colleagues in France). The Mitochondrial team works closely with the Therapeutics team in the area of metabolism and hypoxia in drug response. The concept of treating cancers as ‘one size fits all’ does not work and there is a great need to test models to bring personalised medicine closer to the clinic. We, along with our national and international collaborators, want to help bring advances to a place where biological information can help inform clinicians and their teams with therapeutic decisions for patients diagnosed with brain cancer to improve patient outcome.
With the rapid advances in genomic and proteomic information fuelled by the advances in technology and bioinformatics we are in a good position to test novel agents that are safe, inexpensive and effective. Our Therapeutics group aims to target the different aspects of brain tumour behaviour using a multi-modality approach, combining current therapies with novel and established agents, using nanoparticle delivery systems as well as standard medicinal agents. Our experimental therapeutics research group investigates completely new drugs such as novel DNA alkylating agents, putative antibody-mediated therapeutics and combined anti-angiogenesis/anti-invasion approaches obtained from pharmaceutical/biotech companies, in addition to several other repurposed and reformulated agents which have been previously used to treat other medical conditions; these include reformulated liquid aspirin, synthetic cannabinoids, Boswellia, Phenformin, Metformin (a type 2 diabetes drug) and tricyclic antidepressants.
Brain tumours arise in an orchestrated fashion by interacting with host ‘normal’ brain cells – it is as if the cancer cells influence the host cells to help them in their destructive ambition. Additionally, if that is not bad enough, both cell types will adapt to therapies over time (tumour resistance). There are four current areas here on which we concentrate; angiogenesis (and the effects of anti-angiogenesis approaches on downstream tumour biology), invasion (molecular determinants of the various ways tumour cells spread within and around the brain as well as between different organs in the body), immunology (exploring the chemical cross-talk between immune surveillance cells and brain tumour cells) and finally, pericytes (these enigmatic cells not only form part of the BBB, but also exist within brain tumours where they play an essential role in co-option with glioma cells to regulate tumour survival).
Blood Brain Barrier
The blood brain barrier (BBB) can be considered a friend and a foe. As its name implies the BBB is a living fortress that protects the brain from potentially harmful chemicals. While this is a very positive thing in our everyday lives, the BBB is a challenge when trying to get much needed therapies to brains that harbour cancers. In addition, cancers that metastasize from primary tumours and circulate in the blood stream have found ways to infiltrate the brain thereby hiding from therapies. These circulating cells have little understood special abilities to bind the cells of the BBB and enter the brain. We have developed a series of reproducible, dynamic in vitro ‘all human’ three dimensional (3D) models of the BBB for use in high throughput screening of potential therapeutics including nanoparticle-delivered treatment. In addition, we also use them to investigate mechanisms for breast and lung cancer cell attachment to the brain endothelium and subsequent infiltration across the BBB and colonization of the brain, resulting in significantly poorer prognoses.