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 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).
The Cellular and Molecular Neuro-Oncology Research Group, which was established at Portsmouth following the relocation of Professor Geoff Pilkington from King’s College London in 2003, dedicates its research to focussing on the cellular and molecular mechanisms of brain tumour development and progression.
Our essential research is funded, primarily, by a consortium of 18 adult and paediatric brain tumour charities, ‘Brain Tumour Research’. Additional funding is by ‘Brain Tumour UK’, ‘Lord Dowding Fund’, ‘Isle of Man Anti-Cancer Association’, and the ‘Biotechnology and Biological Sciences Research Council’. Our research would not be possible if were not for the efforts of dedicated brain tumour charities. Although the survival times of brain tumour sufferers is poor (e.g. the average survival time of glioblastoma sufferers, with current ‘gold standard’ therapies remains to be only 14 months), research into this area reportedly receives less than 0.7% of government funding.
BRAIN TUMOUR RESEARCH AT PORTSMOUTH
Our overall University research in the area of Medicine is configured within the Institute of Biomedical & Biomolecular Sciences, in which there are five Research Divisions: Professor Pilkington heads the Cellular & Molecular Medicine Research Division which is, itself, composed of five research groups each headed by a Professor or Reader and composed of various academic staff members, postdoctoral researchers, PhD students etc.
Our Neuro-oncology Research laboratories boast excellent equipment including a new research histology suite (for paraffin, frozen and resin sectioning and staining), a state-of-the-art microscope imaging suite (with 2 & 3 colour confocal , live cell imaging, TIRF, Epifluorescence, Calcium imaging, live cell intracellular imaging, RAMAN, laser capture microdissection, atomic force, scanning electron microscope and new transmission electron microscopes). We also have excellent tissue culture and molecular biology facilities, ECIS cellular electrophysiology apparatus, flow cytometry, AutoMACS magnetic bead immuno separation, NMR, FTIR, microarray etc etc
Research in our Institute of Biomedical & Biomolecular Sciences (IBBS) submitted under the Subjects Allied to Medicine Unit of Assessment gained a grade 5 in the 2001 Research Assessment Exercise (RAE) and in the recent (December 2008) RAE we were rated 3rd out of approximately 70 University submissions in England and 5th in the UK with 55% of our researchers gaining 4* & 3* International Quality research gradings.
OUR RESEARCH STRATEGY:
In particular, we will try to overcome the diffuse, infiltrative nature of glioma by:
i) Establishing methods of effectively delivering therapeutic substances to invading tumour cells (small molecules, baculovirus & nanoparticles).
ii) Targeting invading tumour cells by interference with molecules which are over-expressed by these cells and used in facilitating their invasion into normal brain (eg CD155, CD44, GD3, Gas6/Axl, TGFβ1).
iii) Triggering mitochondrially-mediated, tumour cell-specific apoptosis (cell death) eg by tricyclic agents and GD3/GD3A deacetylation.
This is of major importance, clinically, as brain tumour cell invasion is urguably the most important biological feature of primary brain tumours which hampers successful therapies.
We will also investigate in depth the potential role in cancer stem cell-like populations of brain tumour cells in initiating (tumour-initiating cells) brain tumours as well as their differentiation-potential, innate therapeutic resistance and role in migration. In particular we will try to establish the biological function of the putative brain tumour stem cell “marker” protein, CD133.
Although the concept of Cancer stem cell-like populations within the brain is generally accepted and thought to provide a major therapeutic obstacle, the role of CD133 as a “good” marker of such populations is under considerable discussion within the scientific world. This is a very “hot” topic in Neuro-oncology and of vital importance to our knowledge of how brain tumours resist therapy and recur.
We are also interested in evaluating the influence of novel “natural products” at a cellular and molecular level on brain tumour cells for any possible therapeutic potential. We have previously studied tangeretin and other plant-derived products and are currently evaluating – in pilot experiments – the ability of three isoforms of Boswellic acid (derived from Frankencense), which we have access to in highly bioavailable forms, to influence glioma progression, possibly via STAT-3 control pathways.
Patients are increasingly searching for new “natural” approaches to help with management of their brain tumours. Internet searches are frequently unreliable and often misleading therefore the more scientific evidence available on such new agents is not of interest to them but also of importance in informing translational medicine approaches. Preliminary evidence suggests that Boswellic acid may not only help to combat brain tumour cells but may also have steroid-like (eg reduction of oedema) properties without the untoward affects of agents such as dexamethasone.
Finally, we are using novel, all-human models of the blood-brain barrier which we have recently established in vitro in concert with an electrical cell impedance system (ECIS) and live cell microscopic imaging to investigate the role of various candidate genes in determining passage through the barrier of various cancer cells (eg lung, breast, melanoma etc) to form secondary cancers within the brain.
The importance of discovering why certain tumours have a high propensity for metastasizing to the brain is of great significance. Around a quarter of all cancers spread to the brain at some stage, following which the prognosis for these patients is dramatically worsened. Once in the brain these multiple cancers are extremely difficult to treat. If we can establish which genes play a regulatory role in determining whether such cancer are likely to spread to the brain will help in preventing this.
In addition to the projects outlined above we are also currently investigating the possible role of insulin-like growth factor binding proteins (IGF-BPs 1, 2 & 7) on brain tumour invasion, the possible role that breakdown products such as DKP, from dietary sweeteners may have in causation or promotion of brain tumour growth and the role played by differential expression of ion channels on glioma cells in tumour progression and biology.