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University of Portsmouth

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The first Centre of Excellence to be funded by Brain Tumour Research was established at the University of Portsmouth under the direction of Prof Geoff Pilkington in 2009.

It is focused on the study of the cellular and molecular mechanisms of brain tumour development, and the identification of new drug targets for the development of new therapies. The Centre is well developed now and has five research groups, each focused on specific topics with brain tumour research.


The Blood-Brain Barrier (BBB): 

The BBB provides a living fortress that protects the brain from potentially harmful chemicals. While this is a positive thing in our everyday lives, the BBB can stop drugs which may be effective in treating brain tumours getting into the brain. In addition, cancers that spread (metastasise) from tumours in other parts of the body and circulate in the blood stream have found ways to infiltrate the brain, thereby allowing then to hide from therapies. 

The team has developed an ‘all human’ three dimensional model of the BBB which is made up of human cells grown in a dish in the lab. This can be used to screen whether existing drugs or novel therapies can enter into the brain. In addition, it is being used to investigate mechanisms for breast and lung cancer cell attachment to the BBB cells and their subsequent infiltration into the brain.

 

Therapeutics: 

Our increased understanding of the differences between normal brain cells and tumour cells has allowed us to identify potential targets in tumour cells at which drugs may act to kill the cells. The therapeutics group is using a number of new experimental approaches, combining current therapies with novel agents. In order to overcome the problems associated with the BBB, the group is also examining the possibility of using molecular tools as a way to facilitate the movement of drugs into the brain. 

One of these is a nanoparticle delivery system. Drugs are attached chemically to a bead which can cross over the membrane and then release the drug so that it can get to the site of the tumour.

In addition to testing existing cancer drugs, the group are also interested in the potential therapeutic benefit of drug repurposing. A number of studies have shown that drugs which have been licensed to treat one condition may have potential to treat brain tumours. Some of the drugs which the group are currently testing include reformulated liquid aspirin, synthetic cannabinoids, Boswellia, Phenformin, Metformin (a type 2 diabetes drug) and tricyclic antidepressants.

 

Paediatric Brain Tumours:

There is a great need to develop novel therapies which are less toxic and tailored for children with brain cancer. The group currently focuses on two types of paediatric tumour – medulloblastoma and paediatric high-grade glioma. The group is working to gain a better understanding of the factors that contribute to the growth of these cancers, as well as testing therapies which may modify the genes responsible for protecting tumour cells from chemotherapies. 

They are also investigating how some medulloblastomas spread to the spine, which significantly worsens the prognosis. With recent medical advances in understanding the molecular pathology involved in driving childhood brain cancers, it is hoped that the identification of specific subgroups of tumour will help identify new therapeutic targets, as well as reduce the toxic effects of the current treatments. 

 

Cellular Energy: 

Normal cell function and metabolism is dependent on many thousands of miniature energy-producing batteries known as mitochondria. Defective mitochondria are a hallmark of cancers, including brain tumours. 

This team has identified numerous, small defects (mutations) in the genetic material of mitochondria in brain tumours. They are investigating how they may contribute to tumour formation and changes in sensitivity to anti-cancer drugs. This research will aid the development of new personalised therapies, improving patient outcomes. 

Specific mutations have already been identified in sub-groups of GBM patients. The group is working to map drug response to some re-purposed therapeutics which modify the activity of the mitochondria. The mitochondrial team works closely with the therapeutics team to assess the response of the cells to different drugs. The concept of treating cancers as ‘one size fits all’ does not work and there is a great need to use a variety of research tools to bring personalised medicine closer to the clinic.

 

Tumour Micro-environment: 

Brain tumours interact closely with normal brain cells – it is as if the cancer cells influence the host cells to help them in their destructive ambition. Additionally, both cell types develop resistance to anti-tumour drugs. There are four current areas here on which the team concentrates: 

  • The development of blood vessels within the tumour to provide it with nutrients (angiogenesis)
  • The spreading of tumour cells within and around the brain
  • The chemical cross-talk between the immune cells in the brain with brain tumour cells
  • The role of a particular cell type – pericytes -  which not only form part of the BBB, but also exist within brain tumours where they play an essential role to regulate tumour cell survival

Publications

Monteiro AR, Hill R, Geoffrey J. Pilkington GJ, Madureira PA. (2017).  The Role of Hypoxia in Glioblastoma Invasion. Cells, 6(4), 45; doi:10.3390/cells6040045

Maherally Z, Fillmore HL, Tan S:L, Tan SF, Jassam SA, Quack FI, Hatherell KE, Pilkington GJ (2017). Real-time acquisition of transendothelial electrical resistance in an all-human, in vitro, 3-dimensional, blood–brain barrier model exemplifies tight-junction integrity. FASEB J. In press doi: 10.1096/fj.201700162R

McGeehan RE, Cockram LA, Littlewood TJ, Keatley K, Eccles DM, An Q (2017). Deep sequencing reveals the mitochondrial DNA variation landscapes of breast-to-brain metastasis blood samples. Mitochondrial DNA (Part A). In press

Jassam SA, Maherally Z, Smith JR, Ashkan K, Roncaroli F, Fillmore HL, Pilkington GJ. (2017). CD15s/CD62E interaction mediates the adhesion of non-small cell lung cancer cells on brain endothelial cells: implications for cerebral metastasis. Int. J. Mol. Sci,.18, 1474; doi:10.3390/ijms18071474 

Stangl S, Foulds GA, Fellinger H, Pilkington GJ, Pockley AG,  Multhoff G. (2017). Immunohistochemical and flow cytometric analysis of intracellular and membrane-bound Hsp70, as a putative biomarker of glioblastoma multiforme, using the cmHsp70.1 monoclonal antibody. Methods in Molecular Biology. In press

Vouri M, Croucher DR, Kennedy SP, An Q, Pilkington GJ, Hafizi S (2016). Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells. Oncogenesis. 5(10):e266.

Rooprai HK, Martin AJ, King AN, Appadu UD, Jones H, Selway RP, Gullan RW, Pilkington G (2016). J. Comparative gene expression profiling of ADAMs, MMPs, TIMPs, EMMPRIN, EGF-R and VEGFA in low grade meningioma. International Journal of Oncology, 49(6):2309-2318

Song Z, Laleve A, Vallières C, McGeehan JE, Lloyd RE, Meunier B (2016). Human mitochondrial cytochrome b variants studied in yeast: not all are silent polymorphisms. Hum Mutat. 37(9):933-41. 

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