Our first Brain Tumour Research Centre was established at the University of Portsmouth in 2010 under the leadership of Professor Geoff Pilkington.
Mitochondria: supplying energy for brain tumours
Mitochondria are small ‘rugby ball’ shaped structures within cells that act like batteries providing energy, but they are abnormal in glioblastoma (GBM) cells compared to normal brain cells.
Mitochondria also have their own DNA called mitochondrial DNA (mtDNA). Portsmouth researchers are investigating which mtDNA features, such as mutations, contribute to the mitochondrial abnormalities observed in glioblastoma, and consequently contribute to malignant progression, resistance to chemotherapy, and ultimately patient survival.
If they can discover which mtDNA features are important then they can be used to place patients into more meaningful and therapeutically targetable groups, as well as to develop new drugs or repurpose existing medications.
This dynamic team led by Rhiannon McGeehan has already discovered numerous interrelated mtDNA factors that are important to the biology of glioblastoma (GBM) and which could be useful as indicators of tumour behaviour and hence prognosis. They are now investigating which of these therapeutic markers can be used as targets to develop better and more novel personalised therapies in the future.
The Blood-Brain Barrier Models
The Research Centre at Portsmouth specialises in developing animal free models of the brain and the blood-brain barrier that are derived from human cells donated by patients who have undergone brain surgery. These are not only designed to reduce the need for using animal models in the laboratory, but also to provide a more accurate indication of how drugs are likely to act in a human brain and hence increase the likelihood of successful clinical trials.
The blood-brain barrier provides a living fortress that protects the brain from potentially harmful chemicals. While this is a positive thing in our everyday lives, it also means that it can stop drugs that may be effective in treating brain tumours from getting into the brain. This isn’t just an issue for people diagnosed with a primary brain tumour, because over 40% cancers can spread (metastasise) into the brain, thereby becoming incurable. The blood-brain barrier is also proving to be a challenge in other neurological diseases such as Parkinson’s disease, Alzheimer’s disease and Multiple Sclerosis and it applies to humans of all ages.
One model invented by the team simulates the blood-brain barrier itself and is used to study the delivery of drugs: for example by developing tiny carriers called ‘nano particles’ in which drugs can be contained. It is also being used to find a means with which to temporarily open the blood-brain barrier for a short period to deliver drugs, before allowing it to close again afterwards. The team also use this model to study how breast cancer and lung cancer is able to metastasise to the brain, in order to identify ways to stop this from happening.
Another model is a 3D structure made of tumour cells growing within a matrix of normal brain cells. The reason that this is important is because if you grow brain cells in a petri dish and put a drug on them you might manage to kill the tumour cells. However if you test the same drug on tumour cells grown amongst normal brain cells, the tumour cells can sometimes persuade normal cells to protect them and so the same drug may be less effective. Therefore these more realistic, human models can save time and money by helping to ensure that only the most effective drugs make it through to clinical trials.
The Portsmouth team tests repurposed drugs (previously used to treat different types of disease), reformulated drugs (altered to enhance their performance or enable them to cross the blood-brain barriers), as well as new drugs as a vital first step towards the development of clinical trials. A big advantage of repurposing and reformulating existing drugs is that when they have an established safety record of use in one patient group, they can be bought into clinical trials for other diseases more quickly than is possible for a new drug.
We are delighted that a report on the importance of repurposed medicines has been published and sent to the Health Minister, Lord O’Shaughnessy. The Brain Tumour Research charity was one of the main stakeholders who helped to put together this report, along with the National Institute for Health and Care Excellence (NICE), the Medicines and Healthcare products Regulatory Agency (MHRA), the Medical Research Council (MRC), Royal Colleges and other research charities. The report was compiled by the Association of Medical Research Charities (AMRC) resulting from an extensive series of meetings and collaboration following a request by the Government in 2015.
The 2018 publication of the Report of the Task and Finish Group on Brain Tumour Research has confirmed that drug repurposing should be a “key research priority” for the brain tumour community. We have always been supportive of attempts to boost repurposing and hope that this report is another step towards a system that encourages innovation and identifies effective treatments as quickly as possible. We need to ensure that drug repurposing adheres to the strict safety measures and laws that are in place to protect patient safety, whilst not being stifled by them, and are at the forefront of both research and campaigning around this issue.
Targeting Autophagy: Cellular Recycling Processes
A key aspect of brain tumour cell metabolism that the team at Portsmouth are investigating is autophagy, a process so important to the way our cells work that the discovery of its mechanism won the Nobel Prize in Physiology and Medicine in 2016.
What is autophagy?
Autophagy, meaning 'eating itself', is one of the basic mechanisms of our cells. This process allows for a controlled breaking down of cell parts that do not work, or are not needed, including nutrients as well as actual physical structures that play a part in how a cell works. These cell parts can then be recycled as required by the body.
The Portsmouth team has identified that autophagy is significantly dysregulated in both adult and paediatric brain tumours, promoting tumour progression and contributing significantly to both intrinsic and acquired resistance to chemotherapy. Importantly, autophagy can be targeted using a range of therapeutic drugs – new, repurposed and reformulated.
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 blood-brain barrier, 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 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.
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
Jassam SA, Maherally Z, Ashkan K, Pilkington GJ, Fillmore HL.(2019) Fucosyltransferase 4 and 7 mediates adhesion of non-small cell lung cancer cells to brain-derived endothelial cells and results in modification of the blood-brain-barrier: in vitro investigation of CD15 and CD15s in lung-to-brain metastasis. J Neurooncol. 2019 Jul;143(3):405-415. doi: 10.1007/s11060-019-03188-x.
Keatley K, Stromei-Cleroux S, Wiltshire T, Rajala N, Burton G, Holt WV, Littlewood DTJ, Briscoe AG, Jung J, Ashkan K, Heales SJ, Pilkington GJ, Meunier B, McGeehan JE, Hargreaves IP, McGeehan RE (2019) Recurrent germ-line mutation in mitochondrial cytochrome b correlates with alterations in complex III properties, growth rate and drug sensitivity in patient-derived glioblastoma cells. Int J Mol Sci. 2019 Jul 9;20(13). pii: E3364. doi: 10.3390/ijms20133364.
Mather RL, Loveson KF, Fillmore HL.(2019) Human Sialic acid O-acetyl esterase (SIAE) - mediated changes in sensitivity to etoposide in a medulloblastoma cell line. Sci Rep. 2019 Jun 13;9(1):8609. doi: 10.1038/s41598-019-44950-5
McGeehan RE, Cockram LA, Littlewood DTJ, Keatley K, Eccles DM, An Q.E (2018) Deep sequencing reveals the mitochondrial DNA variation landscapes of breast-to-brain metastasis blood samples. Mitochondrial DNA A DNA Mapp Seq Anal. 2018 Jul;29(5):703-713. doi: 10.1080/24701394.2017.1350950.
Pullen N, Pickford A, Perry MM, Jaworski D, Loveson K, Arthur D, Holliday J, Van Meter TE, Peckham R, Younas W, Briggs S, MacDonald S, Butterfield T, Constantinou M, Fillmore HLF (2018) Current insights into Matrix metalloproteinases and glioma progression: transcending the degradation boundary. Metalloproteinases in Medicine. 2018:5 13–30 doi: 10.2147/MNM.S105123
Al-Khalidi R, Panicucci C, Cox P, Chira N, Róg J, Young CNJ, McGeehan RE, Ambati K, Ambati J, Zabłocki K, Gazzerro E, Arkle S, Bruno C, Górecki DC.(2018) Zidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonism. Acta Neuropathol Commun. 2018 Apr 11;6(1):27. doi:10.1186/s40478-018-0530-4.
Valvona CJ, Fillmore HL.(2018) Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility. Brain Sci. 2018 Mar 30;8(4):56. doi:10.3390/brainsci8040056.
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. 32:168-182 doi: 10.1096/fj.201700162R
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. 2017 Jul 10;18(7):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 Mol Biol. 2018;1709:307-320. doi: 10.1007/978-1-4939-7477-1_22.
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 GJ (2016). 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 doi: 10.3892/ijo.2016.3739
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. doi:10.1002/humu.23024
Lloyd RE, Keatley K, Littlewood DT, Meunier B, Holt WV, An Q, Higgins SC, Polyzoidis S, Stephenson KF, Ashkan K, Fillmore HL, Pilkington GJ, McGeehan JE.(2015) Identification and functional prediction of mitochondrial complex III and IV mutations associated with glioblastoma. Neuro Oncol. 2015 Jul;17(7):942-52. doi: 10.1093/neuonc/nov020.