Imperial College London
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The Brain Tumour Research Centre at Imperial College London undertakes a comprehensive array of interlinked laboratory, computational, artificial intelligence and clinical projects. The close collaboration between the research laboratories at Imperial College London and Imperial College Healthcare NHS Trust, particularly Charing Cross Hospital, places them in a strong position to ensure that basic laboratory science is quickly translated into the clinic where patients can benefit from their cutting edge research.
Artificial Intelligence for brain tumour research
The overall theme at Imperial College focuses on a systems biology approach: the development of artificial intelligence, computational and mathematical models of complex biological systems that is focused on helping them to understand how brain tumour cells function, and hence how they can be manipulated to cure this dreadful disease.
This use of artificial intelligence enables them to quickly investigate key pathways and genetic mutations that drive brain tumour growth and identify ways to sensitise tumours to existing therapies (hence making them more effective, potentially at lower doses to reduce side effects).
In their laboratories they explore ways to manipulate metabolic pathways in order to identify new therapies, but also have a strong focus on exploring existing drugs currently used for other diseases that affect cancer pathways and hence could quickly be repurposed for use in brain tumours, as they are ideally placed to test such drugs in preclinical and early phase clinical trials.
Consultant Neurosurgeon Kevin O’Neill leads the team working on Raman Spectroscopy, a method of using light from a non-destructive laser to identify different molecules within a brain tumour.
The aim is to enable instant analysis during surgery to identify the type of brain tumour, highlight which parts are most malignant, and therefore guide the neurosurgeon as to how much of the tumour to remove. For example, they may decide to remove less of a slow-growing form of brain tumour and more of an aggressive tumour, if it is an area of the brain with a risk of side effects likely to affect quality of life. This may also mean that patients could gain an instant diagnosis during their first surgery, rather than having to wait for pathology reports.
Repurposing drugs for glioblastoma multiforme (GBM)
One example of the benefits of the “bench to bedside” working that forms the heart of the Research Centre at Imperial College and Charing Cross Hospital is that the cross-disciplinary team can see if there are any patterns in patients’ clinical history that can give clues as to why some people survive longer than others. The laboratory team then study the metabolic pathways affected by, for example, a certain medication that a group of people may have been taken for other unrelated health issues. This helps them to understand if correlations are more than just coincidence, and if so, how that medication may be able to be manipulated or supported by other drugs to become more effective at increasing survival.
Such an innovative approach to research is made possible by their highly efficient tissue banking service. A clinical trials co-coordinator, Lillie Shahabi, has been funded by the Brain Tumour Research charity to connect clinical information to the brain tumour tissue samples donated by patients during routine biopsy and surgery at Charing Cross Hospital. This means that instead of tissue just being labelled as a particular tumour type it can also be connected to anonymised clinical information such as sex, age, treatment history, symptoms, side effects, other health conditions and medications as well as rate of tumour progression on scans. This enables the research team to gain a much deeper understanding of the implications of what they can glean from studying those tissue samples.
With your support, we can employ more researchers so that more tissue samples can be studied in such depth. At the moment the team focus on GBM tumours, but could easily extend such detailed analysis to brain metastases from melanoma (skin cancer) and the meningioma samples that have already collected in their tissue bank. Meningioma are low-grade (slow growing) brain tumours that cause multiple, progressive symptoms in patients who currently have to endure repeated surgeries and radiotherapy. In fact over 30% patients discussed at multidisciplinary team meetings at hospitals up and down the country have meningiomas, demonstrating how often these patients need to be treated and how much impact a breakthrough in their treatment could make.
Many of these meningioma samples will have an NF2 mutation, so insights into the behaviour and management of this tumour subtype may also be of benefit to young people living with the devastating disease Neurofibromatosis 2. Diagnosed in childhood, this disease carries a prognosis of around 15 years: by their teenage years, these children have usually developed multiple tumours of the nervous system, causing devastating and ultimately life shortening effects.
Arginine depletion clinical trial: plus expansion of research into paediatric and teenager / young adult tumours
The research team led by Dr. Nelofer Syed has a strong track record in studying the nutrients used in brain tumour metabolism, and were the first to identify the fact that arginine (an amino acid, one of the building blocks of protein) is used differently by brain cancer cells compared to healthy brain cells, and that by manipulating the relevant metabolic pathways, arginine levels could be used to influence tumour growth. They have now completed an early stage clinical trial led by Dr Peter Szlosarek at Barts and the London School of Medicine, and are preparing to take these promising results into a larger trial alongside re-irradiation for adult patients with recurrent glioblastoma multiforme (GBM).
With your support we could not only move this trial forward more quickly so that patients can start to be offered this new treatment as soon as possible, but could start to work towards clinical trials for children, teenagers and young adults. In collaboration with Prof Tracy Warr at the University of Wolverhampton, Dr Syed and her team are already exploring the effectiveness of arginine deprivation in the laboratory using cells from paediatric ependymoma (a slow growing form of childhood brain tumour) and GBMs found in patients who are 18 to 20 years old.
A huge challenge in brain tumour research is that there are many subtypes of tumour within each category, so a brain tumour in a younger patient shows distinct differences from a tumour found in an adult, even if they are classified within the same general name or arise from similar cells. Their tumours are therefore likely to respond differently to treatment, and as we move forward into an exciting era of personalised medicine, it is crucial that no patient group is left behind. With your help we can ensure that those working at the Brain Tumour Research Centre at Imperial and Charing Cross include these younger patient groups in their research, moving all age groups closer to a cure.
Ketogenic Diet research
The laboratory team led by Dr. Nelofer Syed are part of a global network of researchers investigating this long established medical diet, originally invented for the control of epilepsy at the Mayo Clinic in the 1920s and still used throughout the NHS for children whose seizures are unable to be controlled by medication alone. Dr. Syed’s work is starting to shed light on how this high fat, low carbohydrate, adequate protein diet affects the metabolism of brain tumour cells: in other words, how it changes the way that brain tumours use nutrients to provide the energy that they need in order to grow.
Working in collaboration with experts across the UK, a clinical trial protocol is close to completion and we now need extra funds to move this forwards as quickly as possible. Researchers in the US have shown that when the ketogenic diet is used alongside radiotherapy in a mouse model, brain tumours disappear from the brain and, amazingly, stay away even when the mice are then moved back onto a normal diet. There is obviously a big difference between obtaining this result in a laboratory and in humans, but research in other laboratories (including those at Imperial College) also indicates that the ketogenic diet may make surgery, chemotherapy and radiotherapy work more effectively so it is vital that we explore this possibility.
To date, the laboratory work has focused on adult brain tumours, but the team at Imperial College now has the opportunity to collaborate with a research team at Phoenix Children’s Hospital, Arizona. This means that they could expand their research to include the most deadly of childhood brain tumours, Diffuse Intrinsic Pontine Glioma (DIPG). The prognosis for children diagnosed with this dreadful disease is currently only nine to twelve months, during which time they endure radiotherapy and chemotherapy that may extend their life but can not save them.
Improving the effectiveness of brain tumour drugs
An important aspect of the laboratory work at Imperial College is to modify existing therapies to make them more effective, so that they can be used at lower doses to reduce side effects whilst still producing the maximum survival benefit to patients. For example, through a collaboration with chemists in Greece they can now stabilise molecules of an existing chemotherapy drug used for brain tumour patients (Temozolomide) so that instead of the of the drug being active for two hours, it can be extended to three days, whilst also proving to be more effective at crossing the blood-brain barrier and hence reaching the tumour more effectively.
This exciting discovery now needs to move into early stage clinical trials and we urgently need to recruit new staff to make this possible.
Renziehausen A, Tsiailanis AD, Perryman R, Stylos EK, Chatzigiannis C, O'Neill K, Crook T, Tzakos AG, Syed N (2019) Encapsulation of temozolomide in a calixarene nanocapsule improves its stability and enhances its therapeutic efficacy against glioblastoma. Mol Cancer Ther. 2019 Jun 18. pii: molcanther.1250.2018. doi: 10.1158/1535-7163.MCT-18-1250.
Atkinson A, Renziehausen A, Wang H, Lo Nigro C, Lattanzio L, Merlano M, Rao B, Weir L, Evans A, Matin R, Harwood C, Szlosarek P, Pickering JG, Fleming C, Sim VR, Li S, Vasta JT, Raines RT, Boniol M, Thompson A, Proby C, Crook T, Syed N.(2019) The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma. J Invest Dermatol. 2019 May;139(5):1118-1126. doi: 10.1016/j.jid.2018.10.038.
Renziehausen A, Wang H, Rao B, Weir L, Nigro CL, Lattanzio L, Merlano M, Vega-Rioja A, Del Carmen Fernandez-Carranco M, Hajji N, Matin R, Harwood C, Li S, Sim VR, O'Neill K, Evans A, Thompson A, Szlosarek P, Fleming C, Stebbing J, Proby C, Tzakos AG, Syed N, Crook T.(2019) The Renin Angiotensin System (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention.Oncogene. 2019 Mar;38(13):2320-2336. doi: 10.1038/s41388-018-0563-y.
Chatziathanasiadou MV, Stylos EK, Giannopoulou E, Spyridaki MH, Briasoulis E, Kalofonos HP, Crook T, Syed N, Sivolapenko GB, Tzakos AG. (2019) Development of a validated LC-MS/MS method for the in vitro and in vivo quantitation of sunitinib in glioblastoma cells and cancer patients. J Pharm Biomed Anal. 2019 Feb 5;164:690-697. doi: 10.1016/j.jpba.2018.11.030.
El Mubarak MA, Stylos EK, Chatziathanasiadou MV, Danika C, Alexiou GA, Tsekeris P, Renziehausen A, Crook T, Syed N, Sivolapenko GB, Tzakos AG. (2019) Development and validation of simple step protein precipitation UHPLC-MS/MS methods for quantitation of temozolomide in patient plasma samples J Pharm Biomed Anal. 2019 Jan 5;162:164-170. doi: 10.1016/j.jpba.2018.09.019
Przystal JM, Hajji N, Khozoie C, Renziehausen A, Zeng Q, Abaitua F, Hajitou A, Suwan K, Want E, Bomalaski J, Szlosarek P, O'Neill K, Crook T, Syed N. (2018) Efficacy of arginine depletion by ADI-PEG20 in an intracranial model of GBM. Cell Death Dis. 2018 Dec 13;9(12):1192. doi: 10.1038/s41419-018-1195-4.
Vaqas B, Cameron SJ, Alexander J, O’Neill KS, Takats Z. (2018) Book chapter: The use of REIMS/iKnife for clinical molecular phenotyping in Handbook of Metabolic Phenotyping, 1st Edition (Edited by John C. Lindon, Imperial College London) ISBN 9780128122938, Publication date 1st September 2018, Elsevier
Pankratova S, Klingelhofer J, Dmytriyeva O, Owczarek S, Renziehausen A, Syed N, Porter AE, Dexter DT, Kiryushko D. (2018) The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival. Theranostics. 2018 Jul 1;8(14):3977-3990. doi: 10.7150/thno.22274.
Hajji N, Garcia-Dominguez, Hontecillas-Prieto L, O’Neill K, de Alava E, Syed N. (2018) The bitter side of epigenetics: variability and resistance to chemotherapy. Epigenomics. 2018 Jun 22. doi: 10.2217/epi-2017-0112
Hall PE, Lewis R, Syed N, Shaffer R, Evanson J, Ellis S, Williams M, Feng X, Johnston A, Thomson J, Harris F, Jena R, Matys T, Jefferies S, Smith K, Wu B-W, Bomalaski J, Crook T, O’Neill K, Paraskevopoulos D, Khadeir R, Sheaff MT, Pacey S, Plowman PN, and Szlosarek PW (2018) A Phase I expansion study of pegargiminase, cisplatin and pemetrexed in argininosuccinate synthetase 1-negative recurrent high-grade gliomas. Journal of Clinical Oncology. 36, no. 15_suppl Published online June 01, 2018 DOI: 10.1200/JCO.2018.36.15_suppl.e1408
Gray E, Butler HJ, Board R, Brennan PM, Chalmers AJ, Dawson T, Goodden J, Hamilton W, Hegarty MG, James A, Jenkinson MD, Kernick D, Lekka E, Livermore LJ, Mills SJ, O'Neill K, Palmer DS, Vaqas B, Baker MJ.(2018) Health economic evaluation of a serum-based blood test for brain tumour diagnosis: exploration of two clinical scenarios. BMJ Open. 2018 May 24;8(5):e017593. doi: 10.1136/bmjopen-2017-017593.
Mörén L, Perryman R, Crook T, Langer JK, Oneill K, Syed N, Antti H.(2018) Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM. BMC Cancer. 2018 Feb 8;18(1):167. doi: 10.1186/s12885-018-4040-3.
Williams M, Cross H, Jenkinson MD, Martin K, Wood S, Scheck AC, Syed N, O’Neill K, Sheen KJ, Zabilowicz C, Breen K, Oliver K, Williams E, Johnson M, Fulcher W (2018) The ketogenic diet for patients with brain tumours: Two parallel randomised trials. Neuro-Oncology. Volume 20, Issue suppl_1, 31 January 2018
Grech-Sollars M, Vaqas B, Thompson G, Barwick T, Honeyfield L, O'Neill K, Waldman AD (2017) An MRS- and PET-guided biopsy tool for intraoperative neuronavigational systems. J Neurosurg. 2017 Mar 17:1-7 DOI: 10.3171/2016.7.JNS16106
Camp SJ, Apostolopoulos V, Raptopoulos V, Mehta A, O'Neill K, Awad M, Vaqas B, Peterson D, Roncaroli F, Nandi D.(2017) Objective image analysis of real-time three-dimensional intraoperative ultrasound for intrinsic brain tumour surgery. J Ther Ultrasound. 2017 Feb 16;5:2. doi: 10.1186/s40349-017-0084-0.
Bassiri K, Ferluga S, Sharma V, Syed N, Adams CL, Lasonder E, Hanemann CO (2017) Global Proteome and Phospho-proteome Analysis of Merlin-deficient Meningiomaand Schwannoma Identifies PDLIM2 as a Novel Therapeutic Target EBioMedicine. 2017 Feb;16:76-86. doi: 10.1016/j.ebiom.2017.01.020.
Woolf EC, Syed N, Scheck AC.(2016) Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy. Front Mol Neurosci. 2016 Nov 16;9:122. doi: 10.3389/fnmol.2016.00122.
Nevedomskaya E, Perryman R, Solanki S, Syed N, Mayboroda OA, Keun HC. (2016) A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity. J Proteome Res. 2016 Jan 4;15(1):280-90. doi: 10.1021/acs.jproteome.5b00793.