University of Plymouth
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The Plymouth team, led by Prof Oliver Hanemann, has a world-leading track record in researching low-grade brain tumours occurring in teenagers and adults. By identifying and understanding the mechanism that makes a cell become cancerous, the team can explore ways to halt or reverse them.
The team is focusing on meningiomas and schwannomas, which are two common brain tumours that form both spontaneously and when associated with an inherited condition -- neurofibromatosis 2. At present, there are no drugs approved to treat either of these types of tumour. Patients have only surgery and radiotherapy as their treatment options and these are not always effective, or even possible, depending on the location of the tumour within the brain.
The researchers have a particular focus on ‘personalised medicine'. Not all patients respond to treatment with existing medications. This is largely due to the massive diversity between tumours, the presence of many cells within a tumour expressing different proteins (that dictate how a person will respond) or how likely their tumour is to become resistant to a particular drug. The research programme aims to identify particular subgroups of patients which will respond to specific treatments which will be more effective.
Using a technique called mass spectrometry, the researchers can analyse brain tumour samples which have been obtained from patients following surgery. They analyse the cellular ‘proteomic signature’, which identifies the proteins that are expressed differently in cancer cells when compared with normal cells. This information to can be used to identify potential target targets which may be responsive to drugs already available.
These can then be tested on tumour cells in the laboratory, as a pre-clinical assessment of their effectiveness, and quickly form the basis of early stage clinical trials.
The researchers can also take brain tumours known to have specific genetic mutations, define their proteomic signatures associated with these mutations and again compare them with those in normal cells. This will allow the researchers, in the longer term, to look directly for specific features in each patient’s tumour that will help them choose the best personalised treatment option.
Their most recent project is looking at patient blood samples to identify biomarkers. These are factors present in the blood which may change in people with specific types of tumour. They can help us to decide on the best course of action based on the fingerprint of the tumour. The advantage of this technique is that it is much less invasive than a tumour biopsy.
Other research groups in the centre work on low-grade astrocytoma. Although great efforts have been made in past decades to understand how glioma initiates and progress to malignancy, the mechanism of malignant progression of low-grade gliomas is still largely unknown. A mutation in the IDH1 gene is a key event in tumour cell development, although it insufficient on its own.
Other pathways within the cell play a key role and one of these is called Notch signalling. This is a biochemical pathway associated with early brain cell development and it is reactivated in low-grade tumours. There is evidence showing that Notch signaling stimulates cancer stem cells, which are involved in tumour initiation, as well as mediating tumour recurrence and also the development of temozolomide-resistance. Prof Ji Liang’s group is working to further understand how this pathway is involved in tumour development, malignant progression, or drug sensitivity of low-grade gliomas and how it may serve as a new therapeutic target.
Dr Claudia Barros has screened tumours for genes involved in brain tumour initiation and has identified some which may play a key role in the process. She is using the highly-informative drosophila fruit fly model to characterise these genes which may be key in low-grade gliomas and then translating findings from the fly model into human tumours.
The analysis of proteins expressed in low-grade tumours showed an increase in the levels of factors called cytokines in low-grade, NF2 mutated tumours. These are associated with the immune response in the area of the tumour. Dr David Parkinson will work on targeting macrophages, which are an important part of the inflammatory reaction within the brain, in schwannoma tumours.
Previous research has shown that human schwannoma tumours show large numbers of macrophages within the tumours. However, their role in schwannoma tumours with altered expression of the Merlin gene has not been tested. Tumour infiltrating cells will particularly be characterised in meningioma as they are thought to play a particular role, although very little research has been carried out in this area.
A key innovation which has been developed within the Centre is a fast track drug screening programme - testing new drugs in human cells grown in the lab. This information will be used for the development of innovative early-stage clinical trials in order to make new drug therapies available to patients both safely and faster.
The team's long-term vision is that they will be able to characterise each tumour into subcategories, giving patients a higher chance of responding to a particular drug. They aim to use this process within the next few years using a modern trial design.
"Our aim is to find new biomarkers and drugs for low grade tumours and try to get these into the clinic as soon as possible.” – Professor Oliver Hanemann, Associate Dean Research and Research Lead for Brain Tumour, Plymouth University
Stepanova DS, Semenova G, Kuo YM, Andrews AJ, Ammoun S, Hanemann CO, Chernoff J. (2017). An Essential Role for the Tumour-Suppressor Merlin in Regulating Fatty Acid Synthesis. Cancer Res. 77(18):5026-5038. doi: 10.1158/0008-5472.CAN-16-2834.
Provenzano L, Ryan Y, Hilton DA, Lyons-Rimmer J, Dave F, Maze EA, Adams CL, Rigby-Jones R, Ammoun S & Hanemann CO (2017). Cellular prion protein (PrPC) in the development of Merlin-deficient tumours. Oncogene 36(44):6132-6142. doi:10.1038/onc.2017.200
Cooper J, Xu Q, Zhou L, Pavlovic M, Ojeda V, Moulick K, de Stanchina E, Poirier JT. Zauderer M, Rudin CM, Karajannis MA, Hanemann CO, Giancotti FG. (2017). Combined inhibition of NEDD8-activating enzyme and mTOR suppresses NF2 loss–driven tumorigenesis. Mol Cancer Ther 16(8):1693-1704. doi: 10.1158/1535-7163.MCT-16-0821
Bassiri K, Ferluga S, Sharma V, Syed N, Adams CL, Lasonder E, Hanemann CO (2017). Global proteome and phospho-proteome analysis of Merlin-deficient meningioma and schwannoma Identifies PDLIM2 as a Novel Therapeutic Target. EBioMedicine. 2017 Feb;16:76-86.
Zhou L, Lyons-Rimmer J, Ammoun S, Müller J, Lasonder J, Sharma V, Ercolano E, Hilton D, Taiwo I, Barczyk M Hanemann CO (2016) The scaffold protein KSR1, a novel therapeutic target for the treatment of merlin deficient tumours, Oncogene, 35(26):3443-53.
Schulz A, Buettner R, Hagel C, Baader SL, Kluwe L, Salamon J, Mautner VF, Mindos T, Parkinson DB, Gehlhausen JR, Clapp DW, Morrison H (2016) The importance of nerve microenvironment for schwannoma development, Acta Neuropathologica 132,(2), 289–307
Hanemann CO, Blakeley JO, Nunes FP, Robertson K, Stemmer-Rachamimov A, Mautner V, Kurtz A, Ferguson M, Widemann BC, Plotkin SR, Evans DG, Ferner R, Carroll SL, Korf B, Wolkenstein P, Knight P (2016). Current status and recommendations for biomarkers in Neurofibromatosis 1, Neurofibromatosis 2 and schwannomatosis, Neurology, 87(7 Suppl 1):S40-8.