Investigating the role of the actin-myosin regulatory protein MRCK in promoting radiation induced infiltration by glioblastoma cells.

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Glioblastoma is one of the most common types of brain tumour. It is a very aggressive form of cancer and is currently incurable despite treatment with surgery, chemotherapy and radiotherapy. One important reason why it is so difficult to treat is because the tumour cells are highly invasive. They spread into the surrounding healthy brain tissue to such an extent that the tumours cannot be completely removed by surgery. Invasion of the normal brain also leads to devastating neurological and cognitive symptoms. Radiotherapy is a crucial part of treatment for patients with glioblastoma, and although it isn't curative, it increases life expectancy for most patients with this disease.

Recently, however, several researchers including ourselves have found that radiotherapy can increase the ability of tumour cells that survive treatment to invade into the brain. This previously unknown effect might be partly responsible for our inability to cure glioblastoma, and for its relentless spread into the healthy brain.

Our research group has recently identified a key molecule, MRCK, that is involved in promoting tumour cell invasion into the brain, and have shown that blocking the activity of MRCK with a specially designed drug can prevent radiotherapy from stimulating this invasion. We now propose to undertake more detailed research that will uncover the complex mechanisms that link radiotherapy with MRCK function and with the invasive behaviour of glioblastoma cells. The results of our research will identify new treatments that could be combined with radiotherapy to improve outcomes for patients with glioblastoma. At the same time we hope to identify molecular 'signatures' that will tell us which patients are most likely to benefit from these new treatments.

Technical Summary

Glioblastoma (GBM) is an aggressive and incurable primary brain tumour that causes severe neurological, cognitive and psychological symptoms. Symptoms are caused and/or exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain, disrupting normal function. Tumour infiltration also renders complete surgical resection unachievable, thus contributing to the high recurrence rates that are observed despite aggressive treatment with radiotherapy and chemotherapy. Targeting the mechanisms that drive invasion has potential to alleviate symptoms and extend survival in GBM patients.
Resent research has indicated that, while radiotherapy extends life expectancy of patients, it can provoke a more infiltrative phenotype in those GBM cells that survive treatment. This may increase the likelihood of recurrence at or beyond the tumour margin, and adversely affect outcomes after recurrence. We have identified myotonic dystrophy kinase-related CDC42- binding kinase (MRCK) as a key mediator of this response, and have shown that a novel MRCK inhibitor can prevent it, both in vitro and in vivo. We now propose to characterise the signalling cascades up- and downstream of MRCK activation to increase our understanding of the mechanisms by which radiotherapy promotes invasion and thus identify new therapeutic targets and predictive biomarkers.
Key to the success of this project will be access to our repertoire of specialised in vitro and in vivo techniques and models that are based on our panel of well characterised primary GBM lines. Specific assets include an ex vivo brain slice model of invasion and an intracranial window model that allows intravital imaging of GBM cells within the brains of live mice. Using these techniques we will characterise the effects of radiotherapy on GBM cell invasion in the most relevant preclinical environment possible, and use our findings to develop and refine new treatments for this cancer of unmet need.

Planned Impact

Academic researchers will be the largest group of beneficiaries from this project. We will foster existing collaborations and well as actively seek out collaborators whose research compliments our own to the mutual benefit of both parties.

Our proposed project will generate a large amount of data that will be made publically available (ProteomeXchange Consortium, PRIDE) for other researches to access to aid their own studies. During the course of this study we expect refinement and expansion of specialised techniques such as the intracranial window model and we will share our protocols and expertise through existing and arising collaborations.

The research project may generate intellectual property which will be managed by the University of Glasgow Research Strategy and Innovation Office or Cancer Research Technology as appropriate. This will ensure the right partners are selected for project development through their network of contacts.

Another impact of this research proposal will be on the researchers directly involved in the project. They will be given the opportunity to develop new specialist skills including training in experimental techniques. Their transferable skills will also be developed by regular oral and written communication of their work, both internally during lab meetings and departmental seminars, and externally at conferences. The implementation of the project plans on a day to day basis will improve their organisational skills and time management planning.

In the medium term we are optimistic that data arising from this research will underpin translation of the MRCK inhibitor (or related compound(s)) to early phase clinical trials, either as single agent treatment for recurrent GBM or as first line treatment in combination with standard of care. If this occurs there will be potential for benefit for GBM patients in terms of the potential for improved clinical outcomes and from the well documented benefits associated with participation in clinical trials. There may also be potential for clinical and IP benefits associated with predictive biomarkers that we aim to develop in parallel with new treatment schedules.
 
Description Tessa Jowell Brain Cancer Mission
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Establishing and exploting a cranial window model of glioblastoma for live imaging in vivo 
Organisation German Cancer Research Center
Department Research Group Experimental Neurooncology
Country Germany 
Sector Public 
PI Contribution Scientific expertise and primary glioblastoma cell lines. Specific expertise on radiation induced invasion of glioblastoma cells.
Collaborator Contribution Expertise and training in a novel cranial window model for studying glioblastoma.
Impact Nothing yet
Start Year 2016
 
Description GBM drug delivery consortium 
Organisation Pharmidex
Country United Kingdom 
Sector Private 
PI Contribution We organised a workshop with the aim of forming a consortium aimed at understanding and improving drug delivery to glioblastoma.
Collaborator Contribution Partners attended the workshop and have been allocated roles in taking forward three workstreams.
Impact Workstreams and partners identified.
Start Year 2019
 
Description GBM drug delivery consortium 
Organisation ReproCELL Europe Ltd
Country United Kingdom 
Sector Private 
PI Contribution We organised a workshop with the aim of forming a consortium aimed at understanding and improving drug delivery to glioblastoma.
Collaborator Contribution Partners attended the workshop and have been allocated roles in taking forward three workstreams.
Impact Workstreams and partners identified.
Start Year 2019
 
Description GBM drug delivery consortium 
Organisation University of Glasgow
Department School of Engineering Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution We organised a workshop with the aim of forming a consortium aimed at understanding and improving drug delivery to glioblastoma.
Collaborator Contribution Partners attended the workshop and have been allocated roles in taking forward three workstreams.
Impact Workstreams and partners identified.
Start Year 2019
 
Description Novel imaging methods for glioblastoma 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed research concept and obtained funding to obtain data on which subsequent studies were based. Appointed Antoine Vallatos as post-doctoral researcher who acquired skills and expertise and has subsequently moved to the University of Edinburgh, thus enhancing the collaboration.
Collaborator Contribution William Holmes and his team at the Glasgow Experimental MRI Centre have developed and applied novel MRI sequences and undertaken data analysis. Gerard Thompson and Adam Waldman at University of Edinburgh have provided clinical radiology expertise and assisted with translation of concepts and techniques to the clinic.
Impact Publication: Multiple boli Arterial Spin Labelling for high signal-to-noise rodent brain imaging. A. Vallatos, L. Gallagher, L. Gilmour, A. J. Chalmers & W. M. Holmes. Magn. Res. Med. 2017. Research funding: Award from Edinburgh Brain Cancer Development Fund £14500, 2017.
Start Year 2015
 
Description Novel imaging methods for glioblastoma 
Organisation University of Glasgow
Department Institute of Neuroscience and Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed research concept and obtained funding to obtain data on which subsequent studies were based. Appointed Antoine Vallatos as post-doctoral researcher who acquired skills and expertise and has subsequently moved to the University of Edinburgh, thus enhancing the collaboration.
Collaborator Contribution William Holmes and his team at the Glasgow Experimental MRI Centre have developed and applied novel MRI sequences and undertaken data analysis. Gerard Thompson and Adam Waldman at University of Edinburgh have provided clinical radiology expertise and assisted with translation of concepts and techniques to the clinic.
Impact Publication: Multiple boli Arterial Spin Labelling for high signal-to-noise rodent brain imaging. A. Vallatos, L. Gallagher, L. Gilmour, A. J. Chalmers & W. M. Holmes. Magn. Res. Med. 2017. Research funding: Award from Edinburgh Brain Cancer Development Fund £14500, 2017.
Start Year 2015
 
Title PYRROLO[2,3-B]PYRIDINE COMPOUNDS AND THEIR USE IN THE TREATMENT OF CANCER 
Description The present application relates to a compound of Formula I, or a salt, hydrate or solvate thereof, as defined herein. The present compounds are found to have pharmacological effects, particularly at MRCK. Further provided are pharmaceutical compositions comprising said compounds. The present invention also relates to the use of these compounds as therapeutic agents, in particular, for the treatment and/or prevention of proliferative diseases, such as cancer. 
IP Reference WO2019034890 
Protection Patent application published
Year Protection Granted 2019
Licensed No
Impact Pending
 
Description Delivered the biannual Royal College of Radiologists Public Lecture in June 2019. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I delivered the biannual Royal College of Radiologists biannual Public Lecture on the topic: Targeting cancer through new radiotherapy-drug combinations. The lecture was attended by 50 people in person with additional remote viewers. The lecture was filmed and posted online where it has been viewed 300 times.
Year(s) Of Engagement Activity 2019
URL https://www.rcr.ac.uk/discover-and-explore/rcr-talks/targeting-cancer-through-new-radiotherapy-drug-...
 
Description Invited speaker National Cancer Research Institute Cancer Conference November 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact 25 minute presentation on new models of glioblastoma for preclinical research
Year(s) Of Engagement Activity 2018
 
Description Presentation at launch meeting of Tessa Jowell Brain Cancer Mission 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation on Clinical Trials and Treatments for the launch event of the Tessa Jowell Brain Cancer Mission
Year(s) Of Engagement Activity 2018