LOUGHBOROUGH GRAMMAR SCHOOL PLAYING FIELDS | 16TH JULY 2022
Jake McCarthy, a former Loughborough Grammar School pupil, was found to have a large brain tumour whilst on holiday in December 2012. Jake underwent emergency surgery to remove this, but tragically did not regain consciousness, and passed away aged 24. His condition had gone undiagnosed. As a result of overwhelming support from those who knew Jake, his family decided to set-up a Foundation in his memory.
Through fundraising events The Foundation aims to raise money for further research into the treatment of brain tumours as well as improve earlier diagnosis by alerting medical professionals, parents and carers, through clearer guidelines, to identify the signs of those with persistent symptoms to seek urgent further treatment. Catching this condition in its infancy can dramatically increase a patient’s chance of survival.
The main aim is to raise enough money to buy a pioneering piece of equipment, in Jake’s name, to enable surgeons to distinguish brain tumours from healthy tissue and therefore give the patient a much greater chance of survival & leading a normal life.
The Foundation donated vital funds to a research programme about the blood-brain barrier called "The Grand Challenge" (further details below), a unique fundraising partnership between Brain Tumour Research and another leading UK charity, The Dr. Hadwen Trust for three years. Understanding the blood-brain barrier is fundamental in the quest into finding ways to treat brain tumours.
Charity Number – 1151542
DEVELOPING A HIGH THROUGHPUT 3D ALL-HUMAN IN VITRO MODEL OF IN THE BRAIN MICROENVIRONMENT FOR SCREENING RE-PURPOSED AND RE-FORMULATED DRUGS FOR THE TREATMENT OF GLIOBLASTOMA.
Glioblastoma (GBM) encompasses a range of highly malignant, invasive primary brain tumours arising in both children and adults where it is the most common primary brain tumour and carries a mean survival period of some 15 months. The current approach of treating these tumours through a combination of surgery, radiotherapy and DNA alkylating cytotoxic drug therapy has brought only a modest increment in survival and quality of life. The major biological obstacles to successful treatment which have to be overcome are; the propensity of GBM cells to diffusely invade the normal brain, the cellular heterogeneity of GBM reflecting a mixed population of both drug/radiation sensitive and resistant tumour cells and the passage of suitable therapeutics into the brain via the blood brain barrier (BBB) which protects the brain from possible toxic insults but constitutes a barrier to many effective anti-cancer agents. In addition to these factors, the brain, and indeed, the tumour itself have regions which differ markedly in oxygen concentration, a factor which can influence tumour metabolism and the response of tumour cells to various therapeutic agents. Moreover, GBM cells have been shown to communicate with non-neoplastic cells such as microglia (which incredibly can compose up to 50% of the tumour cell population) and astrocytes and these cells can exert a major effect on the tumour’s response to therapy.
We have recently developed a series of dynamic 3D all human in vitro models of the BBB which reflect the properties of the barrier in situ within the brain and can be used for live cell imaging of blood flow reflecting the different diameter blood vessels within the brain. These models, which are constructed of human endothelial cells, human astrocytes, human pericytes, human serum and human proteins, are currently being used in our laboratories to investigate breast and lung cancer metastasis to the brain as well as delivery of therapeutic agents into the tumour but, more importantly, into areas away from the main tumour mass where rogue, invasive GBM cells are protected by the regions of intact BBB in which they are invested.
Over the past few years, we have put together a list of re-purposed drugs (previously used to treat conditions other than brain tumour) and re-formulated drugs (altered so as to enable them to become more ‘bioavailable’ ie permit a greater, or therapeutically appropriate, level of the agent into the brain) which show considerable promise in the treatment of GBM. We are evaluating these using current monolayer and colony/spheroid based assays of GBM cells alone which are tested against non-tumour cells.
Although we can test the delivery of such agents through our state of the art human BBB cellular models we now wish to produce some all human multicellular 3D all human models composed of GBM cells, microglia and non-neoplastic astrocytes for testing our panel of re-purposed and re-formulated drugs under more realistic ‘brain micro-environment’ conditions. In addition, we are able to grow these living 3D systems under different oxygen conditions to reflect he possibility of regional differences in drug response.
The new postdoctoral researcher will join a small team within the University of Portsmouth Brain Tumour Research Centre led by the Head of the Centre who has vast experience in brain tumour invasion studies and with two existing Research Fellows who have experience in 3D human modelling and drug treatment of GBM respectively. The new postdoctoral researcher will be responsible for intellectual molecular/genetic input to the project and will learn/undertake a wide age of techniques from within the Centre’s very well-equipped histology, cellular, molecular, and metabolic laboratories and microscope imaging suite. The project also builds upon an established research collaboration with the University of Cardiff where two joint PhD students are currently working on related projects. Through the research programme we hope to establish new models for pre-clinical testing which will enable us to fast track re-purposed and re-formulated agents into clinical trials for GBM as well as provide a more accurate means to establish drug sensitivity in GBM to both nuclear and mitochondrial targeted therapies.
The Senior Research Associate, postdoctoral researcher will be funded by a grant from the Jake McCarthy Foundation for a period of three years.