Dr David Bailey and IOTA Pharmaceuticals 'focused on curing glioblastoma'
Cambridge Biomedical Campus company is part of international WINDOW Consortium working to defeat this deadly brain tumour
It is a highly aggressive form of cancer for which there is no known cure.
Glioblastoma – which claimed the life of Labour peer Dame Tessa Jowell in May – is the most common malignant brain tumour in adults.
Each year, more than 2,500 patients are diagnosed with the disease in the UK and, despite growing knowledge of its genetic causes, the average length of survival is just 12 months with standard treatments.
Dr David Bailey is a man on a mission to do something about it.
He is co-founder of IOTA Pharmaceuticals, based on Cambridge Biomedical Campus.
“We are 100 per cent focused,” he tells the Cambridge Independent. “The goal is not just increased knowledge of disease – IOTA’s objective is to help cure glioblastoma. At the moment, we can’t even give patients the hope of a cure – the end is always the same.
“It cuts off people in the prime of their lives. The window in which we can help each of those affected is terrifyingly short.”
IOTA has just unveiled a new weapon in the battle against this deadly disease. The glioblastoma drug bank is designed to accelerate drug discovery research.
Funded by the Brain Tumour Charity in the UK, the GBM Drug Bank is an open access searchable database.
“The point of the drug bank is to bring together all the compounds that have been tested on glioblastoma and put them in the context of future treatments,” explains Dr Bailey.
“Within the drug bank, we have 500 compounds at the moment that are known to work on different model systems of glioblastoma as well as in clinical trials.
“I think it’s very exciting work. We should be able to extract features of those drugs that enable them to be redesigned – which is what IOTA does – to fit particular clinical situations.
“It links chemical information with biological and looks at the translation of that information into the clinical context.
“It’s a pre-clinical tool primarily but, in the next iteration of the work that we will be doing, we will be comparing drugs going through clinical trials to see how well they perform in various systems of glioblastoma.”
The drug bank, delivered six months ahead of schedule by IOTA, is part of the Dutch-British WINDOW Consortium for glioblastoma drug discovery, named after the short period of time in which patients can be treated. The consortium is being expanded to include other European groups and American researchers as the battle against this intransigent disease steps up.
The causes of glioblastoma are not well understood, although the genetic mutations underlying it in some patients may result from high-dose exposure to ionising radiation or the cumulative effect of carcinogens.
Researchers are also exploring the possibility that DNA defects leading to glioblastoma can be inherited.
A key reason why glioblastoma has proved so difficult to treat so far is its diverse nature, or ‘heterogeneity’.
A form of glioma also known as grade IV astrocytoma, four sub-types of glioblastoma have been identified within the last decade,which vary in their genetic abnormalities and clinical characteristics, or ‘phenotypes’.
“It is thought the stem cell populations in the tumour are capable of changing their phenotypes quite quickly, so if you put a constraint on them by giving them a drug, almost like chameleons, they can change their phenotype and evade the drug,” says Dr Bailey.
“The question which scientists are addressing at the moment is exactly how diverse these heterogeneous cells are. A wide variety of other cancers also show heterogeneity, and developing new strategies for countering drug resistance is central to cancer therapy.
“That is one of the areas that we are trying to address within the WINDOW Consortium.
“We have a network of labs looking at combination therapies to address the issue of drug resistance.”
Standard treatments for patients include surgery to remove as much of the glioblastoma as possible. But the tumours feature threadlike tendrils extending into other parts of the brain, which means a combination of radiotherapy over a period of several weeks with rounds of a chemotherapy drug – temozolomide – is needed to target cells that cannot be removed by surgery.
But Dr Bailey says: “If the disease shows extreme heterogeneity then you will need a portfolio of drugs to treat it.
“Combinations of therapies that the WINDOW Consortium are developing can address that because you can use two, three, four or five drugs and you can also change the point at which you administer them.”
Such combinations are showing some encouraging results in trials.
Last month, for example, US biopharmaceutical firm Abbvie reported that 20 per cent of patients receiving its drug, Deputax-M, in combination with temozolomide survived more than two years, compared to under three per cent of those receiving just temozolomide.
The diversity within the disease means personalised treatments are a key goal for researchers.
“The sub-division of tumour types into several phenotypes is opening the door into personalised treatments. But we’ve got to get the drugs and ligands that can identify the precise lineages that the tumour is developing within each patient and that’s going to take some time,” says Dr Bailey.
Work by Cancer Research UK in Cambridge on advanced scanning techniques – which the Cambridge Independent is continuing to raise money for through its Rapid Scan Appeal – has a key part to play here.
“There are some advanced technologies available in Cambridge to look at the way in which a patient’s tumour presents,” says Dr Bailey. “As the tools and drugs become more precise, we should be able to use non-invasive screening techniques such as MRI to identify the phenotype of the tumour. We can design compounds that can identify features of the glioblastoma.
“If we know what the heterogeneity of the tumour is, we can begin to focus our attention on treating that particular patient’s tumour. This personalised medicine is brought much closer with these sorts of MRI.”
IOTA takes two approaches to developing its drugs.
Like fellow Cambridge company Astex, founded by Dr Harren Jhoti, IOTA employs fragment-based drug discovery, which involves screening for smaller compounds that have a better chance of interacting with their target.
IOTA also uses a process called phenotypic screening.
“When you look at every tissue in the body, it’s composed of millions if not trillions of different cells. When you look at each cell in great detail, the protein complement, the genes that are expressed and the whole mechanism behind how each cell works is subtly different.
“Phenotypic screening looks at those details with the eye of either proteomics or genomics and segregates each individual cell into its functional position within a tissue or the body.
“It enables us to look at the complexity of glioblastoma on a cell-by-cell basis,” explains Dr Bailey.
A key challenge is to get drugs through the blood-brain barrier.
“What we want is a smart drug that you can take as a pill but which has been optimised throughout its development to get into the brain using various chemical tricks. It’s usually intrinsic in the drug structure. It’s another reason we are interested in the drug bank. All those structures tell us something about the way in which the drug will behave,” says Dr Bailey.
Priming the body’s own immune system is an approach that is generating much excitement across oncology.
“At many levels, immunotherapy could be a great success. At the moment, glioblastoma is being a bit incalcitrant. But there have been some interesting developments with CAR T-cells therapy, which look as though they might be able to address individual cell surface receptors which are important in the genesis and continuance of glioblastoma,” says Dr Bailey.
Among the immunotherapies being trialled is a vaccine approach from Northwest Biotherapeutics in America.
DCVax-L is created by taking immune cells from a patient and growing them in the lab into dendritic cells, which co-ordinate immune responses. These are exposed to antigens from a patient’s tumour, collected during surgery, then injected into the bloodstream where they recruit other immune cells to attack the tumour and multiply.
“The key thing there is you’ve got to select a set of antigens that enable you to do this very selectively. Otherwise what you find is these immune cells will hit other brain cells and might cause collateral damage, which you want to avoid. So it’s early days for DCVax and vaccination but initial results are very encouraging and interesting,” says Dr Bailey.
“One of the things we’re very interested in is priming the immune system with drugs because we know you can stimulate immune recognition using compounds. If you can stimulate the immune system as well as beginning to destroy the glioblastoma cells then you’ve got a double whammy.”
While the science is progressing, Dr Bailey admits IOTA’s goal of curing this deadly disease remains a distant one.
“This is not going to be easy. Having said that, we know much more about glioblastoma than we ever have. We know what its phenotype is, how it’s structured and functions and therefore we know what the targets are better than we ever have.”
Calling for seamless collaboration to help combat the disease, he adds: “If we fail, we are failing patients, and each month we fail to give 100 per cent to the search for an effective drug, another swathe of men and women will die. We should feel that urgency.”
More by this authorPaul Brackley