Drug repurposing – the development of potential new therapies

Following trials to assess their safety and efficacy, drugs are usually approved for use in the clinic by the regulatory authorities for the treatment of a specific disease. This is referred to as the drug “license” – the condition for which it can be prescribed. However, an increasing number of studies have shown that drugs which have been approved for one condition may be effective in the treatment of others. This is referred to as drug repurposing. The advantage of this approach is that the drugs will have passed the initial safety stage of drug development so that they can immediately go into clinical trials.


How can we identify these drugs?

A drug acts by influencing certain chemical reactions, or pathways, within a cell. This usually influences how the cell works. In the brain, for example, it may cause nerve cells to produce chemicals that are associated with the transmission of electrical activities between cells. However, in certain circumstances, modification of these pathways may damage or even kill cells. This is what we want to harness in order to destroy the cells within brain tumours. In addition to drugs that are in use for other conditions, there may be others which had been tested in trials for another condition, but failed to show any significant clinical benefit for that specific illness. It is worthwhile testing some of these based on our knowledge of how they work. Brain tumour cells grown in a dish in the laboratory can be used to carry out initial tests to determine whether the drug will kill the cells. We can also grow normal nerve cells in the lab. This is important because we want the drug to target tumour cells without harming the other brain cells.


Are there other factors that we should consider?

One of the challenges associated with treating brain tumours is the ability of the drug to get into the brain. The blood brain barrier – which is a membrane that surrounds the brain – prevents many drugs from entering the brain. But Prof Geoff Pilkington at the Brain Tumour Research centre at the University of Portsmouth has developed a model of the barrier. So as well as being able to test whether the drugs may be effective to treat tumours, we can also assess their potential ability to enter into the brain.


Is there any evidence of this for the treatment of brain tumours?

Research funded by Brain Tumour Research has demonstrated that a specific formulation of aspirin may enter into the brain and could be effective for the treatment of glioblastoma . This research is still at an early stage, and will need further studies before clinical trials can begin. However, the results to date are promising. Our research centre at Portsmouth have also demonstrated that an anti-depressant drug, clomipramine, may also be able to kill tumours. However, this drug may have harmful side effects so the researchers are trying to understand the mechanisms by which it may kill cells and whether there may be other drugs which can have the same effect on the cells without the side effects. Studies have also been carried out on the anti-epileptic drug sodium valproate with mixed results. While there is no indication that people who take the drug over a long period of time have a lower  incidence of brain tumours, there is some evidence that it may act to increase the efficacy of temozolomide, which is the primary drug use to treat brain tumours.


So, what is the next stage?

The UK Department of Health is leading a new initiative to develop guidelines for the repurposing of drugs. This is a key component of Brain Tumour Research’s manifesto and we will be working very closely with this group to develop guidelines to get potential repurposed drugs into clinical trials as quickly as possible. We will also be highlighting this as a priority for the research centres





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The Valley of Death -some problems associated with new drug development

A paper which was recently published in the New England Journal of Medicine discussed the design of clinical trials for the testing of new anti-cancer drugs. It suggested that the introduction of a more streamlined format may help to overcome some of the problems associated with existing studies which can have quite rigid design formats in accordance with the regulatory authority requirements.

Hoe does this relate to the treatment of brain tumours?

Before we can think about the design of future clinical trials, we first need to develop new drugs. At a meeting that I recently attended, I spoke with a number of drug companies who specialise in the development of anti-cancer drugs. None of them appear to have any therapies in the pipeline for the treatment of brain tumours. The problem arises because very few studies have never been performed to determine whether some of the potentially suitable drugs would enter the brain.

What prevents drugs entering the brain?

The brain is a very delicate organ and is surrounded by a covering membrane called the blood-brain barrier. While this prevents toxic agents from entering the brain, it also provides an obstacle for drugs which could potentially treat brain tumours. So, while many of the drugs currently under development may not be suitable for the treatment of brain tumours, research needs to be carried out to identify the small number which may enter the brain and be useful for the treatment of tumours.

What role can charities such as Brain Tumour Research play?

In the early stages of drug development, there is a phase which is commonly referred to as the “valley of death“. This represents the period between a preclinical trial (in cells or animal models) which shows that the drug may be effective and the subsequent clinical trials to assess its safety and efficacy in humans. For the development of drugs to treat brain tumours, the valley of death could be considered as assessing whether the drug will cross the blood brain barrier.

So, this is where research charities can play a key role. By acting as a bridge across the “Valley”, they can help to assess whether a drug will enter the brain, as well as providing evidence that the drug is effective in killing brain cells. At the Brain Tumour Research Centre of Excellence in Portsmouth, Prof Geoff Pilkington has developed a model of the blood brain barrier which can be used to provide initial evidence of the potential for the drug to enter the brain. If the drug passes this initial test, it can be assessed in other model systems in order to provide evidence that it may appropriate to commence clinical trials. In addition to the pharmaceutical industry, the National Institute for Health Research, which is the research arm of the NHS, can provide support for carrying out clinical trials.

What happens next?

The key advantage to using existing drugs for the treatment of brain tumours is that these drugs are likely to be already in use in the clinic for other cancers. Therefore, early stage trials which assess the safety of the drug may not be required. The drug can be then be rapidly assessed for its effectiveness in the treatment of brain tumours using the appropriate clinical trial format. This will ensure that, if effective, the drugs can be used in the clinic as soon as possible.

So, working together, charities such as Brain Tumour Research can work collaboratively with the pharmaceutical industry and the clinical trials units within the NHS can help to bring us forward to the stage when there will be the potential introduction of new and more effective treatments. The charities can play a key role in catalysing the development of this process due to their close interaction with patients who will be the best beneficiaries of the new therapies.

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Do mobile phones cause brain tumours?

There have been a number of reports which suggest that radiofrequency electromagnetic fields (REF), which are generated by mobile and cordless phones, may increase the risk of developing brain tumours. However, the evidence is often contradictory making it a difficult to draw a definite conclusion.


What is the current evidence?

A recent research paper from a group in Australia examined a potential relationship and concluded that the general increase in brain tumours which has been observed in over the last 20 years can probably be attributed to improved diagnostic techniques and is unlikely to be associated with an increase in mobile phone use. However, a group in Sweden suggest that some of the cancer registries which have been used previously may be unreliable and that they have failed to detect all cases of brain tumours, so the effect of REF cannot be ruled out. We also don’t know how the phones might stimulate tumour development. Although the phones give off microwave radiation, this has millions of times less energy than, say, an X-ray and is therefore unlikely to be powerful enough to damage our DNA to make cells cancerous. But we can’t discount the fact that there may be other ways by which REF could be having an effect.


How can we study the potential of radiofrequency electromagnetic fields in the generation of rain tumours?

The key research challenge is to identify the appropriate information that is available and determine how this could be used to assess any causal relationship between REF and brain tumours. We know that there is a great variation between the time between tumour initiation and the development of symptoms. This can depend on both the tumour type and the area of the brain in which it is located. In some cases, the tumour may remain dormant for a number of years before symptoms appear. If we can’t tell accurately when the tumor initially developed, it is extremely difficult to try to identify specific causes. So we need to carry out “population studies” and look for trends in disease incidence and general lifestyle changes. However, the results that have been obtained from a number of studies in this area are inconsistent and are very much determined by the data that is available and how it is analysed.


What is the current position?

The International Agency for Research into Cancer, which is part of the World Health Organisation, convened a panel of experts in 2011 to examine the evidence which was available at the time. They concluded that REF should be classified as a Group 2B carcinogen, which means that it “possibly” causes cancer in humans. While there may be an association, that the available evidence did not allow for a definitive conclusion to be drawn. This is the same category as lead, engine exhaust, DDT, and jet fuel. However, others suggest that REF should be reclassified as Group 2A (probable̓ human carcinogen). WHO is currently conducting a formal risk assessment of all studied health outcomes from radiofrequency fields exposure and a report is due to be published later this year.


What should we do?

The UK Department of Health has published a leaflet which recommends that children under 16 should only use mobile phones for short essential calls as children have been found to absorb 60% more radiation into the head than adults when they use a phone  Mobile phone user manuals warn customers to keep the phone away from the body when turned on and not to hold it right up to the head


Brain Tumour Research recommends that mobile phones and wireless-free telephone receivers should be used with care and remote speakers or microphones should be used whenever possible.



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Immunotherapy for brain tumours

A piece of research, published in the journal “Science” got widespread coverage on the BBC. This described the potential personalization of immunotherapy for people with different types of cancer which may help us to be more accurate in the targeting of new therapies.


What is immunotherapy?

When a new substance enters the body, it is seen as foreign by the immune system which immediately goes to work to get rid of it. There are two components involved. Firstly, the body produces antibodies. These are designed to attach to the substance itself. This then activates the second component of the immune response which are the white blood cells. These attach to the antibodies in order to eat up and destroy the foreign substance. The production of the antibodies spark off the increase in the scavenging white blood cells and target them to the specific area.


Can this be used in cancer?

Cancer cells are different to normal cells. In the brain, for examole, specialist cells are involved in very complex functions including maintenance of the structure and the transmission of electric signals. When these become cancer cells, they can no longer play this role. They essentially become primitive, form a clump of cells together and then start to divide and multiply. In some cases, a group of cells will split of and spread to other parts of the brain or even other parts of the body. This is a process called metastasis. Unfortunately, they trick the immune system into thinking that they are normal cells and they do not spark off an immune response. This is despite the fact that they do contain factors on the surface of the cells. referred to as antigens, that have subtle differences to those present on normal cells. So we can try to harness this difference to spark off an immune response. There are three ways in which this can be achieved:

  • Generate artificial antibodies directed against these altered proteins so that they can bind and attract white blood cells into the area. These are called monoclonal antibodies are made outside the body and infused back into the patient.
  • Use large doses of one of the proteins on the surface of the cancer cells, which have been produced artificially, to stimulate the body to produce its own antibodies and spark off the immune response. This is a vaccination approach.
  • Artificially generate white blood cells to recognize the cancer cells. This involves taking white blood cells from the patient, exposing them to one or more of the factors on the surface on the cancer cells so that when they are infused back into the body, they will attach directly to the cancer cells and kill them. A novel approach is currently under development to manufacture these using techniques which modify the genetic material of the cells.


What is novel about the new approach?

Normally, the therapy targets one or more protein that is expressed on most of the cancer cells in a specific tissue. However, not all of the cells in a particular tumour type will have this protein and will not respond to the immune therapy. In the new approach, the researchers will look at the genes of the tumour cells and generate an immune response that is specific for the individual tumour. So, we can effectively produce a new medicine that will be specific for that person’s tumour


Can these be used for brain tumours?

The major obstacle for the treatment of brain tumours is the blood brain barrier. This membrane, which surrounds the brain, prevents drugs, proteins and cells from getting into the brain to kill cancer cells. However, more recent studies have suggested that this may not be entirely the case for some immunotherapies. The story which appeared in The Sun earlier this week described an immune based therapy that used two treatments in combination.

  • Avastin (bevacuizumab) is an antibody which recognizes a specific protein on tumour cells. This has used previously for the treatment of other cancers such as lung, colon and rectum. However, there is some evidence from a small clinical trial that it may have some benefit for people with brain tumours. Although an initial clinical trial for glioblastoma multiforme (GBM) did not show an overall benefit, it was found a subset of the patients in the trial actually showed some benefit.
  • Rindopepimut is a vaccine which recognizes a protein on the surface of cancer cells, including GBM, and is currently used for the treatment of melanoma. It is thought that some of the white blood cells which are produced in the body may actually be able to get into the brain.

These two complementary approaches are now being tried in combination – as a “double whammy”. The study is being carried out in a number of clinics around the world. The UK centre is University College Hospital in London. Although the drugs are already in use in the clinic for specific cancer types, we need to carry out the clinical trials to be able to demonstrate that they are safe and effective against GBM and potentially other brain tumours. However, there is nothing to prevent individual doctors prescribing these drugs, but it is at their own risk.


What is Brain Tumour Research doing in this area?

In the Portsmouth centre, Prof Geoff Pilkington has developed an artificial blood brain barrier and is using this to investigate whether we can modify antibodies and other therapies so that they can cross more easily into the brain. Prof Silvia Marino at QMUL is assessing some of the key differences on the surface of GBM cells that may ultimately be used in the design of immunotherapies. And Prof Oliver Hanemann at the University of Plymouth has identified genes which are changed in “low grade” tumours and is working to determine whether these can be used as targets for new drugs.


So, what next?

There is still a long way to go. We know that existing immunotherapies work in some tumours and researchers are just starting to ask whether they may have some benefit for brain tumours. However, there is still a long way to go. Even if the research announced today is successful, it will be trialed first in the more common cancers such as breast, prostate and leukaemia. It will be some time before brain tumours will be considered.

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The development of proton beam therapy for the treatment of brain tumours

The results of a study on the use of proton beam therapy for the treatment of medulloblastoma has just been published. This is the most common type of brain cancer in children and the current standard treatment is radiotherapy in combination with chemotherapy. While this is effective in up to 80% of people who undergo the treatment, there can be significant side effects. These can effect hearing and memory in the shorter term and give rise to problems in the heart, lungs and intestine in the longer term. Therefore, we need to develop more effective treatments with fewer side effects.

The current study included 59 people up to the age of 20 with medulloblastoma who underwent proton beam therapy the results were compared a similar group of people who had previously undergone conventional radiotherapy. They found that it was just as effective but, more importantly, that it resulted in fewer side effects. This was observed particularly for the longer term adverse effects, thus improving the overall quality of life of the people who undergo the therapy.

While the results are promising and it potentially adds to the range of therapies available for the treatment of brain tumours, we still need to be cautious. This was a relatively small study carried out in a single centre. So we need further research to really understand how it works and who will benefit best from the therapy.

Additionally, there were differences between individual patients. So we need to investigate the participants in greater detail to see whether we can predict who will respond best to the therapy. This would include looking at genetics, clinical symptoms and biomarkers – factors that may be in the blood. To do this effectively, we need to generate further evidence using a larger number of patients across a number of different locations who undergo the therapy. The authors also state that they used “historic controls”. This means that they looked at the medical records of patients who had undergone traditional radiotherapy as controls. In order to really verify the effectiveness of the treatment, they will need to carry out the trial with the two groups of patients being treated in parallel with the two different therapies.

So while we can be cautiously optimistic about the results of this study, it underlines the fact that we need to invest much more into brain tumour research if we are to develop effective and safe therapies for brain tumours and ultimately work towards the development of a cure.

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Genes may help to identify new drug targets for glioblastoma

Glioblastoma Multiforme (GBM) is the most common and aggressive forms of brain tumour. In addition to infiltrating into surrounding brain tissue, it also has a high potential to become malignant and the cancer cells can enter into the bloodstream and move to other parts of the body.

There is an urgent need to gain a greater understanding of GBM in order to develop better therapies that will be more effective in treating the condition. One way in which we can do this is by identifying factors that initiate the tumour and stimulate it to grow, as these can then help us to target drugs to kill the cancer cells or prevent them from spreading.

Many cancer genes have been identified, some of which have associated with inherited forms of tumours. An example is the BRCA gene which significantly increases the chances of developing breast cancer. However, the direct inheritance of GBM is extremely rare, so it is unlikely that any single gene alone is responsible. The situation is made more complex by the fact that not all people with a specific gene mutation will go on to develop a tumour but rather that genetic mutations increase the risk of developing the tumour rather than being the sole factor associated with it. A tumour will only develop if cells that are more sensitive and are then combined with additional external factors, many of which we don’t yet understand.

By examining the genes that may be altered in GBM, we will get a better understanding of what is happening within the cells when they become tumorous but also potentially identify targets at which new drugs can act.

A recently published research paper assessed the potential role of one gene that has been associated with GBM. The GRP94 gene was identified as being expressed at higher levels in glioma cells. In the current study, the researchers used a number of different approaches to bring levels back to normal and this decreased their ability to divide and spread. What is particularly interesting is that the gene is associated with a biochemical pathway within the cell that has previously associated with glioma cells called the Wnt/ß-catenin pathway. This is also controlled by a number of other genes within the cell. Some of these controlling factors may also play a role in controlling cell growth and development and may therefore play a role in cancer development. Specific biochemical pathways within the cell such as Wnt/ß-catenin may therefore provide a potential target for drugs to halt the division and spread of glioma cells.

This study highlights how a greater understanding of how specific genes work within a cell can help us to identify novel drug targets. Work is already being carried out to identify potential drugs which may act on Wnt/ß-catenin pathway. But there are many other potential targets that have been identified to play a role in cell division which may have a relevance for tumour development and for some of these, drugs may already exist. This exciting area of research is called “drug repurposing” where drugs which have been designed for one condition may be of potential use for others. This is a key are of interest for the charity Brain Tumour Research and research funded by the charity has identified that anti-depressant drugs may have a beneficial effect for the treatment of gliomas.

While drug repurposing holds great potential for the treatment of a number of different conditions, regulatory obstacles exist to prevent this being brought forward more rapidly and  Brain Tumour Research is working with a number of other agencies to ensure that these are overcome.

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The pivotal role of “big data” in understanding disease and new therapy development

The increasing use of clinical data is rapidly improving our understanding of many clinical conditions. By studying the natural history of disease progression and identifying objective disease biomarkers, we will move closer to identifying potential new treatments or develop a targeted strategy for the use of existing therapies in patient subgroups in order to obtain maximal benefit.

Our understanding of the value of “big data” in the development of new disease treatments has evolved significantly in the recent past with the development of combined data sets to ultimately improve patient outcomes in clinical practice and new drug development. Two years ago I, in collaboration with a number of colleagues, identified both the need and potential for such an approach to gain a greater understanding of Parkinson’s disease (PD). Other diseases have undergone efforts to standardise and integrate relevant data, which have advanced therapeutic trial designs and enabled model-based drug development and personalised medicine strategies.

A number of data sharing models had already been developed which could provide a model for the sharing of PD data

  • The Alzheimer’s Disease Neuroinaging Initiative (ADNI)
  • The UK Medical Research Council Dementia Platform (DPUK)
  • The European Medical Information Framework (EMIF)
  • Sage Bionetworks DREAM Data Challenge

A meeting was organised by Parkinson’s UK in collaboration with the Critical Path Institute to bring together all of the key players in the field . These included academic and clinical researchers, industry representatives, government agencies and regulatory authorities and resulted in a summary publication.

The first aim of the meeting was to identify the key gaps that existed in PD research. These included:

  • The need for regulatory approved endpoints, trial designs, and modeling tools
  • Identification of early diagnostic tools to maximize the impact of neuromodulatory therapies
  • Development of reliable biomarkers to monitor disease progression, particularly to assess agents that may modify the course of the disease
  • Understanding disease subtypes to enable the stratification of patients to allow for more efficient clinical trials and the development of a personalized medicine therapeutic strategy.

With these in mind, the meeting focused on the information that would be required to address these questions and in particular how the existing clinical data could be integrated into a combined platform to allow for a precompetitive data-sharing approach. This would allow the key questions to be addressed while reducing duplication and increasing the ultimate effectiveness of clinical research.

There are many different PD clinical datasets in a variety of formats and the challenge is to identify the key common data elements that can be combined in order to address the key questions that had been identified. The key questions to be addressed are:

  • Data transferability
  • Remote data accessibility
  • Privacy and consent issues
  • Data remapping to agreed standards
  • Data integration

But there are also challenges to data sharing including:

  • Different data formats
  • The need for reliable longitudinal (rather than single point) data
  • Access to datasets
  • Data protection and “ownership”, with particular reference to patient approval
  • Incentives and recognition for the researchers who have generated the data
  • The development of integrated infrastructures that will allow for the ready access of data
  • The cost of the maintenance and updating of a common data source
  • An understanding of new sources of data such as the use of remote monitoring devices

While these are not insurmountable, all of the potential barriers need to be highlighted and an appropriate strategy put into place. This will ensure that any initiatives will allow for the maximum benefit of the data sharing and that obstacles will be identified, wherever possible, in advance.

But we need to remember that the key stakeholder group in such a project is the patients. Informal discussions that I had with people with PD suggested that the vast majority were happy for their clinical data to be made available under certain conditions – primarily that it would be in an anonymous format and that it would be available for research free of charge. Their view was that, although it may not be of direct benefit to them, it will help to develop new therapies that will impact on future generations of people with PD. In particular, we will get to the stage where the treatments address the condition rather than the symptoms, as at present. But in order to achieve this, we need a much better understanding of the condition and the identification of biomarkers to objectively monitor the progression of the condition. The public view on data accessibility is also highlighted in the AllTrials campaign which seeks openness in the availability of clinical trial data to allow for an objective understanding of data obtained from drug trials. People who have participated in clinical trials would expect no less.

A plan is now being developed to establish a global database for PD. Specifically, it will require:

  • Identification of the key current databases
  • Agreement on data standards and common data elements
  • Establishment of guidelines for data sharing
  • Engagement of all stakeholders

Finally, patient datasets and registries are also being considered in the context of the future clinical trial development to maximise the benefit of patient datasets. The European Medicines Agency has established a Cross-Committee working group on patient registries. This will evaluate the potential use of existing and planned patient registries in the design of clinical trials. This will be a key step forward and it will provide yet another benefit for patients from the data that has been collected.

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