Monday, 9 November 2015

Kick-starting the immune system

One of the hottest topics in oncology right now is the use of the latest generation of immunotherapy drugs, particularly drugs called checkpoint inhibitors – also known as anti-PD1/PDl1 and anti-CTLA4 drugs. The most well-known of these are ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo) – drugs which are making headlines the world over with some truly astonishing instances of remission in metastatic melanoma and other hard to treat cancers. However, as with many other targeted therapies, there are also two major problems with these treatments. The first is that only a subset of patients show any response, and sometimes these responses do not last for very long before resistance kicks in. A second problem is that these drugs are not without side effects, some of them quite serious. It’s this first problem that I want to focus on in this blog post.

Being able to improve the response rate to these treatments would mean that many more advanced cancer patients may benefit from these treatments. This is an area of intense research at the moment, with multiple trials looking at different mechanisms to address the issue. One obvious response has been to investigate combination treatments in which two of these drugs are used together – for example ipilimumab and nivolumab together. Results so far suggest that the combination is effective, with a major Phase III clinical trial in untreated metastatic melanoma showing longer median progression free survival for the combination compared to either treatment alone.

Another approach is to combine checkpoint inhibitors with radiotherapy or chemotherapy. The idea here is to use existing treatments to cause tumour cell death and in the process cause an immune response that the checkpoint inhibitors then amplify in some way. It’s an appealing approach but it does depend on using treatments that are ‘immunogenic’ that is they cause an immune response to develop. One of the recurring problems in cancer treatment is the emergence of immune suppression or skewing of the response to pro-tumour responses. Evidence is emerging that a lack of an anti-tumour response is related to the lack of response to the checkpoint inhibitors in some patients.

All of which brings us to consider whether there is a role for some safe and non-toxic treatments which can aid in reversing this cancer-associated immune suppression. Are there ways in which we can kickstart the immune response in ways which synergise with these checkpoint inhibitors?

A number of possibilities spring to mind using some well-known repurposed drugs. The first is cimetidine (Tagamet), one of the first of the blockbuster antacid drugs and with well-documented anti-cancer activities (summarised in the ReDO paper here). Cimetidine has been shown to cause an increase in the number of tumour-infiltrating lymphocytes and to deplete T-reg and MDSC immune-suppressing cells. This makes it an interesting candidate to explore in cancer even without checkpoint inhibitors, but the combination with checkpoint inhibitors would be especially interesting.

Another possibility is to use some non-steroidal anti-inflammatory drugs which have also been shown to have positive effects in cancer immunity. And it’s not just COX-2 inhibitors like celecoxib which are interesting here, there is evidence that diclofenac, which inhibits both COX-1 and COX-2 may have positive effects via its action on the PGE2/IDO pathway. It may well be that the positive effects that have been shown by ketorolac in reducing breast cancer recurrence rates – now the subject of a study in Belgium – are partly immune related.

Finally, there is also the possibility that gut bacteria may have a role. This is a topic I have written about in the past – it is increasingly clear that our gut bacteria have a systemic impact on our immune system. This should be no surprise when you think about it – as a race we have evolved complex relationships with our bacteria, they are more than just along for the ride and are integral to digestion and  immunity alike. A recent paper published in the journal Science explored the role of gut bacteria in mice and the different rates of melanoma growth in two different sets of mice. These mice were of the same species but differed in their gut bacteria – and interestingly the tumour growth rates were markedly different.

Putting these two sets of mice into shared cages, so that they cross-colonised each other with their bacteria, abolished the different growth rates. The mice with the faster tumour growth rate now had slower tumour growth rates than the mice with the slower rate. This was further tested by taking the ‘fast’ mice and explicitly transferring bacteria from the ‘slow’ mice into them – with the same outcome. Finally, adding these bacteria to treatment with a checkpoint inhibitor almost abolished the tumour growth. This is a fairly stunning result – it suggests that changing the gut bacteria can make a significant difference to immunotherapy with the latest drugs. And, for those who are interested, the bacteria were from the Bifidobacterium family – often used in live yoghurt.

Allowing the immune system to mount an effective anti-tumour response is almost a holy grail in oncology – perhaps we are finally coming to the point where we can look at a using combination therapies which work together to do exactly that.

Tuesday, 6 October 2015

Crowdfunding Against Cancer

One of the many problems associated with repurposing off-patent drugs for new uses in cancer is that there is no commercial sponsor involved in the process of getting the drug into clinical use. On the face of it this might seem like a good thing – surely it means that there will be nobody jacking the price up to make huge profits from previously cheap drugs. But in practice this means that the very expensive process of gaining evidence of efficacy in clinical trials though to applying for a new licence is hamstrung due to lack of funding. Clinical trials, especially the larger pivotal trials which convince clinicians that a treatment is effective, are expensive to design and run. For a new drug anywhere up to 75% of the billion dollar cost of getting it to market is spent on the trials process.

This is a significant problem but not an insurmountable one. The Anticancer Fund, for example, is funding a number of clinical trials using a range of repurposed drugs – for example a trial of the pain-killer ketorolac in breast cancer, or a mix of drugs in recurrent osteosarcoma. Another notable example is the Add-Aspirin trial, which is part funded by Cancer Research UK. Clearly there is a role for the not-for-profit sector to step in – but is there also a role for a more direct role for the public?

The Neo-Art trial is looking at using the generic drug artesunate – a commonly used ant-malarial drug – as a treatment in colorectal cancer. Like the ketorolac in breast cancer trial, this one is looking to reduce the rate of post-surgical relapse. Remember, it’s most often metastatic disease which kills cancer patients. Any intervention which can stop metastatic disease in its tracks can have huge impact on overall survival. This is an idea which we urgently need to explore in a range of cancers, including osteosarcoma, as I have suggested in the past.

In the case of the Neo-Art trial, the team at St George’s Hospital have already got preliminary data in patients suggesting that two weeks of artesunate prior to surgery can have a major impact on the relapse rate. The new trial is aiming to prove that this is the case in a larger population of patients – 140 in all. Much of the funding for the trial is coming from a small charity called Bowel Diseases UK, but there’s an additional £50,000 required – and this is where the public can have a direct role.

In a pioneering move, the St George’s team are working with a crowdfunding platform called FutSci to appeal directly to patients, families and members of the public to raise the funds required to make the trial happen. So far the results have been impressive and the appeal is nearly 70% of the way there – but that still leaves around £15,000 to be raised. So, if you have ever been touched by bowel cancer, or want to be part of something that could be truly groundbreaking -  then please go ahead and make a donation.

Friday, 18 September 2015

The latest ReDO paper - nitroglycerin

A long while back I blogged about the possible anticancer uses of nitroglycerin  - a drug with a history of use going back 125 years or more. This was also the topic of our most recently published paper in the journal ecancer series from the Repurposing Drugs in Oncology project.

Talking of repurposing - a topic which is gaining interest all the time - there are some new developments in the Off-patent Drugs Bill which I will blog about at a later point. This offers a legislative solution to the problem of licensing an old drug for a new disease - an essential step that has to be taken if we are serious about changing medical practice. More on that later.

Thursday, 28 May 2015

LFS - Primed for cancer - Interview

The excellent Living LFS blog has a new piece which covers my latest  paper on Li Fraumeni Syndrome...

This explains the core details of the paper in very non-technical language and explains what it may mean in practice. So, if the technical nature of the original paper gets in the way, then this is certainly a good alternative.

Friday, 22 May 2015

Press release - Primed for cancer?

Li Fraumeni Syndrome (LFS), a rare genetic condition that predisposes sufferers to cancer development, is associated with mutations in the TP53 tumour suppressor gene. Although rare, LFS sufferers have a highly elevated risk of developing one or more cancers, with some estimates putting the life-time risk at 70% for males and 100% for females. However, new research published today in leading online oncology journal ecancermedicalscience, suggests that cancer development may be due to more than a mutated tumour suppressor function.

In a new paper by Pan Pantziarka PhD, a scientist working for the Anticancer Fund and co-ordinator of the Repurposing Drugs in Oncology(ReDO) project, it is suggested that there are other important functions of the TP53 gene that contribute to this elevated cancer risk. 'Our knowledge of the multi-faceted functions of TP53 has grown enormously in the last few years,' Pantziarka says, 'yet much of this new information has yet to be integrated into our understanding of the disease process in people with LFS'.

Sue Armstrong, author of 'p53: The Gene that Cracked the Cancer Code', points out that: 'TP53 is the most commonly mutated gene in human cancer. Indeed it’s probably fair to say that if this key tumour suppressor is functioning properly, it’s almost impossible for cancer to develop. It follows that to be born with mutant - and therefore malfunctioning - TP53 in every cell in the body is to be extremely vulnerable to cancer. This is the tragic fate of people with Li Fraumeni Syndrome, for whom conventional therapies rarely offer more than temporary respite. So, new ways of looking at, and treating, cancer are sorely needed.'

Known as the 'guardian of the genome', the p53 protein is at the heart of an array of signalling networks involved in responding to DNA damage, metabolic stress, immunity, senescence and ageing. In people with normal p53 function, the kinds of damage that cause cells to become cancerous trigger a damage response that normally leads to the cell self-destructing before it can proliferate, a process called apoptosis. But in people born with a mutated TP53 gene this process does not take place. However, there is more to cancer than delinquent cells, increasingly we understand that cancer also involves a supporting micro-environment to provide a blood supply, nutrients, protection from an immune response and so on. These factors may also involve p53, and Pantziarka's hypothesis suggests that people with LFS are born 'primed for cancer' because many of these cancer-support systems are already in place thanks to the mutation.

Pantziarka has first-hand knowledge of this disease process himself, having lost his first wife and his teenage son, George, to cancers due to LFS. George, for example, developed his first cancer at the age of two and subsequently developed two further primary cancers before succumbing to metastatic sarcoma in 2011. The story is told in a recent book, 'For The Love of George' by Irene Kappes, available from Amazon and other booksellers. The family have also established the George Pantziarka TP53 Trust ( to provide support for other families and to promote research into the condition.

This new hypothesis does more than provide a more nuanced view of cancer development in people with LFS, it also suggests that many of these additional factors may be amenable to drug treatment. 'By expanding our view of carcinogenesis in LFS we may also be broadening the range of interventions available to us to change things. The key thing,' Pantziarka underlines, 'is to start looking at active measures we can take to reduce this risk. Drugs such as metformin may hold the promise of reducing that life-time risk by some significant margin.'

In perhaps the most radical section of the paper, it is suggested that some other cancer predisposition syndromes, caused by mutations in other genes, may share some of the same features of LFS despite the different genetic drivers. If this is the case, as the paper suggests, then perhaps some of the active measures which warrant investigation in LFS may also apply to a range of different genetic cancer predisposition syndromes. In such a case the prospect of a clinical trial that targets multiple high-risk patient populations is an alluring prospect. 'With limited population sizes it is difficult to design cancer-prevention trials because the sample sizes are too low,' Pantziarka explains, 'but if my theory is correct then we can pool different populations into the same trial and look for reduced cancer incidence across the board.'

The George Pantziarka TP53 Trust –
Original paper (publication date 21/05/15): ‘Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche’ -

Wednesday, 18 March 2015

Exercise and Breast Cancer

I was alerted today to an interesting new paper in the Journal of the National Cancer Institute that looked at the effect of exercise on tumour blood supply and the response to chemotherapy in breast cancer. Now this is a topic which is worth paying attention to – there is lots of evidence that daily exercise can reduce breast cancer recurrence, have positive effects on physical status and may even improve overall survival in women with breast cancer. With that in mind, what does this new paper tell us?

Firstly, it’s important to note that this isn’t a study in people – this is a study in mice. But these are mice with intact immune systems and they are bearing mouse tumours. It means that although this is an animal model we can trust the evidence a bit more than we can when dealing with immune deficient mice implanted with human tumours. Secondly we should note that these mice were not forced to do exercise – so there was no additional stress involved and there were no enforced amounts of exercise that had to be performed. Basically the mice were given an environment which gave them an exercise wheel they could use, whereas the comparison group didn’t have the opportunity to exercise. Finally, some of the mice had ER+ and some ER- tumours, matching human tumours in hormone responsive and non-responsive sub-types.

What the study showed was that the mice doing the exercise had a reduced the tumour growth rate, an increased the rate of cancer cell death (apoptosis), increased the maturity of the tumour blood vessels, increased tumour blood flow and reduced the areas that were starved of oxygen (hypoxia). These are all things which are positive and which we definitely would want to achieve clinically. Basically these results show that exercise normalises the tumour blood supply. This is a good thing.

Normally the tumour blood supply is chaotic – vessels are immature, leaky, misconnected. This chaotic blood supply has a number of downsides. Firstly it means that the drugs we give cancer patients to kill the tumour often don’t make it into the interior of the tumour – not good because if they don’t in they won’t work. Secondly the chaos causes areas of the tumour to become starved of oxygen and nutrients – this in turn causes the cancer cells to become more aggressive and dangerous as they adapt to these harsh conditions.

So, normalising the blood supply means that tumours are not forced to become more aggressive and, as we see in these results, this can lead to a slower growth rate. It also means that when drugs are administered they can make it into a greater portion of the tumour. And this is where the second lot of results come in. Mice treated with the chemotherapy drug cyclophosphamide had greater response if they were exercising compared to the sedentary mice. Interestingly, mice who did exercise alone (no chemo) showed a similar response to mice treated with chemo alone. But the best response came from mice who had chemo and did exercise.

These are positive results but we do have to keep in mind that this is in mice. However, it backs up what we know from evidence in humans and suggests reasons for why we’ve seen these results. The take home from this is that exercise has a positive effect in breast cancer – and most likely in other cancers too. It doesn’t have to be running a marathon every week either – a study in women with breast cancer back in 2005 found that walking at an average pace for 3 – 5 hours per week had positive effects on survival.

Tuesday, 24 February 2015

Clarithromycin - a repurposed anticancer drug?

An antibiotic may join the ranks of drugs suitable for repurposing as anti-cancer treatments, according to new research from the Repurposing Drugs in Oncology (ReDO) project published in ecancermedicalscience.

Clarithromycin is a very common and effective antibiotic. It is traditionally used for many types of bacterial infections, treatment of Lyme disease and eradication of gastric infection with Helicobacter pylori. It is noted in the World Health Organisation’s list of essential medicines, ensuring it will remain available worldwide at low cost. Dr. Vikas P. Sukhatme of the ReDO project and GlobalCures says "The multiple mechanisms of action of this drug make it particularly attractive for repurposing."

“Clarithromycin is a canonical example of a drug that may have limited antitumor activity on its own, but is extremely valuable against cancer in combination with other drugs,“ says An Van Nuffel, PhD, lead author of the paper and member of the ReDo project and the Anticancer Fund.

An international collaboration between anticancer researchers from across the world, the ReDO project is dedicated to promoting the cause of common medicines which may represent an untapped source of novel therapies for cancer.

In partnership with ecancer, the ReDO project is publishing a series of papers on drugs with enough evidence to be taken to clinical trials. Future papers will address the potential anti-cancer uses of nitroglycerin, itraconazole and diclofenac.

Dr Gauthier Bouche of the ReDO project and the Anticancer Fund describes a serendipitous use of clarithromycin for the treatment of chronic myeloid leukaemia (CML).

In 2012, Italian doctors led by Dr Carella prescribed clarithromycin for an infection in a patient with CML. The patient had developed resistance to his treatment, which reversed after treatment with clarithromycin, reinstalled when the drug was discontinued and then reversed again after re-challenge.

Low- and middle-income countries (LMIC) may pave the way for drug repurposing. The latest randomised trial done with clarithromycin was done in Egypt, demonstrating that patients with a certain form of lymphoma lived longer when clarithromycin was added to chemotherapy.

The faster development of new - but expensive - drugs in High Income Countries may create a role for LMIC to further develop drug repurposing in oncology. Could LMIC with no access to the recent drugs perform trials with clarithromycin?

“If clarithromycin were a new drug with the anticancer potential that it has, we would see companies pushing hard for clinical trials and aiming to get to market quickly,” says Pan Pantziarka, PhD, member of the ReDO project and the Anticancer Fund. “Why isn't that happening now in multiple myeloma or resistant leukaemias?”