Aspirin as an anti-metastatic drug - in 1977

Working on drug repurposing often involves an element of historical research. Drugs like cimetidine, nitroglycerin and propranolol have been around for decades and there’s a lot of good data that we can extract from old articles, clinical trials and retrospective studies. One of the best known examples of old drugs is aspirin - which is attracting a huge amount of attention from clinical researchers in oncology. There is a huge literature on aspirin, with much more on the way as clinical trials are designed, run and reported.

One of the most intriguing things about aspirin is the data that suggests that it might work as an anti-metastatic agent. There is data that shows that aspirin may be effective in reducing the risk of metastatic spread in breast, prostate and colon cancer (for example this recent meta-analysis reported a relative risk of metastasis of 0.77 with aspirin).

That we’ve known about the anti-cancer potential of aspirin for a long time isn’t a surprise – but I have to admit to being surprised to come across a paper from 1977 arguing the case that aspirin might be an effective anti-metastatic drug. The paper is Aspirin for reducing cancer metastases? by Henschke, Luande and Choppala (J Natl Med Assoc. 1977 Aug;69(8):581-4). The paper is available open access (here), and while the data is old, the arguments it makes are still vital and relevant. It really begs the question, how is that things haven’t moved forward more quickly? And, more crucially, how can we make sure that things move forward more quickly in the future. Not just for aspirin but for so many of the other old drugs that have good data in their favour.

Innovative new brain tumour trial kicks off

The Anticancer Fund is pleased to announce that on Tuesday 15th November 2016, the first patient was enrolled in a clinical trial called CUSP9v3 for recurrent glioblastoma at the Department of Neurosurgery, University Hospital of Ulm, Germany. This is a phase 1 clinical trial. The study treatment will be given to 10 patients to assess safety and tolerability.

Glioblastoma is the most frequent type of malignant brain tumour in adults. In Europe and North America, there are 3-4 new cases per 100,000 inhabitants per year. Even when all visible tumour is surgically removed, glioblastoma almost always returns within a year. Therefore, after surgery patients are treated with radiotherapy and chemotherapy. Despite this additional treatment, glioblastomas usually regrow and at some point can no longer be effectively treated, often resulting in death 1-2 years after the initial diagnosis.

 "For decades, researchers have been looking for new experimental therapies for our patients with no real success yet" says Professor Marc-Eric Halatsch, the neurosurgeon leading the trial. "Together with Dr Richard Kast (USA), we sought to address the problem that glioblastomas usually find a way to escape the action of a single drug. In 2013, we teamed up with an international group of researchers to propose a treatment that would act on multiple mechanisms used by glioblastoma cells to grow. This treatment consists of 9 drugs that are currently on the market for other indications than cancer (‘repurposed’ drugs). These nine drugs have ancillary attributes that block several of the mechanisms glioblastoma cells use to grow. These drugs had remarkable effects in preventing growth of glioblastoma cells in preclinical studies. A clinical trial was warranted."

In addition to contributing to the design and set-up of the trial, the Anticancer Fund will provide €300,000 for this study. "This type of treatment is not developed by the pharma industry because the 9 drugs are from different companies and all are off-patent and mostly available as generics" says Lydie Meheus, director of the Anticancer Fund. "This implies that the treatment, if successful, will not generate substantial additional financial return for the manufacturers of the drugs. Since the treatment can benefit patients and the healthcare system, it must be developed with the support of philanthropy and governments."

Patients participating in the trial will receive CUSP9v3 for one year. When all patients have completed 2 months of treatment, a first analysis will be done on the safety and tolerability of the combined treatment.

If the combination is well tolerated, a larger multi-centre study will be initiated to evaluate the treatment’s efficacy.

Further information on the CUSP9v3 trial can be found on www.anticancerfund.org or on www.clinicaltrials.gov (NCT02770378).

Guest Post - Crowdfunding for Pediatric Cancers

Cesare Spadoni, founder of aPODD (accelerate Paediatric Oncology Drug Development), talks to Pan Pantziarka about the problems in drug development in children's cancers, and about the crowdfunding campaign to find a new treatment for Medulloblastoma.

Pan: What is the aPODD foundation aiming to do?
Cesare: aPODD (accelerate Paediatric Oncology Drug Development) was set up with the mission to speed up the development of better and safer treatments for children with cancer. This is a cause that is very close to my heart. I lost my first daughter to cancer a few years ago. That is when I began thinking about doing something for children with cancer.

Obviously, you can have a positive impact on sick children and their families in many different ways. In my case, because of my professional background in drug development, I felt compelled to do something to address the major problem preventing any further clinical improvement for children and adolescents with cancer: the lack of therapeutic options and the delayed access to the most innovative treatments.

Specific anti-cancer drugs are not developed for younger patients because it is not profitable for industry to do so. This is an area where patients’ organisations may play a vital role. Drug repurposing is certainly an area we are very much interested in. By looking at existing drugs we may be in a position to identify possible new treatments much faster and at a fraction of the cost and risk of new drug development

Pan: How is this campaign different to others?
Cesare: We are looking to identify a potential new treatment for Medulloblastoma, a rather aggressive form of brain cancer that is more frequent in children and adolescents. The current therapeutic options for this cancer are limited and very harsh, including high dose chemotherapy and radiotherapy. The impact on patients may be devastating as the lucky survivors may face severe health problems later in life.

For this project we are partnering with Healx, a company based in Cambridge (UK), which offers very advanced technologies and strong expertise in drug re-purposing. Healx is applying advanced computational biology tools, data analytics and machine learning to make sense of complex biological data sets and match those with the profiles of known drugs.

We are now in the process of finalising a list of drugs that we would like to test experimentally in Medulloblastoma cell lines in view of progressing further with the most promising ones.
We are very excited by these early results and we are really hope that this crowdfunding is successful so that we can proceed as fast as we can.

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.

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.

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.

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?”

Cimetidine as an anticancer drug - New ReDO paper

The latest paper from the ReDO project has just been published. Our focus for this paper is the well-known antacid cimetidine (trade name Tagamet, but now available as a generic). The paper summarises the extensive pre-clinical and clinical evidence that shows cimetidine has huge potential in cancer treatment. It has multiple mechanisms of action and there is clinical trial evidence that it is associated with a survival in colorectal cancers.

The paper is published as open access at the journal ecancer.

The press release provides a few more details:

How a common antacid could lead to cheaper anti-cancer drugs

The cancer solution in your medicine cabinet

A popular indigestion medication can increase survival in colorectal cancer, according to research published in ecancermedicalscience. But in fact, scientists have studied this for years - and a group of cancer advocates want to know why this research isn't more widely used.

"Cimetidine is an interesting drug as it's very safe, very well-known, and has clinical results in cancer that have been confirmed in a number of trials," says Pan Pantziarka, lead author of the paper and member of the Repurposing Drugs in Oncology (ReDO) project.

Bisphosphonates in non-bone tumours

Bisphosphonates are a class of bone-targeted drug that act to slow the turn-over of bone (bone resorption). These drugs, including zoledronate, ibandronate and others, are standard treatments for osteoporosis and other bone diseases. And, as I have mentioned previously on this blog they have increasingly found use in cancer treatment to help control bone-related problems - both from metastatic disease to the bone and in primary bone tumours. There is also increasing evidence that as well as controlling bone pain and reducing fractures, these drugs have some very positive effects on overall survival. For example there is now evidence that zoledronate (also called Zometa or zoledronic acid) gives a survival advantage even in early stage breast cancer. Now this is something of a surprise because the effects are there even when there are no bone metastases, so the drug must be acting on non-bone tumour tissue - how is this possible?

New light has been shed on the matter by some recent work that convincingly shows that zoledronic acid is taken up by cancer associated cells outside of bony metastases. Some clever lab work has shown that zoledronic acid attaches itself to tiny crystals of calcium (microcalcifications) outside of the bone. These microcalcifications are then eaten up by tumour associated macrophages, immune cells that actively encourage and support tumour growth. Once these macrophages have swallowed the microcalcifications with the zolderonic acid attached the drug can get to work and interfere with their function. In other words, the drug doesn't affect tumour cells directly, it affects the cells that provide some of the life-support that tumours require. The lab work on mice was also confirmed on a tumour sample from a breast cancer patient.

Nitroglycerin and cancer drug therapy

Following on from the paper on the anti-parasitic drug mebendazole (which I first discussed on this site a while ago) and the antacid cimetidine (paper not yet published), I've been working on another ReDO paper on the drug nitroglycerin. Like all the repurposed drugs we're looking at in the ReDO project this one is commonly used clinically for non-cancer uses, in this case it's a drug used to treat heart problems and blood pressure. Available as tablet you stick under the tongue, or a spray or even a transdermal patch, nitroglycerin is a drug that has been used for over a 100 years as a vasodilator - in other words it relaxes the blood vessels. It's partly this property that makes it interesting in terms of anti-cancer treatment.

Like other tissues, tumours need a blood supply for food and oxygen, and it is well-known that they release chemical signals that cause new blood vessels to form. This is the process called angiogenesis, and for many years scientists have been looking at ways to disrupt the process - with drugs like avastin (bevacizumab) developed to stop this happening. The idea is that with no blood supply tumours can't grow. However, even when angiogenesis does take place and tumours sprout the blood vessels they need, the vessels that are formed aren't normal. The blood supply is chaotic and the vessels are much leakier than normal. Back in the late 1980s some scientists started looking at how we could use this to our advantage. The idea is that you take advantage of the leakiness by using drugs that leak out into the tumours rather than spreading throughout the body (as normal chemo does). Hiroshi Maeda and his co-workers termed this the 'enhanced permeability and retention' (EPR) effect.

Nitroglycerin enters the picture as a way of making the leakiness worse by relaxing the blood vessels, thus encouraging large drug molecules to leak into the tumours. And once they've leaked out, the chaotic structure of the vessels means the drugs are retained in the tumour where they can have an effect. It is, in theory at least, a way of targeting anti-cancer drugs to the tumours and not to the rest of the body. It's an elegant idea and has lots of experimental evidence going for it. And the evidence includes some small trials in humans - primarily in lung and prostate cancers. There are more clinical trials on-going, and we can but hope that their results encourage more work in this area. To really work well we need to team up the nitroglycerin with some reworked chemotherapy drugs that are specifically designed to work with the EPR effect.

ReDO - Repurposing Drugs in Oncology

A theme that I have covered here many times is the potential use of common non-cancer drugs as parts of anticancer drug protocols. Examples that I have covered have included the anti-hypertension (high blood pressure) drug losartan, the anti-fungal itraconazole and the anti-parasitic mebendazole. For the last few months I have been working on a project called Repurposing Drugs in Oncology (ReDO), looking precisely at how we can make more progress in getting these common and low-cost drugs into use clinically against cancer.


I’m happy to report that the first two papers from the ReDO project have been published today, in the open access journal ecancermedicalscience, along with an editorial making the argument for repurposing. The first paper describes the rationale of the project and outlines our thinking in the selection of the candidate drugs, what we hope to achieve in the project and some of the social and political implications involved:

The Repurposing Drugs in Oncology (ReDO) Project

The second paper looks in detail at the first drug on our list – mebendazole. It summarises the evidence for an anti-cancer action of the drug at clinically relevant dosages. Additionally the paper proposes a series of drug combinations for specific types of cancer:

Mebendazole as an anti-cancer agent

The editorial that accompanies the two papers is also online:

Recycling existing drugs for cancer therapy: delivering low cost cancer care

More details on this, including links to some of the clinical trials my colleagues are involved in supporting and links to additional articles, can be found at the project web site:

www.redo-project.org

These papers are just the first, and we hope that in the months to come there will be more publications and a greater intervention in public debates about health policy and drug development in cancer.

Losartan - High-Blood Pressure Drug Helps Fight Cancer

We treat cancer with the most vicious, toxic and carcinogenic drugs available to science in the form of chemotherapy. But the fact is that the chemotherapy drugs are brutally effective at killing cells - at least initially, and at least when they can get to the cells we want to target. But, as we all know, most chemotherapy drugs are not easily targeted and end up killing plenty of non-cancerous cells. Not only that, cancer cells are also able to find various methods of shielding themselves from the poisonous brew or they mutate and become resistant. This means that no matter how good chemo drugs are at killing cells, if tumour cells are able to hide or adapt then that killing power is ultimately useless (not to say downright dangerous to the rest of the body). The upshot of this is that finding ways of getting more chemotherapy to more cancer cells is a hugely useful strategy if we can do it.

One mechanism by which cancer cells cells are shielded from chemotherapy (and other treatments, including radiotherapy), is through the decreased blood supply inside solid tumours. As tumours develop they constrict blood vessels into the interior of the tumour, stopping nutrients and oxygen getting to the cells deep inside the mass. With the vessels so constricted it's also the drugs carried in the blood supply - like chemotherapy drugs - which are cut off from the cells at the heart of the tumour. Furthermore, in response to this restrict supply of food and oxygen, the cancer cells adapt and become more aggressive and able to cope with the harsh conditions that surround it. These adapted cells are also more likely to form metastases, spreading the cancer to other parts of the body where conditions are easier, at least initially.

One possible way to stop this is to look at 'tumour vasculature normalisation' as a therapeutic strategic. The idea behind this is that by reducing the constriction of blood vessels into the tumour, then blood, oxygen and blood-borne drugs can make it into the heart of the tumour. In this way there is a reduced push towards more aggressive mutations, reduced risk of metastases and of course a greater delivery of cancer-killing drugs like chemotherapy. It seems counter-intuitive to want to make it easier for tumours to have a blood supply, but sometimes it's the counter-intuitive ideas that work the best in practice.

Itraconazole - Anti-fungal and anti-cancer

One of the common themes of this site is the use of existing drugs as anti-cancer agents. Given the many years and millions of dollars it takes to get new drugs from the lab and into early phase human trials, it makes a lot of sense to re-look at existing, approved drugs to see if they can be re-purposed as anti-cancer therapies. Prominent examples of such drugs include metformin (used in diabetes), aspirin (pain killer), beta blockers (used for treating hypertension) and mebendazole (used as an anti-parasitic agent).

The latest example is the anti-fungal drug Itraconazole. A Phase II trial has just been reported in a paper in the Oncologist - freely accessible to all here: http://theoncologist.alphamedpress.org/content/18/2/163.full. The drug was used to treat advanced prostate cancer (metastatic castration-resistant prostate cancer to be exact). Two dosing schedules were used, low-dose (200 mg/day) or high-dose (600 mg/day), and the men were treated for 24 weeks and then assessed for a reduction in PSA and, more importantly, for progression free survival.

The low dose arm of the trial was abandoned early because of the low levels of response, however the higher dose arm continued to completion. The results were fairly impressive. The primary end-point of the study was stopping the increase in PSA levels, and this was acheived in 48% of men on the high dose (12 of 25 men). The main secondary end point was freedom from disease progression (which is the more important measure overall), and here the result was that 24-week PFS rate was estimated to be 61.6%.

Mebendazole - Tumours and Tapeworms

There’s a big push by some in the cancer research community to look at old drugs to see if they’ve got some anti-cancer activities. It makes a huge amount of sense to do this as it short circuits all of the phase I trials to test a drug’s toxicity, often these drugs are cheap generics and there’s many years of data on pharmacokinetics and side effects and so on. It means that in a best case scenario you can cut out years of preliminary work. Some of the drugs, like the anti-diabetic drug Metformin or plain old Aspirin also have evidence of anti-cancer effects in the population rather than just from test-tube experiments or computer simulations. And the good news is that the list of such drugs is growing longer by the day, and the evidence continues to mount up that some of the best candidates will enter use soon either as support to existing treatments or, in some cases, as part of new protocols to prevent recurrence of disease after treatment.

One of the more surprising drugs in Mebendazole, an old drug that has been around for a long time as a treatment for parasites like tape-worms. Mebendazole, which is available over the counter in any case, has got a surprising amount of evidence in its favour as an anti-tumour drug. This evidence comes from modelling the molecular profile of the drug to see how it fits with particular cancer pathways, from experiments in test tubes and in animal testing using human tumours. As pre-clinical evidence goes, that’s pretty much the works.

Lansoprazole and resistance to chemotherapy

For this first post of 2012 I want to start on a positive note by highlighting an interesting and relevant piece of research from Italy. Chemoresistance is the term used to describe the process whereby cancer cells become resistant to chemotherapy. Unfortunately this is a serious and widespread problem, right across the spectrum of cancer types. Tumours that regress quickly from the initial rounds of chemo, sometimes shrinking away to nothing almost, suddenly seem to bounce back, growing again and shrugging off repeated rounds of the chemo that seemed to knock them out. In many cases these resistant cancer cells become ‘multi-drug resistant’, which means that second and third line chemotherapy treatments also have little or no effect. So, finding a way of reversing this resistance is an important aim in cancer research, and one which is clinically relevant across most kinds of cancer.

It’s this problem that a team of researchers and clinicians in Italy have tackled in a clinical trial. Building on work previously done in the laboratory, Stefano Fais and his co-workers carried out a clinical trial on cats and dogs (now called ‘companion animals’ rather than pets!) with cancers that were resistant to standard chemotherapy. Don’t for one minute think that because the patients were animals that this is not relevant research. Cancers in cats and dogs are much closer to human cancers than cancers in rats and mice. In some types of disease, such as osteosarcoma, the disease acts in exactly the same way that it does in people, and is treated with the same drugs and treatments.

These animals were treated with the common anti-acid drug lansoprazole at high doses – a drug that is available over the counter in the UK – along with the chemotherapy drugs that often fail due to the development of chemoresistance. The response of these animals was compared to another set of animals that had the conventional chemo-only treatment (it was the owners of the animals who decided to stick to the conventional treatments only).

The results were very clear. In the lansoprazole treated group, more than two thirds of animals showed partial or complete responses, compared to 17%of animals in the chemo-only group who showed short-lived partial responses. What’s more, even in the non-responders in the lansoprazole group, the owners of the animals indicated that their pets showed improved quality of life – less pain, less weight loss, greater agility etc.

Beta blockers and cancer

There was a recent flurry of headlines about possible new uses of beta blockers - normally prescribed for high blood pressure - and that they might have anticancer properties. For example the BBC headlined the story as Beta blockers 'may stop breast cancer spreading'. The trigger for the story was the announcement an analysis of 800 patient records showed that those cancer patients who had also been treated with beta blockers had lower rates of metastatic disease - in other words there are indications that beta blockers stop or slow breast cancer from spreading to other parts of the body. The real headline is from the abstract of the paper that reported the results:

In addition, there was a 57% reduced risk of metastasis, and a 71% reduction in breast cancer mortality after 10 years. This proof-of-principle study showed beta-blocker therapy significantly reduces distant metastases, cancer recurrence, and cancer-specific mortality in breast cancer patients suggesting a novel role for beta-blocker therapy

This is not the first report on beta blockers and cancer - for example there was also a very recent study looking at beta blockers and malignant melanoma. That study concluded:

Increased survival time of patients with melanoma receiving beta-blockers suggests that use of this drug may hold promise in treatment strategy for these patients.Impact: The observations described here suggest that catecholamines may retard melanoma progression and that beta-blockers may have unrecognized potential as a therapeutic intervention for melanoma.