Wednesday, 26 April 2017

Myc, Models and Tumour Growth

When I wrote the NEATG model of tumour growth, published in the journal PeerJ (, I focused on the behaviour of individual cells and on the role of cell competition and cell death in tumour growth. All models have to simplify and abstract, and the NEATG model does exactly that. The model steered clear of the molecular basis for the behaviour of the cells – my working assumption was that cells produce soluble factors and signalling proteins that mediate their cell-cell and cell-tissue interactions. It was one of the reasons I called the model NEATG (Non-physiological Evolutionary Algorithm for Tumour Growth – though as Sebastien Benzekry pointed out to me, the fact that the model has cells and tissues already makes it fairly physiological… ).

Despite the level of abstraction, the model clearly does show cellular behaviours that mimic aspects of tumour growth and response to cytotoxic chemotherapy.  A surprise for me was that the model showed that accelerated tumour regrowth following chemotherapy is driven by cell competition and the levels of cell death. I spent time looking at the research literature on these topics and found that my results were actually in line with clinically relevant phenomena – which is what makes the model interesting.

A recent paper from a group of researchers from the University of Bologna entitled MYC, CellCompetition, and Cell Death in Cancer: The Inseparable Triad  (available open access from the journal genes – it’s well worth a read), casts some interesting light on the topic. C-Myc is one of the most important of the master genes involved in cell cycle progression and tissue growth. It’s a transcription factor, which means it regulates the activity of other genes, and is often switched on permanently in tumours rather than coming on and off as required. It’s widely associated with a whole range of different cancers.

In this paper the authors review recent evidence from Drosophilia (fruit fly) models of cancer and how they are implicated in cell growth, cell death and cell competition. They outline the way that competition selects for cells that are ‘fittest’ and that less fit cells are effectively killed off – in just the way that they do in software in my model. The evidence that they outline suggests that one of the drivers for the behaviour of these cells is c-Myc, making it an important component at the physiological level missing from NEATG.The authors themselves make note of the results from the NEATG model:

Our findings suggest that CC [cell competition] is an innate process governing both cancer initiation and progression, where cell death fuels the clonal expansion of the fittest cells in the context. CC and apoptosis thus appear to be strictly linked one another, and emerge as fundamental cancer drivers also in a computational model of tumour growth, where several parameters of malignancy such as intra-tumour heterogeneity and accelerated repopulation have been taken into account.

For the next stage of work on this model I will be investigating the metabolic impact of cell growth in tumour growth, and the impact that cell death has on this. My prediction is that the model will show that populations of ‘super-feeders’ will emerge during tumour growth – and that chemotherapy helps to select for these populations of cells. However, as this stage I don’t really know that that’s what happens – I have to wait and see what the data tells me…

In the meantime I’ll finish with some final words from the team at Bologna :

Cells cooperate to build an organ and, in a similar way, they cooperate to build a cancer. Although the contexts are impressively distant, MYC-mediated cell competition seems to be at work in both cases with the same basic, sequential elements: cell–cell disparity in MYC contents, death of the cells with lower MYC levels, and proliferation of the cells with higher MYC levels. This stereotypical module shapes organ development and, possibly, cancer evolution. In growing tumours, an excess of dying cells is known to contribute to mass expansion, but the implication of MYC-mediated cell competition in this cancer trait has just begun to be investigated. Further research is warranted on the intricate “life and death” signals exchanged by confronting cell populations within the cancer community.

Wednesday, 22 February 2017

The Star Throwers Guide To Cancer

One of the reasons for starting this website was the wish to share information with patients, carers and other people directly affected by a cancer diagnosis. The site came out of a series of discussions I had with my son George while he was in the middle of his battle against osteosarcoma. We wanted a site that could be used to share science-based information that was likely to be useful, particularly for people looking for treatment options, as we often were. However,  I have to admit that in recent months the site hasn’t been getting the attention it used to – the number of new postings has been really light on the ground. One of the reasons for this has been that for a long time I had been working with the UK charity Star Throwers to produce a book that would provide a lot of that type of information in ebook and paperback form.

The Star Thowers Guide To Cancer, as the book is called, is now available via Amazon or, if you’re in Wymondham, Norfolk, direct from Star Throwers. The book covers similar ground to this website: science-based, heavy on information, concise and geared very much to looking at new treatment options. Does the world really need another new book on cancer? Book shops are full of new cancer books: memoirs, diet guides, histories of oncology and much more. But this one is different.

I like to think of this book as a ‘how to be a difficult patient’ guide. It shows you how to read the cancer literature. How to assess the breathless stories about new ‘cures’ that are frequently highlighted in the mass media. There is a detailed discussion of the tricky subject of cancer and diet. Searching for clinical trials and looking for treatments abroad are also covered in some detail. Local ablative treatments such as cryoablation are covered, including the vital information on where to look for these useful but underused treatments. Finally, there is also a chapter on drug repurposing, a topic I have covered here many times and which I now work on pretty much full-time.

In the past I have considered taking the best articles from this site and putting them together as a single download via PDF. But there’s no need now. This book provides the best of this site and much, much more.

Tuesday, 6 December 2016

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.

Wednesday, 23 November 2016

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 or on (NCT02770378).

Wednesday, 22 June 2016

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.

Monday, 14 December 2015

NEATG - A software model of cancer

For a huge chunk of my working life I have built computer models which were used to assess operational activities in different industries. The combination of mathematics and software can provide enormous power to help understand and assess complex processes. My doctorate put these skills to good use in that I used software implementations of evolutionary processes to build a system that evolved mathematical models which could validate the correctness, or otherwise, of large data sets. In plain English I used genetic algorithms to discover mathematical models which could pick out incorrect data values in large volumes of data. Think of a system that could take the largest Excel spreadsheets and automatically flag those rows of data which were most likely to be in error – all without knowing what the spreadsheet data represented or who had put it together or why.

Of course cancer is the ultimate in evolutionary systems – if you wanted to design a system to illustrate the evolution at work you’d come up with something pretty much like it. When we look at cancer and see that some treatments have fantastic initial responses, with tumours shrinking away to almost nothing, followed by a rebound in which the cancer comes back more aggressive and resistant to the treatment then we’re seeing evolution at work.

Given my background in computer modelling and my current work in oncology it should be no surprise that I’ve worked on a software model of tumour growth. I’ve called it NEATG – for Non-physiological Evolutionary Algorithm for Tumour Growth. It’s a computational model – it’s about algorithms rather than about trying to recreate in software the vast complexities and details of cells, proteins, signals and pathways. Although it’s a simple model by design, it does illustrate some interesting behaviour that brings to mind the behaviour of real tumour growth.

Tumour growth in NEATG

For example, the NEATG system can model the growth of a tumour mass (in two dimensions), it can model the rise of genetically different sub-populations of cancer cells, and it can model different interventions such as chemotherapy or nutrient deprivation. What is more it displays emergent behaviour – such as a more aggressive growth pattern following the cessation of treatment. This is behaviour that emerges naturally from the interactions between cells and tissues, not behaviour that has been explicitly programmed into the system as a set of predefined rules.

For now NEATG is a tool that can be used to explore different algorithmic scenarios – you can play try out different thought experiments to see what happens. It’s good for thinking about some of the most fundamental aspects of cancer without getting bogged down in the molecular biology. For example, while most people think of cancer as primarily a disease of disordered genes – a view known as the ‘somatic mutation theory’ of cancer – there is an alternative theory called the ‘tissue organisation field theory’ of cancer. In this theory disordered genes are more of a by-product than a cause of cancer, and it places more emphasis at the disordered tissue environment. Simplistically we can ask: is it the delinquent cell or the bad neighbourhood that causes cancer? This is a good question to explore using a suitable software model – and I hope that NEATG can be applied to this.

While it’s still early days for this piece of work, I have written a paper on it which is available as a preprint (i.e. prior to peer review) at PeerJ. If you’re interested please take a look.

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.