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.

Li Fraumeni Syndrome and Cellular Metabolism

A while ago I wrote about the trial of the anti-diabetic drug metformin  in individuals with Li Fraumeni Syndrome (LFS) and the importance of starting to look beyond the idea that LFS is just about a defects in the self-destruct mechanism of damaged cells. Another clinical trial in LFS, also at the National Institutes of Health in the United States, is also taking place and this one too is about looking at a different aspect of LFS. The ‘Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome’ study (http://www.clinicaltrials.gov/ct2/show/NCT00406445) is looking specifically at whether a mutated TP53 gene causes metabolic changes in humans, as it does in mice and in test tube studies.

This is not just an academic question – ultimately we are looking to see whether there are factors that can change the cancer risk in individuals with LFS. This is the key idea in my own research on LFS, see for example the paper on ‘Li Fraumeni syndrome, cancer and senescence: a new hypothesis’.

Dr Paul Hwang, one of the investigators on this new trial kindly agreed to respond to a few questions on his work:

Pan: In your experiments you have found that mice with a mutated TP53 gene show different patterns of cellular metabolism compared to mice with non-mutated TP53. How would this difference manifest itself day to day? For example, would you expect to see different responses to exercise and diet?

PH: In a preliminary study of individuals carrying mutations in the TP53 gene (encoding p53 protein), we have observed evidence of increased muscle oxidative metabolism which is carried out by sub-cellular compartments of the cell called the mitochondria. In a mouse model of LFS, where genetic and environmental variables between individuals can be well controlled, we see a marked increase in aerobic exercise capacity which is also dependent on muscle mitochondria. Thus, in individuals with LFS this intrinsic characteristic could manifest itself as higher baseline endurance exercise capacity. Additionally, with exercise training, it could be possible to see a more robust improvement in fitness compared to individuals who do not carry the TP53 alteration. However, it should be noted that there are many different mutations of TP53 that can cause LFS, and it is not known whether our finding of increased oxidative metabolism is applicable to all individuals with LFS. With respect to diet, we have observed that some p53 mutations result in unresponsiveness to nutrient deprivation at the cellular level but how this affects the relationship between diet and cancer in people would only be speculative at this time.

The LDN Research Trust - Q & A Linda Elsegood

The LDN (Low Dose Naltrexone) Research Trust is at the forefront of raising awareness of the potential of low dose naltrexone as a treatment in auto-immune diseases and cancer. Not just in the UK, the LDN Research Trust has done an outstanding job on the international as well as the national stage. At the heart of this hive of activity – with multiple projects on-going at any one time – is Linda Elsegood, who founded the Trust in February 2004. Ahead of a busy schedule in organising the 2014 LDN Research conference, Linda was kind enough to answer a few questions on LDN and cancer.

Pan: There seems to have been a real rise in the level of interest in LDN and cancer, what’s driving that?

Linda: It’s been incredible really, there is so much interest coming from all areas now – not just in this country but internationally too. Social media has made a huge difference to this. People can access information much more easily than when we started more than 10 years ago. And it’s not just from patients. We get a lot more interest from doctors too. People want to know. And we’re really busy at the LDN Research Trust. We’ve got seven projects on the go at the moment, including the filming of a documentary, there’s the conference which we really want to live stream to everyone for free, to achieve this we have to raise the money. Again, social media is making the difference to this sort of thing.

Pan: In terms of this level of interest, how much is it driven directly by doctors, and how much is it doctors pushed to find out by their patients?

Osteosarcoma - A Proposal for Reducing the Relapse Rate

As has been mentioned on this site before, there has been little progress in the treatment osteosarcoma – the disease that killed my son,George – in the last twenty-five to thirty years. The actual figures vary by country, but generally the five year disease free survival is around 60% - 70%, though in the UK the last published figures were an absolutely appalling 43%. But these figures mask what’s really going – osteosarcoma of the extremities (the long bones in the arms and legs) has a much higher disease free survival rate than osteosarcoma at other sites. So the figures for England show that the rate is 48% for osteosarcoma of the extremities and only 16% for other sites. And, regardless of site, the prognosis for relapsed disease (whether it’s a local recurrence or a distant metastasis) is truly grim.

Looking at the patterns of relapse however shows us something really interesting and, hopefully, significant. The vast majority of relapses occur within 18 months of surgical resection (and in osteosarcoma the only way for definitive cure is to surgically remove the tumour). What is more, most of these relapses take the form of distant metastases, the majority appearing as new tumours in the lungs. This begs the question as to why this pattern? It suggests that there’s something systemic going on – and it’s a similar pattern to the relapse/recurrence of breast, lung, head and neck and other cancers. 

One possible mechanism involves the surgery itself. The body responds to the trauma of surgery by releasing different growth factors, cytokines and other inflammatory responses. This is necessary for wound healing, but it also creates an environment that is conducive to cancer growth – there are pro-angiogenic growth signals, immune suppression and so on. It all adds up to an environment that gives any microscopic pockets of cancer cells the chance to expand and grow into new tumours, particularly in the lungs.

The Case of Dr Henry Mannings

It was back in December 2012 that I first wrote about the case of Dr Henry Mannings, the founder of Star Throwers, a charity in Norfolk that helps late stage cancer patients with nowhere else to go. Let me state at the outset that I am a Trustee of Star Throwers and proud to be one. Henry Mannings treated my son George when we had no place else to go. In the many years of treatment that my poor son endured before his death, we met few doctors as dedicated, concerned and open minded as Henry Mannings. George was the first patient that Henry treated with Coley’s Toxins, but by then the disease was so advanced that nothing could stop it – but George, and the rest of the family, appreciated the care and advice from Henry, and the hope that the treatment gave us when there was no place else to turn. And, let me add, Henry made no promises, he did not give us false hope and everything he said or recommended he backed up with evidence and reasoning. In the years since George’s death I have come to know Henry Mannings well and I know that the trust he inspired in us he continues to inspire in the many patients who come to Star Throwers.

However, his popularity with his patients, and his open-minded approach to oncology, makes him unpopular with some of the powers that be. And so in late 2012 a complaint was made by a senior oncologist in Norwich to the General Medical Council. The complaint alleged that Dr Mannings was prescribing chemotherapy drugs in an unsafe manner that put patients at risk, with specific mention of two cases. In neither case was the complaint made by the patient or the patient’s family. In fact the complaint was made without first asking the people concerned whether they had any complaints to make against Dr Mannings.

Based on these complaints the GMC instituted proceedings against Dr Mannings, and initially took the step of taking away his power to prescribe treatment at Star Throwers. This meant that patients who were being actively treated had to stop treatment, even if these treatments were successfully keeping cancer at bay. In response there was an outpouring of support from patients and patient families, from other clinicians familiar with Dr Mannings and his work and from experts in the field who could see no wrong in the work that he was doing or the scientific rationale behind it. He wasn’t offering miracle cures or ripping patients off or acting in any way unethically. The restriction on prescribing was removed in January 2013 but in many senses the damage had been done - doubt had been cast on Dr Mannings competence and the work he did to fund himself while working for free at Star Throwers dried up. More than that, it put him under great personal strain and incredible levels of stress that no amount of public support from patients and friends could quite counteract.

Organic Food and Cancer Risk

There is a theory popular in certain alternative and complementary medicine circles that cancer is caused by environmental toxins, radiation, microwaves, mobile phones and just about every modern convenience in the household. While there's little evidence for any of this, the idea that there are 'chemicals' lurking in the environment has become common-place, particularly when it comes to food. Hence one of the most common questions from newly diagnosed cancer patients: should I switch to an organic diet? There are enough people out there pushing the idea that 'organic' food is healthier than conventionally grown food, so it should be no surprise that people naturally feel that food grown 'without chemicals' will help them in the fight against cancer. After all conventional crops depend on 'chemicals' and organic food doesn't. And we all know that chemicals, in this case mainly pesticides, are bad for you. Therefore organic food should be healthier, and the strong growth in organic food sales in the last ten or fifteen years shows how popular opinion has accepted this assertion. 

However, the results of a new UK study that looked at cancer risk and the consumption of organic food seems to suggest that popular opinion is pretty much wrong in this case (http://www.nature.com/bjc/journal/v110/n9/full/bjc2014148a.html). While organic food and alternative medicine advocates have pushed organics as a way of reducing cancer risk, the study shows that it makes little difference one way or another. The study in question appears in the British Journal of Cancer and is by Oxford University cancer epidemiologist Dr Kathryn Bradbury and co-workers. Part of the Million Women Study funded by Cancer Research UK and the Medical Research Council, this particular bit of research tracked 623 080 middle-aged British women for almost ten years and looked at their pattern of organic food consumption and the incidence of sixteen different cancer types, as well as overall cancer incidence.

Based on their reported eating habits the women were put into three groups: never, sometimes, or usually/always eating organic food. The headline result showed that eating organic was not associated with overall cancer incidence one way or another (in fact there was a tiny increased overall risk of about 3%, but it’s the sort of noisy result one can ignore). The results for the different types of cancer are mixed, with some showing increased or decreased risks, but no overall pattern or anything too dramatic. These results, in contrast to the myths of wholesome organic, have upset some people, especially the British Soil Association, the guardian of all things organic in the UK (including being the premier organic certification body in the country). 

Guest Post - Genetic Alliance UK: The My Condition, My DNA Project

 My Condition, My DNA

Would you be willing to take part in a research study to help us understand what patients affected by genetic conditions and their families think about the use of genomic sequencing in the NHS?

When the first person had their entire DNA sequenced as part of the Human Genome Project back in the 1990s, it took over 12 years. Today it is possible to have your entire genome sequenced in just a matter of weeks. A new technique has been developed which means it is faster and cheaper to do this, and as a result has the potential to dramatically change the way that conditions may be diagnosed and treated.

The aim of this research is to find out what patients and families think about genomic sequencing. This will involve exploring the ethical, societal and practical issues raised by the NHS using genomic sequencing to collect large amounts of an individual’s genetic information with the view to improving healthcare. As the ease of genomic sequencing and its potential uses becomes greater, people working in the NHS and other healthcare providers will be thinking about these issues and making decisions. By being a part of this research, you can help to bring the perspective of patients into the decision making process and form a key part of shaping how genomic sequencing could be used in UK healthcare to benefit patients.

What is the purpose of this project?

To help patients and their families understand what genomic sequencing is and how it might be used in a healthcare setting; and to understand from them their opinion of the ethical, societal and practical issues raised by using genomic sequencing in the NHS.

Who can take part?

If you or a member of you family has a diagnosed or suspected genetic condition we would like to hear from you. We are particularly interested in having families take part. This may include children under the age of 18, although an individual under 18 cannot take part without a parent or guardian.