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...

http://livinglfs.blogspot.co.uk/2015/05/primed-for-cancer-with-pan-pantziarka.html

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 (www.tp53.org.uk) 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.'

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Links/Contacts:
The George Pantziarka TP53 Trust – www.tp53.org.uk
Original paper (publication date 21/05/15): ‘Primed for cancer: Li Fraumeni Syndrome and the pre-cancerous niche’ -http://ecancer.org/journal/9/541-primed-for-cancer-li-fraumeni-syndrome-and-the-pre-cancerous-niche.php

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?”

Thursday, 19 February 2015

Book Review - A Scientist in Wonderland

Keywords: Homeopathy, memoir, medicine
Title:A Scientist in Wonderland
Author: Edzard Ernst
Publisher: Imprint Academic
ISBN: 978-1845407773
Edzard Ernst initially came to prominence in the UK as Professor of Complementary Medicine, holding the first such chair anywhere in the world. That was in 1993, and Ernst, who already had a pedigree both as a clinician and a researcher, expected that his quest to rigorously apply the scientific method to the various fields of ‘complementary and alternative’ medicine would be welcomed by practitioners and adherents who would want to prove the efficacy of their different ‘modalities’. Now fast forward to 2015 and Ernst is in the public eye once more in the UK with the publication of ‘A Scientist in Wonderland’, his memoir that tells the story not just of his research findings, but also lays bare the meddling of Prince Charles, heir to the British throne and arch-proponent of homeopathy, detoxification theories and a raft of other ‘alternative therapies’.

The book describes Ernst’s circuitous route to that Professorship – from his unconventional upbringing in post-War Germany, his love of jazz and his hesitant move into medicine. This is an environment in which homeopathy and naturopathy are accepted to a greater extent than in the UK. Indeed his first posting is in Germany’s only homeopathic hospital, where patients seemed to respond well to the endlessly diluted concoctions which are homeopathic medicines. As he points out in graphic detail, there can be not a single molecule of active ingredient left in these medicines, but yet patients recovered. Evidence of effect? Or evidence of the natural evolution of many illnesses and the positive power of the placebo effect?

In time Ernst moves to more conventional medical institutions. In addition to growing clinical experience he also begins a research career, finding the role of scientist enormously rewarding and intellectually satisfying. His observes, wryly that:

An uncritical scientist is a contradiction in terms: if you meet one, chances are that you have encountered a charlatan. By contrast, a critical clinician is a true rarity, in my experience. If you meet one, chances are that you have found a good and responsible doctor. 

There are certainly plenty of patients who will echo that, and indeed it is a complaint that many cancer patients will recognise. Indeed, many of us hope that the Medical Innovation Bill (aka the Saatchi Bill, which Ernst does not support), will encourage more of this critical and scientific thinking in our doctors.

Wednesday, 4 February 2015

GcMAF Factory Raided

News from the UK's medical regulator, the MHRA, following a raid on the Cambridgeshire lab which was manufacturing GcMAF. This is a blood product that is sold over the internet as a cure for cancer, autism and a host of other conditions. While there is one bona fide early trial on GcMAF on-going in Israel, the product is being sold from a variety of websites as an actual cure. There is no evidence that it is a cure - and the Anticancer Fund of Belgium has been working hard examining the evidence that exists. To date a number of the papers that the people selling GcMAF have been using as 'evidence' have been retracted (withdrawn from the journals in which they were published). There is a good summary of the evidence at the Anticancer Fund website.

In this latest news from the MHRA, concern was raised about the safety of the product:

The blood plasma starting material being used to make this drug stated “Not to be administered to humans or used in any drug products”. It was concluded that the production site does not meet Good Manufacturing Practice (GMP) standards and there are concerns over the sterility of the medicine being produced and the equipment being used. There are concerns that the product may be contaminated.

The conclusion from the MHRA is stark:

These products may pose a significant risk to people’s health. Not only were the manufacturing conditions unacceptable but the originating material was not suitable for human use. GcMAF products labelled as ‘First Immune’ are not licensed medicines and have not been tested for quality, safety or effectiveness. People should not start treatment with these specific products. It is important that patients currently taking these products seek their doctor’s advice as soon as possible. People should continue taking prescribed medicines and follow the advice of their doctor.

Update: The BBC have reported that the government of Guernsey, where many of the companies selling GcMAF are based, has banned the importation of GcMAF. 

Monday, 2 February 2015

Open Letter - Medical Innovation Bill

Today's Daily Telegraph includes an open letter in support of the Medical Innovation Bill (aka the Saatchi Bill). The letter was conceived and organised independently of the official Saatchi campaign. The letter, which carried 52 signatures, was edited for publication. The full text is reproduced below:

------------------------------------------------------------
The Letters Editor
Daily Telegraph
London
29/01/15

Dear Editor,

We note with considerable interest the successful third reading of the proposed Medical Innovation Bill, aka the Saatchi Bill. While there have been significant advances in cancer treatments in recent decades there remain areas where there has been no meaningful advance. Diseases such as glioblastoma, sarcoma, pancreatic cancer and others have seen no clinically relevant improvements over those same decades. Refractory metastatic solid tumours remain a challenge and a significant cause of morbidity and mortality. Furthermore, for many less common diseases the landscape of clinical trials is barren.

While it is true that clinicians have lee-way to prescribe drugs ‘off-label’, we know from our direct experience with patients that viable clinical options are not being accessed in the vast majority of ‘terminal’ cases. When all standard therapies have failed, and there are no clinical trials available for the patient, the response is almost uniformly to move that patient into palliative care. Too often it appears that clinicians are reluctant to try treatment alternatives – be they metronomic chemotherapies, repurposed non-cancer drugs with evidence of efficacy or compassionate use/medical needs programs. Note that these are all options with often considerable levels of clinical and pre-clinical evidence; this is not junk science or quackery.

We do not dispute that the clinical trial is necessary in order to identify those advances that work and those that do not. However, the evidence base for medicine can come from many different sources. Data collection is a necessary corollary of increased off-label usage and the new registry included in the Bill will record information (including side-effects and outcome data), in every instance of an innovative treatment under the terms of the Bill. This ground-breaking registry will enable us to mine and analyse real world data so that we are not dealing with a set of anecdotes, but validated and clinically useful information and so providing greater patient protection than exists at present. Physicians treating patients with no other options would be empowered to evaluate off-label interventions with the highest evidence of efficacy.

The reluctance of physicians to explore alternative options may not be solely due to a fear of litigation, as Lord Saatchi contends. There are other social, cultural and institutional barriers at work – individual and institutional comfort zones – which often preclude off-label prescribing. However, if the passing of the Bill affects a change in thinking such that there is a greater willingness to explore potentially helpful treatments, then it will have provided benefit to patients. Passing the Bill sends a positive message that encourages responsible use of off-label options. Not passing the Bill sends a strong negative signal that off-label usage is neither encouraged nor supported.

Ultimately the question that must be addressed is: what can we responsibly offer to those patients for whom there are no suitable clinical trials?

Yours Sincerely,
  • Pan Pantziarka PhD, The George Pantziarka TP53 Trust, London (UK) & Anticancer Fund, Brussels (Belgium)
  • Dominic Hill - www.survivingterminalcancer.com Film maker & patient advocate (UK)
  • Professor Marc-Eric Halatsch, Oncological Neurosurgeon and Professor of Neurosurgery, University of Ulm (Germany)
  • Lydie Meheus PhD, Managing Director, Anticancer Fund, Brussels (Belgium)
  • Dr. Gauthier Bouche, Medical Director, Anticancer Fund, Brussels (Belgium)
  • Richard Gerber, PhD, long-term glioblastoma survivor and patient advocate (Italy)
  • Professor Angus Dalgleish, St George's Hospital, University of London (UK)
  • Professor Ahmed Ashour Ahmed, Professor of Gynaecological Oncology, University of Oxford, Consultant Gynaecological Oncology Surgeon (UK)
  • James Hargrave, Empower Access to Medicine (UK)
  • Dr John Symons, Director, Cancer of Unknown Primary Foundation (UK)
  • Fl√≥ra Raffai, Findacure (UK)
  • Professor Stephen Kennedy, Professor of Reproductive Medicine, University of Oxford (UK)
  • Dr Ian N Hampson, Reader in Viral Oncology, University of Manchester (UK)
  • Professor Andy Hall, Associate Dean of Translational Research, Newcastle University (UK)
  • Professor Emeritus Ben A. Williams, Psychology, long-term glioblastoma survivor, patient advocate, Moore’s Cancer Center, University of California, San Diego (USA)
  • Dr Al Musella, President, Musella Foundation, founder The Grey Ribbon crusade: umbrella organisation for over 100 brain cancer charities (USA)
  • Professor John Boockvar, Director, Brain Tumor Center Lenox Hill Hospital NYC, Professor of Neurosurgery (USA)
  • Professor Emil J Freireich, Ruth Harriet Ainsworth Chair, Developmental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (USA)
  • Brett Shockley - patient advocate (USA)
  • Professor David Walker, Professor Pediatric Oncology, University of Nottingham (UK)
  • Laura Mancini, PhD, Clinical Scientist, National Hospital for Neurology and Neurosurgery, UCLH NHS Foundation Trust, London (UK)
  • John Morrissey, Adviser to the Childrens Cancer Research Fund (USA)
  • Stephen Western, patient advocate, Astrocytomaoptions.com (Canada)
  • Richard E. Kast, MD, IIAIGC Study Center (USA)
  • Charlie Chan DPhil FRCS, Consultant Breast Surgeon (UK)
  • Professor Chas Bountra, Professor of Translational Medicine, University of Oxford (UK)
  • Dr Henrietta Morton-King, North Cumbria University Hospitals Trust (UK)
  • Dr Andrew Brunskill, Clinical Assistant Professor of Epidemiology and Health Services, University of Washington Seattle (USA)
  • Vincent Galbiati, President & CEO of Tomorrow’s Cures Today, Washington DC (USA)
  • Neil Hutchison, Founder - Magic Water Pediatric Cancer Foundation - San Diego (USA)
  • Fiona Court, Consultant Oncoplastic Breast Surgeon, Cheltenham (UK)
  • Professor Alastair Buchan, Head of the Medical Science Division and the Dean of the Medical School at the University of Oxford (UK)
  • Dr. Georgios Evangelopoulos, patient advocate, lawyer & political scientist (Greece)
  • Professor John Yarnold, Professor of Clinical Oncology at The Royal Marsden and Institute of Cancer Research (UK)
  • Professor Jerome H Pereira, Consultant General & Oncoplastic Breast Surgeon, Norwich Medical School University of East Anglia (UK)
  • Dr Lynne Hampson, Non Clinical Lecturer in Oncology, Institute of Cancer Sciences, Manchester (UK)
  • Professor Robert Kirby, MD, FRCS, Consultant Surgeon and UHNM Hospital Dean (UK)
  • Professor Gareth Evans, Professor of Medical Genetics and Cancer Epidemiology, University of Manchester (UK)
  • Dr Rupert McShane, Coordinating Editor Cochrane Dementia and Cognitive Improvement Group, Oxford University (UK)
  • Michael Shackcloth, Consultant Thoracic Surgeon, Liverpool Heart and Chest Hospital (UK)
  • Professor Vikas P. Sukhatme, Professor of Medicine, Harvard Medical School, Co-founder Global Cures (USA)
  • Vidula Sukhatme, Co-founder Global Cures (USA)
  • Sarah Lindsell – CEO, The Brain Tumour Charity (UK)
  • Neil Dickson - Chairman, The Brain Tumour Charity (UK)
  • Alex Smith (Founder, Harrison’s Fund) (UK)
  • Giles Cunnick, Consultant General & Breast Surgeon, Bucks Healthcare NHS Trust, (UK)
  • Dr Piers Mahon, Biotech Consultant, (UK)
  • Paul Fitzpatrick, Chairman, Duchenne Now, (UK)
  • Dr David Faurrugia, Consultant Oncologist, Cheltenham General Hospital (UK)
  • Dr Chris Govender, Medical Officer in Addictions, (UK)
  • Sue Farrington Smith, Chief Executive, Brain Tumour Research, (UK)
  • Professor Steven Gill, Professor in Neurosurgery, University of Bristol (UK)