Monday, 17 November 2014

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.

Friday, 14 November 2014

Book Review - p53 : The Gene That Cracked The Cancer Code

Keywords: Cancer, p53, Li Fraumeni Syndrome
Title: p53 : The Gene That Cracked The Cancer Code
Author: Sue Armstrong
Publisher: Bloomsbury Sigma
ISBN: 978-1472910516

If any single gene deserves a biography, it’s TP53 (more commonly known as p53). This is the gene, memorably christened the ‘guardian of the genome’ by David Lane, one of its co-discoverers, which is the tumour suppressor that is most commonly lost or mutated in cancer. It’s also the gene most commonly mutated in the rare and deadly cancer predisposition condition called Li Fraumeni Syndrome. Science writer Sue Armstrong has crafted that biography, delivering a book that is engaging, interesting and has a real page-turning quality that you might not expect for a book on the workings of a single gene.

Adopting a largely historical narrative, the book explores the evolution of our understanding of cancer via our expanding knowledge of p53. Early on, before the structure of DNA was unravelled, scientists explored the viral transmission of cancer in animal models – sarcoma viruses could reliably infect animals with tumours. If it worked for animals, they reasoned, why not for people? How did the virus create tumours? Investigations showed that these viruses triggered changes in cells that eventually developed into cancers. Individual genes and pathways were discovered that were termed oncogenes – these were the culprits that caused cancer.

But of course most cancers that develop in people are not virally transmitted, but as technology and scientific tools expanded the theories developed and changed. Our understanding of DNA spawned a revolution in our thinking, including our thinking about cancer and the role of genetic change. When it was first discovered – independently by multiple groups – p53 was assumed to be just another oncogene, a driver of cancer development.

Thursday, 6 November 2014

The Burzynski Con

There is a lot wrong with current oncology practice and the research that underpins it. The pace of change is slow. Promised breakthroughs fail to deliver what they initially promised. The clinical trials process is slow and getting slower. Patient needs remain unmet and patients are dying while regulations multiply and conspire against change. But with that in mind, that doesn't mean that science is wrong, that clinical trials are wrong or that there are 'cures' out there which the drug companies are suppressing. As I have written before, there is no such thing as a miracle cure.

Unfortunately there are some people who take what are valid criticisms of the clinical trials process or the lack of progress in oncology and then imagine that there are conspiracies at work to deliberately stop progress happening. And of course there are some people out there who will use that to their advantage. Probably the most notorious example of this is a man called Stanislaw Burzynski.

Burzynki came up with the idea that there were chemicals in the body, which he called antineoplastons, which could be effective against cancer. His idea was that people with cancer were deficient in these antineoplastons, and that by taking them externally they could mount an effective defence against cancer. It's a simple idea, but rather than go through the normal process of testing, Burzynski set up a clinic and began treating patients very early on. He has been doing this for decades, and still there is no proof that his treatment works. In the years that he has been operating his Burzynski Clinic in Texas, he has treated many thousands of patients, at great financial cost to them. It's not a cheap treatment. And, despite what he says, it's not non-toxic either, patients have died from the side effects of his treatment. And still there is no evidence that this stuff works.

Friday, 31 October 2014

For The Love of George - Book

The starting point for this blog was a conversation with my son, George, in the middle of his battle with osteosarcoma. I’d had been immersed in reading about treatments, supplements, theories and he thought that it would be good to share that knowledge with other people. We talked about it for a while and he came up with some ideas for a logo, we talked about the domain name and so on. It was typical George, thinking about the future, coming up with plans and schemes. The other web site he was really keen on starting was eat positive, that was one he was really keen on and I’m glad that I’ve managed to kick that off in a very low key sort of way too. Unfortunately not every story has a happy ending, and George did not live to see either of these sites become real. And of course after his death we created the George Pantziarka TP53 Trust to support other individuals and families afflicted with Li Fraumeni Syndrome in the same way that he was.

But for all this activity, I do sometimes worry that people will lose sight of who George was. He was a kid who suffered three different cancers, and who tried just about every treatment available before finally succumbing to the disease at the age of 17. It’s a painful story, but one that is common to families with LFS, or to families with a child with cancer. It’s a story that needs telling. And to that end my wife, Irene Kappes, has written a book called ‘For The Love of George’. I’ll be honest, it’s not an easy read. It doesn’t have a happy ending, though we all hope that what we are doing in his name can make something positive out of what he went through.

We worry that the book is harrowing and will scare some people, but then how can we make clear what families with LFS have to go through if we’re not honest? The only way is to show what George was like. To show what a fantastic kid he was, how we had good times even when the medical situation was grim, and to hope that there things in the book that people can learn from.

A portion of the proceeds from the book will go into the Trust.

The book is available on Kindle and as hard copy from Amazon.

In the UK: Kindle or Paperback

In the US: Kindle or Paperback

Friday, 24 October 2014

Book Review - Surviving 'Terminal' Cancer

Keywords: Cancer, glioblastoma, drug cocktails
Title: Surviving Terminal Cancer
Author: Ben Williams, PhD
Publisher: Fairview Press
ISBN: 978-1477496510

While there are some cancers for which we have made progress in treatments and consequent survival, there are also some for which progress has been pretty much non-existent. Glioblastoma multiforme (GBM) is one of the latter – the survival statistics are abysmal and have remained unchanged for many years. Which is why this book, by professor of Psychology Ben Williams, is so inspirational. When faced with this terrifying diagnosis, he got through the shock and then decided he was going to do more than just sit back and accept the standard of care treatment that was almost guaranteed to fail. Instead he took matters into his own hands and sought out other options, whatever and wherever they might be. He is, therefore, one of the few very long-term survivors of GBM. What is more, he has done more than just seek out something for himself, and he has dedicated the last twenty years to helping others do the same. This book is his story and it is, without doubt, one of the most inspirational and yet practical books in the vast literature of cancer.

Written in three sections, ‘Surviving Terminal Cancer’ is more than just a memoir, it also includes a section on the need for change in the system of clinical trials and drug development and a final section on some of the specific treatments and supplements that Williams has found to be useful. In all this is a comprehensive range of material that moves far beyond a memoir and becomes more of a manual for the activist patient who wants to go beyond what the standard treatments.

The book starts, however, with Ben William’s own story. He describes the terrifying diagnosis and his initial shock and paralysis in the face of it. But this changes as he responds by using his skills as a scientist to understand the disease and to look at what was being researched. Over time he expands this to develop an approach to his treatment that incorporates multiple additional treatments over and above the standard treatments in place. In the process he comes face to face with an oncological community unwilling to experiment or offer additional choices even when they know that outcome will be dismal. If people are going to die then why is it unethical to treat them with non-standard drugs?

The memoir is profoundly moving and also disturbing in that it reveals a degree of conservatism in the oncology profession that does no favours for patients. 

The next section of the book picks up on many of the issues that his own direct experience raised regarding medical institutions, clinical practice and the clinical trials process. The issues raised are not unique to Ben Williams, nor specific to glioblastoma or even cancer in general come to that. The system is clearly not optional, and it actively inhibits change. It is a system designed for regulators and bureaucrats and the needs of patients are low on the list of priorities. The clinical trials process in particular has continued to evolve towards very large Phase III trials that are expensive, time-consuming and often lead to minor incremental changes in outcomes, if at all. Ben Williams does not argue for doing away with trials completely, instead he argues for smaller and more focused trials leading to changes in clinical practice in a way that is more responsive to good results.

In the final section of the book – suitably entitled ‘What your oncologist won’t tell you’ – the attention turns to ‘alternative’ medicine, supplements, and the current state of play in cancer research.  The arguments about what counts as ‘alternative’ are well-rehearsed, and there is an examination of some well-known controversies regarding laetrile, iscador, the case of Stanislaw Burzynski. The pros and cons of each are discussed, in some detail with regards to Burzynski, but what is more important than the details of each is the process of sifting out the details that Ben Williams goes through. In a world where there are numerous scammers promising miracle cures, arming people with the tools to recognise junk science is essential.

In all this is a fantastic read. It’s thought-provoking, polemical, honest and hopeful. What is more, the approach that Ben Williams is suggesting applies to more than glioblastoma and other brain tumours, it applies across the board to cancer.

Thursday, 2 October 2014

Fecal Transplants And Cancer

Fecal transplantation is probably one of the most disgusting medical procedures in existence. It literally means taking a sample of fecal material (poop, in other words) from one person and transplanting it into another. Like I said, it's a pretty disgusting idea, but one that is receiving increasing attention. The more we learn about the role of our gut bacteria the more we understand that having a healthy gut ecosystem is essential to health. Gut bacteria play a big part in how we digest our food, with possibly a role in causing obesity, and in the development of our immune systems. It's the latter that has been explored the most in inflammatory bowel diseases - which is where fecal transplants have been used to treat conditions like Crohn's Disease and similar conditions.

When it comes to cancer there is also a possible role for our gut bacteria. I have previously written about the study that showed mice with a genetic predispostion to cancer and fed with a probiotic had fewer tumours and later onset of disease than similar mice not fed probiotic. Note that these mice were developing breast cancers, not colon, so the effect of feeding probiotics was systemic, not just restricted to the colon. This is really a stunning result and worth taking note of. But I think there is room to take this further...

There is now strong evidence that our gut bacteria are essential for a good response to chemotherapy - again this has been something of a surprising result, but the evidence is that without the right gut bacteria chemotherapy response is severely blunted. And we also know that having the wrong bacteria - gut dysbiosis in the terminology - is also associated with the development of colon cancer.

Where am I going with this? Well, if we know that fecal transplants can be effective in inflammatory bowel conditions, and we know that gut dysbiosis is a factor in colorectal and other cancers, then shouldn't we now be considering looking at fecal transplants as a possible cancer treatment?

Thursday, 25 September 2014

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.