How the ketogenic diet starves a tumour then genetically engineers the cancer cells

EDITORIAL INTRODUCTION to Travis Christofferson‘s  2nd post “How the ketogenic diet starves a tumour then genetically engineers the cancer cells.” (Read below)

The ketogenic diet Part 2. Dramatic improvements when combined with standard therapies

Editorial Comment

Recently the Guardian published an article dismissing the idea that the very low carb ketogenic diet could be beneficial in treating cancer as a ‘pernicious myth.’ This seemed to me to be a serious mistake which is why last week we ran a feature from an expert on the diet, the American science writer Travis Christofferson.

He explained why the diet made sense, what it did to the body and pointed out some of the serious flaws in the Guardian article . You can see it on the home page, do read it if you have time.

The author of the Guardian article, an Oxford physicist called Dr. David Robert Grimes, had said that cancer was solely a genetic disorder and that diets can’t change mutations. Christofferson showed last week why this widely held view is mistaken.

Promising new ways of targeting cancer

This week Christofferson explains how ketones, produced by the diet, can have a direct and beneficial effect on gene activity. The important idea behind the ketogenic diet – the metabolic theory of cancer – is that it switches attention from genes, to the unique way that cancer cells make energy. They become much hungrier for glucose than healthy cells because they use a different method called glycolysis.

This throws up some up promising new ways targeting cancer. For instance, it explains how a number of non-drug treatments fit together because they help to throttle back a tumour’s fuel supply.

 But that’s just one of the new options. The metabolic theory also offers a way of making chemotherapy less grueling and more effective. Christofferson describes the remarkable results being obtained by a clinic in Istanbul, run by oncologists, who first starve the cancer with the ketogenic diet which allows them to use much lower and less damaging doses of chemotherapy. 

 


How the ketogenic diet starves a tumour then genetically engineers the cancer cells 

By Travis Christofferson

 

Last week I ended my post with the finger pointing firmly at sugar (glucose) in the blood as being a vital source of fuel for cancer growth. Turning cancerous has the effect of re-wiring a cell’s energy production system so it becomes more demanding and less efficient (known as glycolosis).  And that opens up many new ways of tackling tunours.

For instance it is already leading to a less grueling way of delivering chemotherapy, which comes with a raft of side-effects because it damages fast growing cancer cells and fast growing healthy cells alike. By focusing on the way that cancer makes energy treatments can be developed that damage cancer cells but not healthy ones.

The original idea behind the ketogenic diet was that it provided the body with an alternative source of energy – one which healthy cells can use and cancer cells can’t because of the changes to their energy production system.

But it turns out that ketones can do much more than supply energy. They are also are potent epigenetic signaling molecules – that is they can turn gene activity up or down. And for reasons not yet understood, they “turn down” about a dozen (maybe many more) cancer related genes (oncogenes). They do this by changing the chemical “tags” on the proteins that package the DNA.

 Ketones slow tumour growth in the lab

Ketones engage cancer cells in a sort of epigenetic diplomacy. Certain beneficial genes get exposed and so become more active, while a host of oncogenes (cancer driving genes) get turned down causing the cancer cells to behave more like normal cells. Far from being unable to affect genes, as Grimes claimed in his article, it now seems that a ketogenic diet could be having an impressive range of very specific genetic effects.

A simple experiment that highlights this signaling action of ketone bodies: picture two petri dishes with cancer cells. Both dishes have the same concentration of sugar for the cells to use as fuel. When ketones are added to one of the dishes the cancer growth dramatically slows. This is one way we know ketones are affecting cancer cells in ways that go beyond energy restriction.

The ketogenic diet is unique among cancer therapies in that it affects healthy cells and cancer cells very differently. The biochemical details of each one are too complex for this article, so I’ll just list them.

  •    Cancer cells are put under energetic stress because they have trouble burning ketones.
  •    Normal cells are actually energized by the ketogenic diet. Per unit of oxygen burned, ketones generate more energy than sugar.
  •    Cancer cells have many important oncogenes turned down.
  •    Normal cells have beneficial genes turned on (many of the same “housekeeping” genes turned on by caloric restriction)
  •    Cancer cells have a diminished ability to generate glutathione—the “master” antioxidant
  •    Normal cell have an increase in glutathione

The diet cuts damaging chemotherapy side effects

So how does all this lead to new approaches to treatment in the clinic? Star researcher Valter Longo of UCLA calls this strange ability of ketones to make healthy cells healthier and cancer cells weaker “Differential Stress Resistance,” or DSR for short.

Longo convinced oncologists to allow their patients to enter ketosis by fasting (cutting calories right down automatically cuts carbohydrates) for 48—140 hour before chemotherapy and a 5—56 hour fast after chemotherapy. He then measured side effects. Every one of the 14 most common chemotherapy related side-effects was diminished. Of particular note: the fasted patients did not vomit at all and had no diarrhea—two of the most debilitating side-effects.

So it appears the ketogenic diet and its ability to create DSR can diminish side-effects but can it increase the efficacy of other treatments? This seems to be where the ketogenic diet truly shines.

For instance, a substantial and growing block of evidence suggests the ketogenic diet can enhance traditional, standard-of-care treatments such as chemotherapy and radiation, by combining them with still unconventional therapies such as hyperbaric oxygen and drugs that affect glucose levels in the blood. 

The diet makes chemo as well as hyperbaric oxygen more effective

The ketogenic diet weakens cancer cells by physically throttling back their energy and while simultaneously increasing the damage done by oxidants by turning down the genes that produce natural antioxidants such as glutathione. This then makes conventional treatments more effective.

The ketogenic diet (or ketosis via fasting) has been shown in animal models to increase the efficacy of: radiation, chemotherapy, hyperbaric oxygen (cancer cells normally operate at a lower level of oxygen than healthy ones) , drugs that cut down the ability of cancer cells to make energy from glucose), and giving supplements of ketone synthesized in the lab.

If the benefits of the diet really were a myth, as Grimes would have us believe, then it seems odd that the ketogenic diet is currently being investigated as a cancer therapy in over a dozen clinical trials.

Remarkable results from a clinic in Istanbul

And we are finally getting glimpses of real clinical data. At the ChemoThermia clinic in Istanbul Turkey, oncologists are giving their patients a protocol they call metabolically supported chemotherapy (MSCT). The goal of MSCT is to enhance standard of care by exploiting the metabolic derangement of the cancer cell. This is the protocol:

  1. Ketogenic diet
  2. 14 hour fast immediately before chemotherapy
  3. 2-Deoxyyglucose (this is what called a glycolytic inhibitor—it makes energy production via glycolysis less effective)
  4. Dichloroacetate (DCA)  – cheap chemical compound that also interferes with glycolysis. (Crucially neither affect the different method of energy production in healthy cells)
  5. Hyperthermia (heating up the body)
  6. Hyperbaric Oxygen

The results:

  • Standard of care: median survival: 8.6 months
  • Metabolically Supported Chemotherapy: median survival: 43.4 months (and climbing because many patients are still alive)

Note the patients getting MSCT were sicker (all stage 4 patients) than those getting standard of care, a group which included patient with stages 3 and 4.

It’s true. There is a problem with the diet

Promising as all this is, one of the criticisms made by Grimes to debunk the ketogenic diet as a cancer therapy is accurate. He claims that that there is a ‘lack of overall credible data’ and he’s right.

This means that there are no double-blind, placebo- controlled phase three trials to support the ketogenic diet as an adjunctive cancer therapy. This is the so-called gold standard of proof and the reflex reaction of most mainstream oncologists faced with a possible cancer treatment is to dismiss it out of hand unless it comes with a full Randomized Controlled Trial costing millions.

So the question becomes just how high should the bar of burden-of-proof be set? A growing number of oncologists and researchers now believe it is insanely high.

Highly respected oncologists—such as the original pioneers of combining chemotherapy drugs—Vincent DeVita and Emil Freireich – have been railing against the absurd criteria that the FDA has arbitrarily established as a threshold to approve a new therapy for years. They point out that good therapies — potentially lifesaving therapies—sit on the sideline because they will never get the billion-dollar backing necessary to shepherd them through a massive phase three trial.

Promising treatments getting side-lined

Listen to Dr. Vincent DeVita: (the former director of the NCI (National Cancer Institute), pioneer of MOPP chemotherapy, author or co-author of more than 450 scientific articles, editor-in-chief of The Cancer Journal, and author of The Death of Cancer)

“At this date, we are not limited by the science; we are limited by our ability to make good use of the information and treatments we already have. Too often, lives are tragically ended not by cancer but by the bureaucracy that came with the nation’s investment in the war on cancer, by review boards, by the FDA, and by doctors who won’t stand by their patients or who are afraid to take a chance.”

And here’s what Dr. Emil Freireich thinks about the current standard of evidence – by the way, the positions he currently holds include: the Ruth Harriet Ainsworth Chair, Distinguished Teaching Professor, Director of Adult Leukemia Research Program, and Director of Special Medical Education Programs, at the University of Texas MD Anderson Cancer Center in Houston, Texas.

Diet is safe and boosts other treatments so why not use it?

 ‘It’s so obvious that if the FDA allowed us to be rational about treating cancer patients we could move the ball 100 times faster…[Do] you have to do a phase 3 randomized trial? No. If you have evidence that’s clear. If you have an objective response. Objective progression free survival. That’s it.”

The debate generally centres around drugs rather than non- drugs but it seems to me that there is substantial evidence that the ketogenic diet is a good, perhaps great adjunctive therapy. So maybe the “lack of overall credible data isn’t as fatal as it sounds.

It appears to enhance the outcome of other treatments while mitigating side-effects. It is also completely safe, something most physicians don’t appreciate.  It has been used for nearly a hundred years as a treatment for childhood epilepsy and is currently approved for that use on the NHS.

From my perspective, it seems difficult to make the case against it—much less flippantly toss it into the garbage bin of myth, as Grimes does. He would seem to demand the multi-million dollar trial that is never going to happen. Dr. Freireich view seems more sane and humane. The ketogenic diet can clearly tick his boxes: ‘clear evidence, an objective response and objective progression free survival’’. So the question for the official view is: Why not? 

Travis Christofferson

Travis Christofferson

Travis Christofferson is a science writer and a graduate of the Montana State Honors Program in molecular biology. He also has an M.S. in Material Engineering and Science from the South Dakota School of Mines and Technology. He is the author of the bestselling book 'Tripping Over the Truth: The Metabolic Theory of Cancer'. It gives an historical perspective on the re-emerging theory that cancer is triggered and driven by damage to mitochondria. Link

6 Comments

  • Not only do good therapies with a record of success not get the funding to go through phase 3 trials, drugs that are no more effective than existing treatments, possibly a little worse in some cases, and certainly more expensive do get this funding and become FDA approved despite abundant evidence that they have been a waste of time and money.

    • Editorial

      Absolutely. Testing new drugs against a placebo is not a strategy that benefits patients or public health. instead they should be trialled against the best existing treatment. That would stop more expensive me-too drugs and might well mean some off patent – and so very cheap -drugs would continue to be first line treatment. It would also provide an incentive to research more effective treatments rather than settling for a minor tweak to an existing molecule.

  • I think many people believe the answer to Mr Christofferson’s question of “Why not?” is that it doesn’t suit pharma to have cheap treatments that work. The profitable answer has to be a drug, regardless of the question.

    Like many people, I have real doubts about chemotherapy. Dr Fiona Godlee, editor of the BMJ, wrote an excellent piece in November 2016 called ‘Too much Chemotherapy’. This was in response to an article by Dr Peter Wise that Dr Godlee encouraged every oncologist to read.

    Dr Wise said the following about the effectiveness of chemotherapy:

    “An important effect was shown on five year survival only in testicular cancer (40%), Hodgkin’s disease (37%), cancer of the cervix (12%), lymphoma (10.5%), and ovarian cancer (8.8%). Together, these represented less than 10% of all cases. In the remaining 90% of patients—including those with the commonest tumours of the lung, prostate, colorectum, and breast—drug therapy increased five year survival by less than 2.5%—an overall survival benefit of around three months.”

    Bearing in mind the side effects and the resulting quality of life for patients, how much informed consent is there for outcomes like this? The alternative of supportive care rarely gets a mention.

    http://www.bmj.com/content/355/bmj.i6027

  • New knowledge about the brain is transforming our understanding of why we get sick and what to do about it:

    The Scientist has begun to confirm what many people have suspected for centuries: our thoughts and emotions influence our immune system’s ability to protect us from the disease.The emotion is running the immune system (Blair justice 1988).
    How to stay well (or get better if you are not well)to begin with
    Do things that bring you sense of fulfillment, joy, and purpose, that validate your worth
    Pay attention to yourself, turning into your needs on all levels, nourishing your needs on all levels and encouraging yourself .
    Express your feelings appropriately.Loving the lovable is easy.Loving those who seem unlovable is a challenge.Release all negative emotions resentment, envy, fear, sadness,anger.
    Create fun loving honest relationships
    Share knowledge make positive contribution to your community
    Make a commitment to health and well-being and develop a belief in the possibility of total health
    Physicians are too rarely aware of individual humans needs for purpose and meaning in life.For some people, their illness is part of what gives their lives a purpose..the search for the good life.Tapping into that source is the key We have to search for the path.
    Medicine can help us manage illness.How can w e get rid of them.?Why the best physicians, the best medicine our bodies still have to face reality.If health care is just fixing us up it’s doomed to failure.We all want a life worth living.

    Prevention
    The fact that for more than fifty years brain chemical imbalances have been repeatedly claimed exist, to have been scientifically established.The main drivers of these claims have been the medical profession and the pharmaceutical companies.Not suprising, many other mental health professionals have been persuded into believing that brain chemical imbalance is a known fact in depression, professional such as psychologist psychotherapists, counsellors, social workers, nurses.The process of persuasion has further spread, to the recipients of mental health care and their families, peer menatl health workers and volunteers, mental health organisations, governments and ultimately the general public.Medicine can save your life but can also kill you prematurely.Is up to you to find out more the path to self-healing.

  • Where is the clinical trial evidence supporting a carb-based diet for cancer patients?

    • Editorial

      Well quite, good question. If it were a drug it would now be being fast tracked through the licencing process to get this breakthrough drug to patients as fast as possible so lives could be saved etc. There is small trial done on terminal patients published about three years ago by a researcher called Eugene Fine that showed some benefit. Since then nothing large scale although there are some trials in the pipeline – at clinical trials.gov.

      There are those who take the view that any treatment not backed up by a RCT edifice is automatically pseudo-science. That doesn’t seem a rational response to a dietary intervention that is demonstrably very safe and has a plausible mechanism and anecdotal reports. Is is unscientific to use it on patients who have full knowledge of what the evidence is so far and are happy to play the odds? After all many cancer drugs benefit only a small proportion of patients often with gruelling side effects.

      My sense is that the doctrinaire response that such an approach should never be done does not have patients interests at heart and are also ignorant of the way drugs are prescribed in the real world – off label prescribing, for instance.

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