The Metabolic Theory of Cancer

Notes on “What Is The Origin of Cancer?” by Travis M Christofferson.

The most useful thing about this article is that it reminded me of the 2010 book, “The Emperor of all Maladies”, by Siddhartha Mukherjee.

The article has is divided into a few sections: a description and dismissal of the genetic theory of cancer, a discussion of the Cancer Genome Atlas project and a dismissal of it, and then the metabolic theory of cancer is described and touted.

The article starts by making some assertion about cancer to frame the discussion. “We are not winning the war against cancer; we are no closer to cures than when Nixon declared the war on cancer in 1971 – in fact, we may be further away.” Cancer has proved a difficult disease–there have been some improvements in survival times in some types of cancer, some cures, but the change in overall cancer treatment has been modest. Currently, a number of targeted cancer drugs are being used and making a difference. Let’s call them 2nd generation drugs to differentiate them from the chemotherapy drugs that kill dividing cells indiscriminately. There are also a bunch of new therapies, several different kinds currently in the works, let’s call them 3rd generation treatments.

In 1971, when the big push to cure cancer began, the difficulty wasn’t clear. At that time, not much was known about what caused cancer and how it progressed. Now we have a decent understanding of it, and there are *several* promising approaches that could substantially improve treatment and outcome.

We’ve understood cancer pretty well for some time, since the 90’s. Unfortunately, treatments have been hard to come by. Treatments are technology, and cancer is a hard nut to crack. Cancer is a body’s cells dividing without limit. These cells start ignoring the signals and controls that keep cells dividing only when and where they are needed. A treatment for cancer needs to get these cells to stop dividing or kill them. It is difficult to treat cancer for two reasons: 1) cancer cells are human cells, so treatments that kill cancer cells and bypass normal cells are hard to engineer, and 2) cancer evolves to resist treatments.

The second factor is the real killer. Think of a cancer of as a population of millions of cells, each a bit from the others due to mutations in DNA or other changes. A treatment that kills almost all of them leaves thousands that are resistant to the treatment. They continue growing and picking up more changes. A second, different treatment will have the same effect. While some of these changes make cancer resistant to treatment, others allow it to escape other limits. A growing tumor runs out of space and out of blood. So cells that can invade surrounding tissue or metastasize to a new place in the body are also successfully evolved tumor cells.

Cancer treatments usually run through these cycles: a treatment initially has great success, but then the cancer comes back. Some cancer cells have survived and they grow and divide and the tumor comes back, changed. If a treatment is repeated, it is less effective each time.

So a cancer cell is a cell that has changed to ignore the normal signals to stop dividing, and as a tumor grows cells that have additional changes keep occurring. Whether a change to a cell’s DNA or metabolism starts it dividing, the process will continue and the cancer cells will keep changing to ignore or bypass things the keep them from dividing. So if a diet change robs cancer cells of glucose or metabolic changes signal them to stop dividing, some cancer cells will not stop dividing and the cancer continues.

A number of genes are known to play a role in cancer, mutations in oncogenes or tumor suppressor genes are found in all (or pretty much all) cancers. The role of mutations in causing cancer is the Somatic Mutation Theory of Cancer. Changes to genes that are involved in controlling cell division allow cells to ignore the normal checks on cell growth and division.

When the Cancer Genome Atlas Project began, years of research had already identified the main cancer genes (hundreds of genes). This link summarizes the project (TCGA). The idea is to get a comprehensive look at what genes are changed in different kinds of cancer at different stages of the disease. Not really expected to be revolutionary, instead just round out the genetic picture of cancer.

A number of 2nd generation cancer drugs target these cancer genes. They knock down cancer for a while, and give patients added months of life. Eventually, the cancers pick up mutations in other genes and bypass the drug. So these drugs usually don’t cure cancer. New methods of characterizing cancer are beginning to reach the clinic that allow each patient to get the drug that targets the genes mutated in their cancer, so these drugs are becoming more effective.

I’ve met Bert Vogelstein, he’s an intense guy. He discovered how p53 mutations cause cancers, and the most common colon cancer gene, APC. He played a role in fleshing out the somatic mutation theory of cancer. The theory is holding up well–sequence a tumor’s DNA, and known cancer genes show up with mutations.

Cancers aren’t all the same. Each one is a cell that pciked up mutations and started dividing and then picked up more mutations. There are lots of cancer genes, so different tumors pick up different mutations, in different orders. The different types of cancer arise from different types of cells. For a particular cell type, it is easier to start dividing if certain genes mutate (a gene already turned on in a cell, for example) so certain cancer genes are common in different types of cancer. There is also a lot of flexibility as cells pick up mutations and lots of potential cancer genes, so each cancer is unique. This has been known for a long time in general terms, but new techniques are allowing each cancer to be characterized in detail. Volgelstein’s review in the journal Science describes this.

The metabolic alterations in cancer have been known about for a long time–biologists developed tools to study biochemistry before the method for genetic studies came along. Cancer cell’s great demand for glucose has been known for a long time. Cell growth and division and metabolism are tightly linked, so changes in cancer genes change cell metabolism and vice versa.

Can changing diet, starving a cancer of glucose stop it, cure it, or at least put it on hold permanently? I can only find a few published studies, mostly in mice. It seems like it may be effective in slowing the progression of some types of cancer, at least temporarily. However, ketogenic diets have been known about for a long time, and trying them for cancer seems obvious. So if it worked well for cancer, it seems likely it would be well known by now.

Thomas Seyfried has worked on cell metabolism in cancer for a long time. He has a book out on his work, and wrote a review for the Medscape site.

In the Medscape article, Seyfried calls “impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin”. This claim seems way too strong. There are many defining characteristics of cancer–things that differentiate it from normal cells. Each one is a potential line of attack on tumor cells, a target for drugs or other treatments. Hopefully, treatments that target metabolic changes can be developed, in addition to Metformin. They would be as welcome, and as profitable for drug companies as any other cancer drug. Most likely, treatments targeting cancer cell metabolism can be effective and retard cancer progression for months, but populations of cancer cells evolve, and they will most likely evolve to bypass each metabolic restraint.

Christofferson’s article touts the metabolic theory all out of proportion to the evidence for it.
He writes that a ketogenic diet cures cancer. He takes the disgraceful step of pulling out a few cases where cancer was ‘cured’ by this diet. Every one of the hundreds of scam cancer treatments comes packaged with patient testimonial ‘cures’. Christofferson quotes Seyfried as saying “If one was able to patent and package the ketogenic diet as a pill for cancer it would be a blockbuster”, but if you read Seyfried’s article in Medscape, written for doctors, he doesn’t make this claim. Either Christofferson or Seyfried isn’t being honest with us.

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