By Jerome Burne
There is a powerful myth, widely believed by cancer patients and their doctors, that soon a greater understanding of genetics will provide the tools to defeat cancer. Unfortunately this optimistic scenario is in serious trouble, yet few are aware of what has been happening.
The data coming out of the latest American genetic screening program, a 500 million dollar project called The Cancer Genome Atlas (TCGA) launched in 2006 – has revealed that the gene changes within the cells of individual tumours are far more complicated and chaotic than anyone had anticipated.
As increasingly sophisticated genetic technologies allow scientists to peer deeper into the DNA of cancer cells, the hope has been that clinicians would be able to identify the genes driving your particular cancer and effectively and safely treat you with one or more drugs that precisely target the rogue genes responsible, making cancer at worst a chronic disease.
However according to a radical new book by Travis Christofferson “Tripping Over the Truth: The Metabolic Theory of Cancer” several of the biggest names in genetics, scientists whose work triggered TCGA, have already admitted defeat.
Cancer’s Dark Matter
‘Something else is driving cancer, it’s not just genes,’ commented Bert Vogelstein, Director of the Ludwig Centerand Clayton Professor of Oncology and Pathology at Johns Hopkins, after wrestling with the hugely puzzling results that have turned the conventional view of cancer upside down. ‘There is some dark matter in the genome that we can’t detect.’
Even more fatal for the project is the view of Nobel Prize winner and co-discoverer of DNA James Watson himself. He now believes that: ‘Further 100 million dollar annual injections … (to cancer gene research) …are not likely to produce the truly breakthrough drugs we so desperately need.’
He also wrote in 2013: ‘The now much touted genome-based personal cancer therapies may turn out to be much less important tools for future medicine than the newspapers of today lead us to believe.’ (The last bit is pretty rich. The papers were only reporting what dozens of scientists including Watson had been telling them.)
The story of how the official view of cancer, sometimes known as SMT (Somatic Mutation Theory) – began with such hope and then ran further and further into the sand is told in this remarkable book published at the end of last year.
Where Dark Matter can be found
Science writer Christofferson’s book gives the first detailed, but also very readable, account of this disaster. Its contents will come as a big surprise to most people.
Since it is such a controversial topic it is worth setting out his credentials for the job. He has an undergraduate degree in molecular biology from the Montana State Honors Program and a master’s degree in Materials Engineering and Science from South Dakota School of Mines and Technology.
However the disaster is only part of the story. The book also brings good news – a highly plausible account of where that elusive “dark matter” might be found. Actually it turns out not to be hidden at all. It involves the way cancer cells make energy (that’s what the “metabolic” part of the title refers to) which was first identified nearly 100 years ago by another Nobel Prize –winning scientist Otto Warburg.
The metabolic theory offers a radical new way of tackling not just gene targets but nearly all cancers by throttling back their fuel supply. That’s because cancer cells generate energy in a different and much less efficient way than the one used by healthy cells. The implication is that it should be possible to degrade the energy supply of virtually any cancer – whatever its complicated pattern of genetic changes – without damaging healthy cells.
The dogged hero
This approach had been declared irrelevant and mistaken by the mainstream in the 1960’s following the discovery of DNA. However the idea that focusing on energy was the key to treating cancer was resurrected and then kept alive for over 20 years by the solitary determination of one of the heroes of this book – Professor Peter Pederson , a dogged biochemist at Johns Hopkins School of Medicine in Baltimore . He not only unravelled the mechanism but was able to predict the sort of drug that could well reverse cancer.
Christofferson describes his shock when in 2012 he first got to examine the data coming out of The Cancer Genome Atlas. When the project had been launched in 2006 researchers ‘largely believed it would reveal an ordered sequence of maybe three to eight genes that when mutated would cause a particular type of cancer. Those genes would be an identifying signature of that cancer, like a fingerprint.’
But what he and other researchers were seeing was nothing like that. Far from there being predictable ‘finger prints’ the mutations were almost entirely random. ‘Critically the mutations identified as starting and driving the disease were vastly different from person to person’ with the same cancer.’
Even worse the mutations, supposedly driving cancer in an orderly manner, weren’t just different from person to person; they could be quite different in different cells in the same tumour. What this meant was the dream of identifying particular mutations and then targeting each one with a drug had vanished in a rude awakening.
Cancer genetics: not what was expected
And the results haven’t been getting any better. In 2013 a study that sequenced 21,000 genes from 100 breast cancer samples found 44 genes that were involved in cancer. The highest number of those genes found in a single sample was six, but 28 of the samples only had one of those genes. “This data,” writes Christofferson ‘flew in that face of everything predicted in the SMT of cancer.’
There have been a number of drugs coming out of this work, targeting genes but despite the hype their benefits have been modest. More problematically for the gene model none has actually cured a cancer. Originally the idea was that knocking out the gene that was driving the cancer would either slow tumour growth right down or stop it completely. This hasn’t happened.
Four years ago the head of the Experimental Therapeutics Section at the National Cancer Institute in Bethesda, Antono Tito Fojo, had this to say:
‘The number of targeted therapies tested in patients with cancer in the past decade was seven hundred, yet no patients with solid tumour have been cured by targeted therapies over the same time period.’
In 1998 the first targeted drug, Herceptin , knocked out a gene mutation known as HER2, only found in 20% of women with breast cancer. It increased survival time by 8.8 percent after ten years. Subsequent gene-targeted cancer drugs had similar modest improvements. None cured a cancer by gene targeting as had been expected.
So it makes a lot of sense to look at what else might be going on. The most plausible alternative candidate for research, according to Christofferson, is the cancer cell’s distinctive energy-generating system first spotted by Warburg.
Cancer’s inefficient energy supply
Virtually all healthy cells use tiny but fantastically complicated units called mitochondria to make energy by combining the glucose from blood sugar with oxygen which produces the energy molecule ATP. It’s an extremely efficient system. Every molecules of glucose (by now turned into a compound called pyruvate) make 30 molecules of ATP.
However in cancer cells, for reasons which are still debated, something goes wrong with this energy generating pathway and instead they have to use their glucose (pyruvate) directly to make energy via a process called glycolysis. This is far less efficient. Without combining with oxygen only two molecules of ATP are produced for every one of pyruvate.
Pederson’s dogged and lonely investigation of cancer cells energy system began producing results. He found that the more aggressive a tumour was the fewer mitochondria it had and the more energy it made directly from glucose. He confirmed that ‘the mitochondria of cancer cells were structurally altered’ in almost every cell type he looked at.
So the question became: how do cancer cells manage to make about the same amount of energy as a healthy cell using a much cruder and less efficient system? Pederson discovered the mechanism for this too and realised that it would provide a promising drug target that could starve cancers.
How diet can also target energy supply
It works like this. Healthy cells can use the glycolysis route to make energy in emergencies because it’s quicker, providing you’ve got good stores of it. In cancer cells the gateway that decides where pyruvate gets channelled – mitochondria or glycolysis – is affected by a mutation that means it all goes to glycolysis. Pederson realised that a drug that could target the protein and prevent the pyruvate from flowing in that direction would create a serious energy shortage.
A cheap off-the shelf drug that should do the job was found over fifteen years ago but legal issues and a lack of funding has meant that 3BP, as it is known, has still not gone through proper testing. It may not be the answer but the long and sorry saga of how it was side-lined suggests that the system for finding new cancer drugs is far too inflexible.
However the metabolic theory has another important implication for dealing with cancer. It suggests a dramatic change in diet might well make a difference. That’s because if shutting off glucose supplies is a plausible target, since the major source of glucose in our blood comes from what we eat, a diet that dramatically reduces blood sugar would seem worth trying.
It’s known as the ketogenic diet and it is being tried by thousands of cancer patients in a kind of freelance way. It involves cutting carbs to around 25 grams a day (and possibly reducing your total calorie to around 1200 a day), which rapidly lowers your blood glucose with the result that fat is release from fat stores, taken to the liver where it is turned into little packets of energy called ketones.
This is a perfectly natural process that has evolved to get us through times of carb scarcity. Humans and many other mammals are like hybrid cars. They can switch from using modified glucose in their mitochondria to using ketones.
But, as we’ve seen, cancer cells have damaged mitochondria and don’t make energy that way, so the ketones are no good for them,. However healthy cells are able to effortlessly replace the lost glucose energy with ketones. It is much harder for cancers to replace the large amounts of glucose they rely on. The cancer begins to starve.
This is a perfectly plausible scenario which for commercial reasons is not getting the trials it merits. (For more details on the ketogenic diet and cancer see HealthinsightUK post.
A company called Genomics England, owned by the NHS, has been set up to sequence 100,000 genomes at a cost of three hundred million pound. The promise is that by discovering more about cancer genes, treatments will improve. Is it really wise to keep all our eggs in this basket, which is looking increasingly frayed? A chat with James Watson would seem in order.