It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their "immortality". The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe.
It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs. Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumors in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.
DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar. Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis's experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020). Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump don't get enough oxygen for their mitochondria to work properly (see diagram). In order to survive, they switch off their mitochondria and start producing energy through glycolysis.
Crucially, though, mitochondria do another job in cells: they activate apoptosis, the process by which abnormal cells self-destruct. When cells switch mitochondria off, they become "immortal", outliving other cells in the tumor and so becoming dominant. Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die. "The results are intriguing because they point to a critical role that mitochondria play: They impart a unique trait to cancer cells that can be exploited for cancer therapy," says Dario Altieri, director of the University of Massachusetts Cancer Center in Worcester. The phenomenon might also explain how secondary cancers form. Glycolysis generates lactic acid, which can break down the collagen matrix holding cells together.
This means abnormal cells can be released and float to other parts of the body, where they seed new tumours. DCA can cause pain, numbness and gait disturbances in some patients, but this may be a price worth paying if it turns out to be effective against all cancers. The next step is to run clinical trials of DCA in people with cancer. These may have to be funded by charities, universities and governments: pharmaceutical companies are unlikely to pay because they can't make money on unpatented medicines. The payoff is that if DCA does work, it will be easy to manufacture and dirt cheap. Paul Clarke, a cancer cell biologist at the University of Dundee in the UK, says the findings challenge the current assumption that mutations, not metabolism, spark off cancers. "The question is: which comes first?" he says.
Cancer drug resurfaces and threatens false optimism
So, we hear news of a miraculous treatment for cancer. Disappointingly, the story is an old one which has somehow resurfaced on the blogosphere. When we originally published the story four years ago, it created a frenzy on the internet which took us by surprise. Our story reported a new type of treatment that in animal experiments showed promise of potentially being able to tackle most types of human cancer. We often report developments in cancer research, but nothing had ever attracted such a wave of interest. The drug involved, a simple molecule called dichloro-acetate, or DCA, appeared to work by blocking the unusual, sugar-gobbling mechanism called glycolysis by which most cancer cells generate their energy, and so which potentially marks them out from healthy cells.
Exposed to DCA, cancer cells stopped making energy from sugar and resumed making it the way healthy cells do, in chambers called mitochondria. This stopped cancer cells from growing and multiplying, and caused them to wither and die instead. What added to the intrigue was that DCA is such a cheap, simple molecule that no-one has ever patented it. Also, it was already being used to treat rare mitochondrial diseases. Within weeks, patients were trying to get their own supplies of DCA, and some entrepreneurs set up websites to sell it, that were subsequently declared illegal and closed down by the US Food and Drug Administration.
So what happened after the frenzy died down?
The answer is that it was finally tested in five patients with aggressive brain cancer by Evangelos Michelakis of the University of Alberta in Edmonton, Canada, who had conducted the original experiments in animals. The results, published last year in Science Translational Medicine, revealed that it probably extended the lives of four of the patients, while one other died. Most importantly, Michelakis demonstrated from brain scans and biopsies that DCA appeared to work as he had predicted, arresting the growth of cancer cells by switching them back to normal energy production in mitochondria. The experiments also showed that beneficial effects took a few months to kick in. Importantly, Michelakis said that despite the small trial, it would be impossible to tell whether DCA works or not until it is tested in a placebo-controlled trial. As far as we know, no further trials have been conducted, so the jury is still out on whether it may do any good.
We reported the new results in New Scientist and included news of other teams around the world developing treatments targeting glycolysis. Some other treatments that disrupt energy metabolism, such as the drug metformin taken by diabetics, were also showing signs of activity against cancer, for example. So for now, we are a little bit wiser about how DCA might work, but until someone does a much larger, well-organised trial, it would be unwise to assume that taking it will be safe or do any good. The more encouraging news is that other teams are now investigating the scope for targeting glycolysis, and although it could be a long haul to demonstrate whether any work, it does provide another avenue of attack against a disease which continues to push medicine to its limits. Any readers wanting to find out more about DCA may find this blog useful, posted by Cancer Research UK. There's also an excellent blog by National Geographic which goes into even more detail.