A DRUG that blocks the way cancer cells generate energy could lead to a new class of cancer treatments.
The first human trial of the drug, published this week, is reported to have extended the lives of four people with an aggressive form of brain cancer.
The result is preliminary, but it suggests that, as an approach, tackling 鈥渃ancer metabolism鈥� is sound. 鈥淲e are still a long way from a treatment, but this opens the window on drugs that target cancer metabolism,鈥� says of the in Edmonton, Canada, who led the trial.
Advertisement
Elsewhere, researchers have started experimenting with a host of other molecules that might target cancer metabolism. 鈥淚t鈥檚 about identifying which target is best,鈥� says of Harvard Medical School in Boston, Massachusetts, whose company is screening for such targets.
Most of these efforts stem from an observation dating back to the 1930s 鈥� that cancer cells generate energy via glycolysis. This is different to the way cells normally make energy, through aerobic respiration in specialised chambers called mitochondria. Ordinary cells do use glycolysis but only if they are short of oxygen, as it is hugely inefficient, gobbling up large amounts of glucose for very little energy (see diagram).
At the time, it was assumed that the switch to glycolysis was a product of the cell becoming cancerous, rather than the other way around. 鈥淚t was seen as a follower, not a leader or driver,鈥� says of the Salk Institute in La Jolla, California.
However, in 2008, Cantley showed that glycolysis may actually benefit cancer cells. Though it is inefficient in terms of energy, the process also generates the chemical building blocks for making cells, including amino acids for making proteins, fats for cell membranes and nucleotides to build a genome. As cancer cells replicate very rapidly, the finding suggests that glycolysis might actually help drive cancer.
A year earlier, Michelakis had shown that mitochondria could be 鈥渞eawakened鈥� in human cancer cells cultured in the lab, and in rats, by a drug called dichloroacetate (DCA). This suggested that mitochondria are not impaired in cancer, just underactive, and that switching cells back to using them might fight cancer.
鈥淭he mitochondria are not impaired, just underactive. Reawakening them might fight cancer鈥�
Now Michelakis has given DCA to five people with an aggressive form of brain cancer called glioblastoma multiforme. One person died of the cancer, but tumours stopped growing in the other four and, in one case, disappeared completely. All four were still alive 18 months later, three times the average survival time following the standard treatment of radiation therapy plus temozolomide, which the patients also received (Science Translational Medicine, ).
Side effects were minimal, but Michelakis cautions against being overly optimistic and points out that larger trials are now necessary. 鈥淐ould the patients have done as well without DCA? Unless we have a placebo-controlled trial, we can鈥檛 tell.鈥�
The trial was useful, nevertheless, not least for the fact that biopsies of the patients鈥� tumours helped confirm DCA鈥檚 mechanism of action. They show that cancer cells produce an enzyme that stops mitochondria from working, and that DCA disables this enzyme.
Once it was blocked, the mitochondria swung into action, opening pores to admit glucose and producing adenosine triphosphate (ATP) 鈥� the energy-storing molecule central to aerobic respiration. A series of beneficial changes followed. First, the reactivated mitochondria began spewing hydrogen peroxide, which blocked a substance called hypoxia-inducible factor 1. In cancerous cells, HIF-1 stimulates the growth of blood vessels that feed the tumour and is responsible for inhibiting cells鈥� natural 鈥渟uicide mechanism鈥�, apoptosis.
Blocking HIF-1 did seem to reactivate signals that encourage apoptosis in normal cells once they have reached the end of their lives. 鈥淭he beauty of restarting the mitochondria is that it hits the command centre of the cancer, and hits multiple other pathways as a result,鈥� says Michelakis.
鈥淭he beauty of restarting the mitochondria is that it hits the command centre of the cancer鈥�
DCA isn鈥檛 the only way to switch on mitochondria in cancerous cells. Drugs which reactivate the cell鈥檚 鈥渆nergy sensor鈥�, an enzyme called AMP-activated protein kinase (AMPK), also looks promising, Evans says.
In normal cells, AMPK senses energy availability. If it is low, the enzyme promotes aerobic respiration in the mitochondria. Cancerous cells, in contrast, often contain genetic mutations that 鈥渂lind鈥� AMPK to a lack of energy. So the mitochondria don鈥檛 get the signal, and glycolysis becomes the main energy producer. One way to fight cancer might therefore be via drugs that reactivate AMPK.
There is already evidence that this works. Diabetes is often treated using a drug called metformin, which ramps up AMPK activity in order to reduce blood sugar levels. While monitoring 850 people with lung cancer, David Small and his colleagues at McGill University in Montreal, Canada, noticed that 79 of them, who happened to have been on metformin for diabetes, had . The researchers reported the finding in 2009 at an American Society of Clinical Oncology meeting.
Also, last month, Phillip Dennis of the US National Cancer Institute in Bethesda, Maryland, presented evidence at the American Association for Cancer Research meeting in Washington DC that metformin inhibited lung cancer in mice exposed to a cancer-causing compound.
Blocking mitochondrial function isn鈥檛 the only event that triggers glycolysis. A protein called Cdh1 is involved too. of University College London has coaxed both human brain cancer and normal kidney cells into either overproducing Cdh1 or not making it at all. Cells with no Cdh1 switched to glycolysis, whether or not they were cancerous, while cells that made too much did not turn glycolytic (Proceedings of the National Academy of Sciences, ).
Cdh1 acts as a 鈥済uardian鈥� against glycolysis, Moncada says, and boosting its levels might be a way to fight cancer. However, he cautions that Cdh1 has other functions too, so its use might lead to side effects.
Cantley is focusing on yet another glycolysis switch. In 2008, he showed that pyruvate kinase M2, an enzyme that normally operates only in fetuses, seems to help switch on glycolysis in cancers. He and his colleagues have developed RNA molecules that block PKM2 in cultured cells and in animals (Nature, ).
Another option is to neutralise the harmful, 鈥渄ownstream鈥� effects of glycolysis, rather than the process itself. Gregg Semenza of Johns Hopkins University School of Medicine in Baltimore, Maryland, has isolated 23 compounds that block HIF-1 directly. He is screening them for their suitability as cancer drugs.
It鈥檚 too soon to know which drugs will eventually make it into the clinic, but the hope is that they will be milder than radiation and chemotherapy, which can have nasty side effects.
Metabolic approaches might even be combined with traditional cancer treatments. and his colleagues at the Massachusetts Institute of Technology have attached DCA to the testicular and ovarian cancer drug cisplatin, creating mitaplatin (Proceedings of the National Academy of Sciences, ). In tests on cultured cancer cells, Lippard found that mitaplatin outperformed or equalled the cell-killing capacity of cisplatin itself, as well as a range of similar anticancer drugs.
DCA is no cure-all, however. Cantley cautions that the wide variation in metabolic pathways in different forms of cancer means it is unlikely that a single treatment will work across the board.
