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DCA

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 "cancer metabolism" is sound. "We are still a long way from a treatment, but this opens the window on drugs that target cancer metabolism," says Evangelos Michelakis of the University of Alberta in Edmonton, Canada, who led the trial.

Elsewhere, researchers have started experimenting with a host of other molecules that might target cancer metabolism. "It's about identifying which target is best," says Lewis Cantley of Harvard Medical School in Boston, Massachusetts, whose company Agios Pharmaceuticals is screening for such targets.

Most of these efforts stem from an observation dating back to the 1930s - 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. "It was seen as a follower, not a leader or driver," says Ronald Evans 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 "reawakened" 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.

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, DOI: 10.1126/scitranslmed.3000677).

Side effects were minimal, but Michelakis cautions against being overly optimistic and points out that larger trials are now necessary. "Could the patients have done as well without DCA? Unless we have a placebo-controlled trial, we can't tell."

The trial was useful, nevertheless, not least for the fact that biopsies of the patients' tumours helped confirm DCA's 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) - 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' natural "suicide mechanism", apoptosis.

Blocking HIF-1 did seem to reactivate signals that encourage apoptosis in normal cells once they have reached the end of their lives. "The beauty of restarting the mitochondria is that it hits the command centre of the cancer, and hits multiple other pathways as a result," says Michelakis.

DCA isn't the only way to switch on mitochondria in cancerous cells. Drugs which reactivate the cell's "energy sensor", 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 "blind" AMPK to a lack of energy. So the mitochondria don't 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 better survival rates. 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't the only event that triggers glycolysis. A protein called Cdh1 is involved too. Salvador Moncada 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, DOI: 10.1073/pnas.0913668107).

Cdh1 acts as a "guardian" 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, DOI: 10.1038/nature06734).

Another option is to neutralise the harmful, "downstream" 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's 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. Stephen Lippard 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, DOI: 10.1073/pnas.0912276106). 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.

A private cancer centre in Toronto is selling itself as the first in Canada to prescribe a possibly poisonous chemical to patients, even though the compound hasn’t been tested on humans and hasn’t been approved by Health Canada.

In February, wife-and-husband team Drs. Humaira and Akbar Khan heard how a University of Alberta researcher used dichloroacetate (DCA) to successfully shrink tumours in rats without damaging healthy cells. Last month, they offered the water-soluble powder to cancer patients in Ontario who have exhausted all other treatments.

They did so despite dire warnings from Edmonton’s Dr. Evangelos Michelakis that the chemical can be toxic and can cause imbalance, finger numbness and nerve damage.

“I agree with the warnings,” said Humaira Khan, a public health epidemiologist who focuses on research in Toronto’s Medicor Cancer Centres. The clinic opened one year ago and charges patients about $150 for one week’s supply of DCA.

“But at the end of the day, it comes down to patients’ rights. It comes to the patient’s choice. That was the philosophy and the motivation because patients come to us and say, ‘We know the risks. We understand it hasn’t been studied. I don’t have much to lose.’ “

Khan said it’s better for her clinic to supervise patients instead of having them self-medicate, as hundreds around the world are doing after hearing about Michelakis’s research, published in the prestigious academic journal Cancer Cell.

WORLDWIDE FRENZY

The paper sparked worldwide frenzy, with patients buying questionable DCA from unproven sources and reporting their outcomes in Internet chat rooms.

“We felt we needed to do it,” Khan said.

Her husband, a family physician with 13 years experience in palliative and cancer care, is the clinic’s medical director. “It didn’t seem ethically right to say no,” he said. “At the end of the day, even if we’ve saved one life, it’s worth it.”

Michelakis refused an interview with The Journal. He has yet to present a revised submission to Health Canada to obtain approval to begin a clinical trial of DCA on cancer patients in Edmonton.

But Dr. Terry Polevoy says the College of Physicians and Surgeons of Ontario should take away the Khans’ licences for offering a compound that hasn’t been proven to shrink tumours in humans.

“They are not oncologists (cancer experts). They should not be making these decisions,” Polevoy said in a telephone interview from Kitchener, Ont.

“I think they should be disciplined for using this stuff. That, to me, is unethical, to use something that has never been proved to do anything.”

A spokeswoman for the College of Physicians and Surgeons of Ontario said it’s not the college’s role to say which therapies a doctor can or can’t use.

“It’s the physician’s responsibility,” said Jill Hefley, associate director of policy and communications for the Ontario college. “It’s about informed consent for patients that they have to understand what sort of drugs they are receiving, understand the risks and benefits.”

‘IT’S NOT ILLEGAL’

Alastair Sinclair, spokesman for Health Canada, said while his department doesn’t recommend the use of DCA in humans for the treatment of cancer, doctors can prescribe it.

“It’s not illegal, but we recommend you don’t use it because it hasn’t been approved,” Sinclair said, noting that no Canadian manufacturer has approval to make DCA.

It’s a fairly cheap, common substance that until now has been used solely for research purposes.

“At the end of the day, if you make the decision to take something that hasn’t been approved and not recommended, those are the risks you’re running,” said Sinclair.

But Polevoy said both the college and Health Canada are shirking their responsibility to protect patients.

“Health Canada has the dubious distinction of not taking it off the market,” Polevoy said.

Humaira Khan said her clinic’s supply of pharmaceutical-grade DCA comes from a major American manufacturer. She and her husband spoke with Health Canada, the physicians college and the local College of Pharmacists before proceeding.

They say patients have already seen improvements.

One woman in her 70s, who almost died from chemotherapy, had a four-centimetre tumour on her shoulder that has disappeared.

One man could walk again after taking a strong dose of DCA. His nausea and severe pain also disappeared, even after he had to go off the treatment when he suffered side-effects. Some patients reported memory loss, stomach upset or tremors in their arms.

“Most of our patients have benefited from it,” Humaira Khan said.

“It’s hard to say how much of a benefit, but they are palliative patients and pretty much had nothing else to go on, so DCA has prolonged their life and given them a better quality of life. That gives us a lot of confidence.”

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