To DCA or Not DCA...That is the Burning Question

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Dr. "DCA"

Dr. Evangelos Michelakis 
Professor of Medicine, Vice-Chair of Research Department of Medicine, University of Alberta

Researcher of the month:

Nov 2010

Science excels in challenging traditional ways of thought. Dr. Evangelos Michelakis is an apt disciple – a medical researcher who shines at confronting scientific and clinical dogma to benefit medical progress.
His work straddles two seemingly unrelated fields, pulmonary hypertension and cancer, which have “more in common than you think,” he says. His pioneering work has contributed to emerging paradigms in both fields and lent credence to an 80-year-old theory of German biochemist Otto Warburg, who believed that the metabolic shift in cellular energy production that occurs within abnormal cells, now called the “Warburg effect”, is a cause – not effect – of cancer.

Tackling traditional thought

In 2001, Dr. Michelakis and colleagues at the University of Alberta began a series of laboratory experiments that led to important discoveries and innovative ways of thinking about pulmonary arterial hypertension (PAH). This rare but deadly disease afflicts women in the 30s and 40s whose 5-year survival rate is worse than for metastatic breast cancer.

They studied the effects of sildenafil (Viagra®) on PAH. This work led to a small clinical trial that showed, for the first time, that this drug is a safe, effective treatment for patients with PAH. The Heart & Stroke Foundation of Canada funded this groundbreaking work, which led to further studies by the drug’s manufacturer, Pfizer, and a new formulation of sildenafil (Revatio®) to treat PAH.

Dr. Michelakis and coworkers were also first to show that a cancer marker called survivin, which was thought to be found only in cancer cells, is heavily expressed in abnormal pulmonary arteries. This work, published in the Journal of Clinical Investigation (JCO), was one of the first comprehensive studies to show a link between PAH and cancer.

One discovery led to another. While investigated excessive cell growth in the walls of pulmonary arteries, Michelakis and his team discovered that the cellular powerhouse – mitochondria – in lung vessels differs from those in other arteries.

The mitochondria play several vital roles within cells. They generate energy, in the form of ATP, by oxidative phosphorylation – the combustion of glucose and other fuels by oxygen. They also act as oxygen sensors and control programmed cell death. This process, known as apoptosis, is suppressed in PAH – and cancer. Both diseases, Michelakis notes, are characterized by uncontrolled cell growth.
He and his team began to search for a drug that would target the mitochondria of pulmonary arteries to reinstate apoptosis. They came upon a substance called dichloroacetate (DCA). This small-molecule drug has long been used to treat congenital mitochondrial abnormalities – for so long, in fact, that it no longer has patent protection.

“We showed that the mitochondria in PAH cells in both animals and humans were suppressed. When we gave DCA, these mitochondria became active again. Apoptosis, which requires functional mitochondria, was reactivated, and abnormal cells within the walls of pulmonary arteries started dying, opening up the lumen and improving PAH.”

DCA works like a molecular scalpel, he explains, targeting abnormally growing cells in PAH without affecting normal cells in other arteries, which do not share the same mitochondrial changes.
This work was published in Circulation (2002, 2006), Circulation Research (2004), PNAS (2007), and Science Translational Medicine (August 2010).

Breathing new life into old theories

In 2007, Dr. Michelakis and colleagues published evidence from laboratory studies in Cancer Cell that showed mitochrondria are suppressed in cancer. They then showed that DCA could reactivate the mitochondria and reinstate apoptosis.

Their findings had a major impact. For the first time, there was proof that cancer actively suppresses the mitochondria to foster abnormal cell growth. This evidence challenged the prevailing dogma, which suggests that cancer is a disease of mutated genes, not a consequence of abnormal metabolism – and it reactivated an interest in Warburg’s belief that abnormal mitochondrial function is a cause, not effect, of cancer.

“The timing was right,” says Michelakis, “because the metabolic theory of cancer was being born.”
DCA inhibits a mitochondrial enzyme called pyruvate dehydrogenase kinase (PDK). This key enzyme is overexpressed in cancer cells. PDK deactivates the pyruvate dehydrogenase (PDH) complex of enzymes on the outer mitochondrial membrane. The PDH complex acts as a gatekeeper that controls the flow of glucose and other fuel into the mitochondrial powerhouse. Without fuel, the Krebs’ cycle cannot function and glucose oxidation does not occur. Apoptosis is shut down.

As a result, cancerous cells suck in more glucose to use in glycolysis – the anaerobic conversion of glucose into energy outside the mitochondria. By shutting down the powerhouse, they cannot produce energy as efficiently but, with apoptosis switched off, they no longer die. Eventually, the uptake of glucose increases to a point that fulfills energy requirements, while the mitochondria remain inactive.
DCA reverses this chain of events. It suppresses PDK and liberates the PDH complex. The mitochondria can resume normal functions, including apoptosis.

Since DCA has been used in the treatment of children with congenital mitochondrial abnormalities since the 1960s, it has a well-known safety profile. With no patent protection, it is an inexpensive medication.

The long, winding road to human trials

Without industry support, it is difficult to advance promising drugs from animal to human trials, says Michelakis. Since DCA had no patent protection, industry was not interested in funding clinical trials.
After fundraising, Michelakis began phase I trials of DCA in small numbers of patients with metastatic cancers at Alberta’s Cross Cancer Institute (CCI). The University of Alberta agreed to cover indemnity which is usually covered by industry sponsors. The Alberta Health Sciences also helped with a number of in-kind contributions. Then, with the cooperation and encouragement of the Director of Neurosurgery Kenneth Petruk, Michelakis’ team zeroed in on one cancer – glioblastoma multiforme (GM), a highly lethal form of brain cancer.

They conducted a clinical trial in a small number of patients with GM. Tissue samples from before and after DCA treatment showed that the small-molecule drug was making a difference.

“We showed that DCA was inhibiting PDK and activated PDH in the tumors of these patients,” says Michelakis. “There was actually some evidence of tumour stability or even regression.”

The results, published earlier this year in Science Translational Medicine (May 2010), once again rocked the scientific community. In addition to challenging scientific dogma about mitochondrial function in cancer, it showed that researchers could conduct human clinical trials without industry support.

The study has opened the door to further DCA trials. Michelakis’ team plans to conduct joint studies of DCA in breast, lung and brain cancer and PAH with several international centers, including UCLA medical school, Memorial Sloan Kettering Cancer Center, and Imperial College in London, UK.

The route less traveled

The biggest challenge in investigating promising small molecules is not learning to think outside the box, says Michelakis, but finding ways to overcome the obstacles that discourage researchers from performing human trials without industry support.

DCA is not a miracle drug, he says, but “it’s very important, because it has helped us to find a new direction. It is pointing the way to the development of better mitochondrial-activating drugs. There’s no question about it.” 

Blog Reprint from the "MAD SCIENTIST" (aka) "PHARYNGULA"

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Dichloroacetate (DCA) and Cancer

Category: Science
Posted on: May 16, 2011 10:02 AM, by PZ Myers (PZ Myers is a biologist and associate professor at the University of Minnesota, Morris.)

So many people have sent me this sensationalistic article, "Scientists cure cancer, but no one takes notice", that I guess I have to respond. I sure wish it were true, but you should be able to tell from how poorly it is written and the ridiculous inaccuracies (mitochondria are cells that fight cancers?) that you should be suspicious. The radical, exaggerated claims make the truth of the story highly unlikely.

Researchers at the University of Alberta, in Edmonton, Canada have cured cancer last week, yet there is a little ripple in the news or in TV. It is a simple technique using very basic drug. The method employs dichloroacetate, which is currently used to treat metabolic disorders. So, there is no concern of side effects or about their long term effects.

The simple summary is this: that claim is a lie. There have been no clinical trials of dichloroacetate (DCA) in cancer patients, so there is no basis for claiming they have a cure; some, but not all, cancers might respond in promising ways to the drug, while others are likely to be resistant (cancer is not one disease!); and there are potential neurotoxic side effects, especially when used in conjunction with other chemotherapies.

So we have one popular account that is badly written and makes exaggerated claims. There is also a university press release, the source for the sloppy popular account, that doesn't contain the egregious stupidities but does tend to inflate basic research studies into an unwarranted clinical significance. And then, of course, there are the actual peer reviewed papers that describe the research and rationale, and also the reservations, on DCA. It's like a game of telephone: you can actually trace the account from the sober science paper to the enthusiastic press release to the web account with its extravagant claims of a simple, cheap cure for cancer, and see how the story is gradually corrupted. It would be funny if the final result wasn't going to dupe a lot of desperate people.

But there is a germ of truth to the story, in that DCA does have potential. Here's how it works.

There are two major pathways that we use to extract energy from sugar. One is glycolysis, which extracts two ATP molecules from each molecule of sugar, and doesn't require oxygen. Then there is glucose oxidation, which as you might guess from the name, does require oxygen, but which takes the byproducts of glycolysis and burns them completely to produce 36 ATP. So there's the tradeoff: if your cells are oxygen-starved, or hypoxic, they can still get energy from sugar, but it's relatively inefficient, but if they do have access to oxygen, they can extract much more. This is why you breathe, and why your heart beats, and why you have an elaborate circulatory system to deliver oxygenated blood to your tissues: without oxygen, you suffer a catastrophic hit to the efficiency of energy production.

Another feature of these two energy-producing pathways is that they are in different cellular compartments. Glycolysis takes place in the cytoplasm, while glucose oxidation occurs in the mitochondria. There is a gate-keeping enzyme, pyruvate dehydrogenase kinase (PDK), that regulates the flow of pyruvate, a product of the glycolysis pathway, into the mitochondria for oxidation. If PDK is active, it suppresses the transport of pyruvate into the mitochondria, and the cell is forced to rely on glycolysis, even if oxygen is available. If PDK is inactivated, pyruvate is shuttled into the mitochondria, even if oxygen is low.

This is where DCA comes in. DCA inhibits PDK, forcing cells to use the more efficient form of energy production. That sounds like a strange way to make a cancer cell uncomfortable, but the other factor here is that mitochondria are primary regulators of apoptosis, or cell suicide. They are loaded with sensors and enzymes that react to abnormalities in the cell (like being cancerous!) by activating a self-destruct mechanism. Shut down the mitochondra, you shut down the self-destruct mechanism that polices the cell. So the idea is a little indirect: by goosing the mitochondria, we also wake up the safety switch that, if all goes well, will cause the cell to spontaneously kill itself.

There are good reasons to think this might work. Many cancer cells arise in hypoxic environments; a poorly vascularized tumor, for instance, is going to be oxygen starved in the absence of blood flow, and the inhibition of mitochondria may be a factor in their survival. There is a well-known phenomenon called the Warburg effect, in which cancer cells will rely on glycolysis even when oxygen is available, suggesting that they have suppressed their mitochondria.

DCA also seems like a relatively safe drug. It's been used for a long time in patients with metabolic disorders, or with metabolic side effects from other problems.

A large number of children and adults have been exposed to DCA over the past 40 years, including healthy volunteers and subjects with diverse disease states. Since its first description in 1969, DCA has been studied to alleviate the symptoms or the haemodynamic consequences of the lactic acidosis complicating severe malaria, sepsis, congestive heart failure, burns, cirrhosis, liver transplantation and congenital mitochondrial diseases. Single-arm and randomised trials of DCA used doses ranging from 12.5 to 100 mg kg^-1 day^-1 orally or intravenously). Although DCA was universally effective in lowering lactate levels, it did not alter the course of the primary disease (for example sepsis).

This is encouraging. It means there is a body of work already published on the effects of DCA, which should simplify the process of moving it into clinical trials. The authors, however, very clearly indicate that it won't be a magic bullet affecting all cancers, but that some are likely candidates.

Dichloroacetate could be tested in a variety of cancer types. The realisation that (i) a diverse group of signalling pathways and oncogenes result in resistance to apoptosis and a glycolytic phenotype, (ii) the majority of carcinomas have hyperpolarised/ remodeled mitochondria, and (iii) most solid tumours have increased glucose uptake on PET imaging, suggest that DCA might be effective in a large number of diverse tumours. However, direct preclinical evidence of anticancer effects of DCA has been published only with non-small cell lung cancer, glioblastoma and breast, endometrial and prostate cancer. In addition, the lack of mitochondrial hyperpolarisation in certain types of cancer, including oat cell lung cancer, lymphomas, neuroblastomas and sarcomas, suggest that DCA might not be effective in such cases. Cancers with limited or no meaningful therapeutic options like recurrent glioblastoma or advanced lung cancer should be on top of the list of cancers to be studied.

Notice that the only work done so far is preclinical: that means it has been tested in mouse models, tissue culture, but hasn't really been tried in cancer patients yet. The authors come right out and say that, express some possible reservations about its effectiveness, and suggest what needs to be done next.

No patient with cancer has received DCA within a clinical trial. It is unknown whether previously studied dose ranges will achieve cytotoxic intra-tumoral concentrations of DCA. In addition, the overall nutritional and metabolic profile of patients with advanced cancer differs from those in the published DCA studies. Furthermore, pre-exposure to neurotoxic chemotherapy may predispose to DCA neurotoxicity. Carefully performed phase I dose escalation and phase II trials with serial tissue biopsies are required to define the maximally tolerated, and biologically active dose. Clinical trials with DCA will need to carefully monitor neurotoxicity and establish clear dose-reduction strategies to manage toxicities. Furthermore, the pharmacokinetics in the cancer population will need to be defined.

Do not rush out and buy DCA and gurgle it down as a cancer preventative. We don't know that it works — the safe concentrations for you may not be sufficient to kill any cancer cells, and the concentrations needed to kill cancer cells may be so high that it will do horrible, unpredicted, and dangerous things to you (some work with patients with congenital mitochondrial disorders also revealed some degree of peripheral neuropathy, for instance). This is why we have clinical trials: to work out safe and effective doses, look for dangerous interactions with other drugs — and if you have cancer, you're already on a complicated cocktail of drugs — and detect unexpected side effects.

We should be urging further investigation of this promising drug with the beginning of clinical trials, but it's far too early to be babbling about "cancer cures". There have been lots of drugs that look great in the lab and have excellent rationales for why they should work, but the reality of cancer is that it is complicated and diverse and there are many more pitfalls between a drug that poisons cancer cells in a petri dish and a drug that actually works well in the more complex environment of a human being.

One other factor that inflames the conspiracy nuts over this drug is that DCA is simple, dirt-cheap, and completely unpatentable — there is no economic incentive for a pharmaceutical company to invest a gigantic bucket of money in clinical trials, because there is no hope for a return on the investment.

This is why an independent academic community with research funded for knowledge rather than profit is so important, and really emphasizes why we cannot afford to privatize all biomedical research. The authors propose a plan for progressing without the involvement of the pharmaceutical industry.

Funding for such trials would be a challenge for the academic community as DCA is a generic drug and early industry support might be limited. Fundraising from philanthropies might be possible to support early phase I - II or small phase III trials. However, if these trials suggest a favourable efficacy and toxicity, the public will be further motivated to directly fund these efforts and national cancer organisations like the NCI, might be inspired to directly contribute to the design and structure of larger trials. It is important to note that even if DCA does not prove to be the 'dawn of a new era', initiation and completion of clinical trials with a generic compound will be a task of tremendous symbolic and practical significance. At this point the 'dogma' that trials of systemic anticancer therapy cannot happen without industry support, suppresses the potential of many promising drugs that might not be financially attractive for pharmaceutical manufacturers. In that sense, the clinical evaluation of DCA, in addition to its scientific rationale, will be by itself another paradigm shift.

I can't blame the industry for not following up on this: a clinical trial costs millions of dollars, and even if DCA pans out, there is no profit at all to be gained from it. For this research, we have to turn to public support (they have an interest in better cancer treatments!) and to scientists and doctors themselves, who of course have a great personal interest in seeing their patients get better.

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Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99(7):989-94.