Wednesday, September 7, 2011

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

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.”

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