Dichloroacetate to enter clinical trials in cancer patients

I’ve written a lot about dichloroacetate, a.k.a. DCA (my last post here, along with links to my previous posts), the small molecule drug that burst onto the scene after Evangelos Michelakis of the University of Alberta published a paper in Cancer Cell in January describing strong anti-tumor activity in preclinical models (in this case, a rat model) of several different cancers.

Scientifically, DCA is interesting because, unlike many previous chemotherapeutic agents, it targets the energetics of the cell, specifically an alteration in cancer cells known as the Warburg effect. This is an idea that goes back 75 years or more, namely that tumor cells are metabolically different than normal cells in that they can survive on the less efficient process of glycolysis, rather than relying on aerobic metabolism, as most cells do. It’s known that many, if not most, tumors are metabolically more active than the normal tissues from which they arise. Indeed, increased glucose metabolism resulting in increased avidity in taking up glucose is the entire basis of positron emission tomography (PET scans). What’s different is that many cancer cells continue to use glycolysis even when there is a level of oxygen present that would normally switch on the aerobic process of oxidative phosphorylation in noncancer cells, a process that takes place in tiny structures called mitochondria. This difference in energetics between tumor cells and normal cells was discovered by Otto Warburg in 1928, hence the name.

A lot of the news stories at the time emphasized that DCA was a small molecule upon which no patent was held. Consequently, pharmaceutical companies were reluctant to fund the large clinical trials that would be necessary for approval by regulatory agencies such as the FDA. This angle of the story was picked up by the blogosphere and the alternative medicine websites, which portrayed DCA as an example of a “cure for cancer” that was being suppressed by evil big pharma. Ignored was what everyone in cancer research knows, namely that few drugs that show activity in animal models ever make it over all the hurdles that it takes to become a drug used in humans. Also ignored was that, although the activity of DCA in these animal models was impressive, it was not a “cure” even in these animals. This misguided hype inspired patients to look for sources of DCA from China and in particular led to a truly misguided pesticide salesman named Jim Tassano to begin making up some home brew DCA, at the same time providing online forums for self-medicating patients to trade stories of tumor response that turned out upon critical examination to be mostly wishful thinking. Fortunately, although it took several months, the FDA finally shut down Tassano’s operation.

The University of Alberta, in fact, has been soliciting donations to fund clinical trials.

It looks as though those clinical trials are going to be a reality. First off the mark will be a phase 2 clinical trial in advanced brain tumors:

Researchers at the University of Alberta have been flooded with calls from people volunteering to take part in human trials for a cancer drug that significantly shrunk tumours in rats.

Health Canada has approved dichloroacetate, or DCA, for a limited trial on people with an aggressive brain cancer called glioblastoma. Researchers are looking for 50 patients in Edmonton who have already tried chemotherapy, surgery or radiation with no success.

The university has already received 100 phone calls from potential volunteers.

Known as “The Terminator,” the cancer has an average survival rate of one year with conventional therapy, said Dr. Kenn Petruk, head of neurosurgery at the university.

The drug, to be tested over the next 18 months, has already showed it can shrink lung, breast and brain tumours in animal and human tissue experiments. Lead investigator Dr. Evangelos Michelakis said doctors will know early into the trial whether DCA is having any effect.

“In six weeks or so, we will know if the drug will have some efficacy on the tumour,” Michelakis said at a news conference Wednesday. “But that doesn’t mean that the job is done. We still have to show that the tumour didn’t increase or, even better, decreased.”

According to a letter by Dr. Michelakis, the University of Alberta has raised more than $800,000, with a goal of $1.5 million.

I’m rather curious about why advanced brain tumors like glioblastoma. I can speculate that it may be because such tumors often exhibit the Warburg effect (not all tumors do) and that the central nervous system relies almost entirely on glucose for fuel and has a high oxygen and glucose content because of its generous blood supply, but that’s just my guess regarding the rationale. Another possible rationale is that these tumors are so deadly that it will take only a short period of time to determine whether DCA has activity against them. The flip side of this rationale, unfortunately, is that such tumors may be so aggressive that DCA alone may have little effect.

In any case, as Dr. Mickelakis emphasizes, it is highly unlikely that DCA is a cure for cancer (or even a cure for a specific cancer):

But Michelakis emphasized that DCA is not a miracle cure.

“Oncology is full of examples of miracle drugs in animals that never make it because they don’t work in human beings,” he said.

“That’s why I want to emphasize of equal importance to this drug itself is the fact that such an effort is taking place and it should inspire other places to develop generic drugs without the support of the industry.”

I’ll be keeping an eye out for the outcome of this trial.

ADDENDUM: After having written this last night to post this afternoon, I noticed this morning that Abel Pharmboy had also commented on this story.

All Orac posts on DCA:

Posts by fellow ScienceBlogger Abel Pharmboy:

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