Respectful Insolence

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:

  1. In which my words will be misinterpreted as “proof” that I am a “pharma shill”
  2. Will donations fund dichloroacetate (DCA) clinical trials?
  3. Too fast to label others as “conspiracy-mongers”?
  4. Dichloroacetate: One more time…
  5. Laying the cluestick on DaveScot over dichloroacetate (DCA) and cancer
  6. A couple of more cluesticks on dichloroacetate (DCA) and cancer
  7. Where to buy dichloroacetate (DCA)? Dichloroacetate suppliers, even?
  8. An uninformative “experiment” on dichloroacetate
  9. Slumming around The DCA Site (TheDCASite.com), appalled at what I’m finding
  10. Slumming around The DCA Site (TheDCASite.com), the finale (for now)
  11. It’s nice to be noticed
  12. The deadly deviousness of the cancer cell, or how dichloroacetate (DCA) might fail
  13. The dichloroacetate (DCA) self-medication phenomenon hits the mainstream media
  14. Dichloroacetate (DCA) and cancer: Magical thinking versus Tumor Biology 101
  15. Checking in with The DCA Site
  16. Dichloroacetate and The DCA Site: A low bar for “success”
  17. Dichloroacetate (DCA): A scientist’s worst nightmare?
  18. Dichloroacetate and The DCA Site: A low bar for “success” (part 2)
  19. “Clinical research” on dichloroacetate by TheDCASite.com: A travesty of science
  20. A family practitioner and epidemiologist are prescribing dichloracetate (DCA) in Canada
  21. An “arrogant medico” makes one last comment on dichloroacetate (DCA)
  22. Finally, the FDA acts on TheDCASite.com

Posts by fellow ScienceBlogger Abel Pharmboy:

  1. The dichloroacetate (DCA) cancer kerfuffle
  2. Where to buy dichloroacetate…
  3. Local look at dichloroacetate (DCA) hysteria
  4. Edmonton pharmacist asked to stop selling dichloroacetate (DCA)
  5. Four days, four dichloroacetate (DCA) newspaper articles
  6. Perversion of good science
  7. CBC’s ‘The Current’ on dichloroacetate (DCA)
  8. Dichloroacetate (DCA) Phase II Trial To Begin

Comments

  1. #1 Jess
    October 1, 2007

    Excellent exposure for UofA, I hope they can get a trial going.

  2. #2 J-Dog
    October 1, 2007

    Thank you for all the work fisking DaveScot and the charlatans, and posting about the positives, and what the actual science of medicine is really all about.

  3. #3 S. Rivlin
    October 1, 2007

    “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.”

    While the brain is known to consume large amounts of glucose and oxygen (the brain comprises only 2% of our body weight, but consumes 20% of the body total glucose and oxygen consumption), the levels of glucose in the brain’s blood are actually lower than their levels in the blood entering the brain. This is due to the brain’s high rate of glucose consumption.

  4. #4 b. sharp
    October 1, 2007

    I apologize for being off-topic, but it does seem that Doherty has posted an attack on you-

    http://autisminnb.blogspot.com/2007/09/jenny-mccarthy-knocks-over.html

    I also found it amusing that he’s willing to take on any of the people on ScienceBlogs in this manner, considering the mix of exaggeration about the actual events that happened, and his lack of medical or scientific expertise. (And speaking of lack medical or scientific, his latest post quoting from a vaccine study is up there too.)

  5. #5 Coin
    October 1, 2007

    So, a question. As I remember the descriptions of Michelakis’ original Cancer Cell paper, they tried two different ways of suppressing glycolysis. One was DCA. The other was some kind of RNA therapy. In the rats, the two had similar effects.

    Are there any circumstances under which after this DCA trial is over, they might try a trial of the RNA treatment or something like it?

    For example if the DCA treatment is shown not to work, or if it works but only at dosage levels where DCA is highly toxic, might they try the RNA treatment? Or if this DCA trial doesn’t show results, is the investigation just over?

  6. #6 Jacob Wintersmith
    October 1, 2007

    A pesticide salesman pedaling a homemade cancer cure?!? You’ve got to be making this up, Orac. Because that is just too perfectly, horribly, ridiculously ironic.

    What’s next? Tongues-speaking televangelists claiming to cure mental illnesses???

  7. #7 Abel Pharmboy
    October 2, 2007

    Thanks for the plug, chief – I, too, wrote my post Sunday night as well but scheduled it for midnight instead of later in the day. Interesting to learn that you are somewhat perplexed by the choice of brain tumors for the first test.

    Coin, the RNA interference approach to inactivating the same enzyme targeted by DCA (PDK; pyruvate dehydrogenase kinase) is quite far off from therapeutic reality, not just for cancer but for any disease. This short review gives some background and explains why the RNAi approach will take awhile to get to the clinic.

  8. #8 bcpmoon
    October 2, 2007

    “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 agree, the interests of “the industry” (people like you and me, working with with your savings, btw) are more often than not profit-oriented, in stark contrast to the motivations of the general populace, and it is a good thing to have a way to develop drugs where the normal way doesn´t work. But.
    Getting a drug to market without the expertise of evil big pharma with regard to filing, production, formulation, distribution, etc pp. will be interesting and don´t forget that CT2 is not CT3. Then you need serious money. It would have been better to get a Pharma company to sponsor this trial (1.5 M$ for AAA+ publicity – a bargain) and tap into their ressources. But what do I know…

  9. #9 Coin
    October 2, 2007

    Abel, that’s very interesting, thanks!

  10. #10 Freddy the Pig
    October 3, 2007

    Apparently there is great enthusiasm for this reasearch in the Peace River area in Northern Alberta. They had an auction to raise money for DCA research with donated items such as $5000 worth of gravel and a 2 minute shopping spree at the CO-OP grocery store that included an entire bison (buffalo) cut and wrapped. Interestingly, Peace River is about the only place in North AMerica that wants nuclear reactors built in their area.

  11. #11 kamagurka
    October 8, 2007

    Could you elucidate why drugs aren’t tested on pigs? I always remember being told that pigs were pretty much the animal that is most similar to humans…

  12. #12 Orac
    October 8, 2007

    I’m not 100% sure of the answer, but my guess is that (1) there aren’t good tumor models in pigs and (2) it’s incredibly more expensive and would take a lot longer.

  13. #13 HealthcareReviews.com
    October 22, 2007

    Why aren’t government research agencies or non profit cancer groups funding this research?

    Why did this lab need to solicit the funds directly from people?

    These questions are almost as important an issue as the cancer research itself.

    It was a gutsy move raising their own funds, they’re probably going to be blacklisted from the main funding agencies for the rest of their careers.

    Hopefully this set a precedent and will encourage other labs to pursue less profitable cures and Cancer groups will start to show some balls and fund something big pharma doesn’t like.

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