Dichloroacetate (DCA) and cancer: Déjà vu all over again

ResearchBlogging.orgLate last week, a crank I hadn’t heard from in a while showed up in my comments. I’m referring to DaveScot, who normally was known for promoting anti-evolution rhetoric in the service of the pseudoscience known as “intelligent design” creationism. This is what he said:

Hi Orac,

terrasig suggested you do a followup article on dichloroacetate (DCA) given the paper just published on the phase 1 trial in Edmonton.

Three years have passed and countless cancer patients were denied this drug. Now at the end of its first phase one trial we know exactly what we did from the reports of people self-medicating in 2007 before the FDA forced it off the market – it shows great promise.

Explain to me again how these controlled trials are oh-so-much better than the ad hoc trial of self-organized self-medicants? Lay that old woo stick on me again, buddy.

How can I refuse such a heartfelt request for a loving application the clue by four (a.k.a. the cluestick). Apparently DaveScot forgot the last time I laid it on him. Oddly enough, it was not over evolution or creationism, and the loving application occurred over three years ago. Specifically, it was about a topic that I hvaen’t written about for about a year and a half now, mainly because there wasn’t any real news to write about, namely (as I’ve put it) the “cancer cure that big pharma doesn’t want you to know about,” dichloroacetate (DCA for short).

Actually, DaveScot wasn’t the first this week. Over the last several days, I’ve received a trickle of e-mails about DCA. These generally fell into two categories. One category was simply asking me to update the story; the other category was of the type demonstrated by DaveScott, gloating that I was wrong when I threw cold water on the ridiculous level of hype over this drug on the basis of a single paper reporting that DCA showed significant efficacy against various cancers in cell culture and rodent models of cancer.

I suppose I shouldn’t be too hard on DaveScot. After all, when the DCA saga began in January 2007, I started noticing a bunch of posts by various bloggers as well as news stories that all had similar titles, such as Cheap, safe drug kills most cancers, Objectively pro-cancer, Gotta pay, When promising cures are ignored, and, my personal favorite, Potential cheap, safe cure for cancer: Will Big Pharma Allow It?

Note that there were two assumptions about the study three years ago. First, these bloggers and pundits assumed that the cell culture and animal work were definitive evidence that DCA might be a “cure” for cancer. Second, the assumption was that, because the drug was out of patent and very cheap to make, neither the government nor pharmaceutical companies would be interested in funding it, thus condemning thousands, maybe millions, of people to die of cancer unnecessarily. Unfortunately, the New Scientist article and articles in the Edmonton Sun featured headlines to that effect and quotes by the investigator Evangelos Michelakis lamenting how he had had difficulties finding funding to do the next step, clinical trials in cancer. As a result of these sensationalistic stories, unscrupulous “businessmen” sought to bring DCA to the masses. A frenzy of sorts was unleashed, with desperate cancer patients scrambling to find DCA. If you’re interested in the details, scroll to the end of this post for a list of the numerous blog posts that I did on the topic as the story was evolving. That’s the past, and all the “Insolence” and science are there for you if you want to read it. I’m concerned with today (well, last week), when apparently DCA bubbled to the surface in news reports such as this, which were apparently what “inspired” DaveScot’s and some e-mails challenging me. For example:

Orphan drug dichloroacetate (DCA) has been found effective against aggressive brain cancer in a small Canadian study. Orphan drugs are meant to treat rare medical conditions. DCA is now used to treat a rare enzyme disorder in children, but researchers have found it useful in brain tumor too.

I’ll admit that the hype this time around isn’t as overblown as it was three years ago, but some of the same elements remain: A nontoxic “highly effective” treatment (or even cure) for some cancers that, because it’s no longer under patent, drug companies won’t touch. But, even now, is DCA worthy of this hype? Let’s step back a minute and refresh our memories about exactly what DCA is and what all the fuss was about three years ago.

DCA and the Warburg effect

DCA is a very simple molecule, deceptively simple. Basically, it is an analog of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. Interestingly, it is only one chlorine atom off from trichloroacetic acid (TCA), a chemical we routinely use in the laboratory to precipitate nucleic acids and proteins from solution.

DCA has been around for a long time (which is why is it no longer under patent) and has primarily been used for inherited diseases of mitochondrial metabolism. Mitochondria are often (and correctly) referred to as the “powerhouses” or the “batteries” of the cell, because it is in the mitochondria that the main energy-containing molecule, ATP, is produced using byproducts of glycolysis and the Krebs citric acid cycle to generate a proton gradient across the mitochondrial membrane, which supplies the energy for the enzyme ATP synthase, which, true to its name, synthesizes ATP for use in the cell as a chemical source of energy. The key thing to remember about oxidative phophorylation is that it requires oxygen, whereas glycolysis does not. When there is insufficient oxygen, the end products of glycolysis end up being turned into lactic acid, which is one of the things that make muscles feel tired after a rapid workout that exceeds the capacity of the body to deliver oxygen to the tissues. The primary activity of DCA in cells is to inhibit the enzyme pyruvate dehydrogenase kinase. The result, to boil it down (and not to have to stress my knowledge of the basic biochemistry of glycolosis, the Krebs cycle, and oxidative phosphorylation too much) is to shift the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. To boil it down even further, DCA shifts the cell’s metabolism from anaerobic to aerobic metabolism.

Why, then, would such an activity be useful as an anticancer therapy?

It all boils down to something known as the Warburg effect, which Otto Warburg first described way back in 1928 and reported in Science back in 1956. Over the last five years or so, cancer researchers have been increasingly coming to appreciate the role of abnormalities in metabolism, in particular the mitochondria, in cancer. To put it briefly, many cancers (approximately 60-90%) favor glycolysis, even in the presence of adequate oxygen for oxidative phosphorylation, leading to a voracious appetite for glucose. Indeed, it is this very avidity of cancer cells for glucose that is the basis of the PET scan, which detects the high uptake of a radiolabeled form of glucose by cancer cells relative to the surrounding normal cells.

Over the last few years, there has been a sort of “chicken or the egg” argument about what is more important and what is the first abnormality leading to cancer. The traditional view has long been that mutations in DNA lead to the activation of protooncogenes into cancer-initiating and causing oncogenes and to the shutdown of tumor suppressor genes. Under this model, mutations leading to cancer also lead to the observations of abnormalities in metabolism. In the wake of the DCA furor, there have been data reported suggesting that the metabolic derangements may actually occur first or simultaneously with the mutations. p53, for instance, the granddaddy of tumor suppressor genes, can trigger the Warburg effect when mutated. Whatever the case, it is now fairly clear that abnormalities in cancer cell metabolism are very important in driving cancer growth and could well represent targets for cancer therapy. AS a result of these new data, studying the metabolism of cancer cells has become a much hotter topic of research than it has been in the past. Everything old is new again, it seems. Why cancer cells might have an advantage due to the Warburg effect is a matter of debate, although, given how tumors frequently outgrow their blood supply, being able to maintain themselves in low oxygen situations would be advantageous.

This fascinating basic science met the public in January 2007, when Michelakis and his colleagues at the University of Alberta in Edmonton published a seminal paper in Cancer Cell. In the study, DCA was tested in multiple cell culture and rodent models of cancer. In rats, tumor weights in animals treated with DCA were approximately 60% lower than the tumors in the untreated control groups. The drug increased apoptosis, decreased proliferation, and inhibits tumor growth by acting on a critical enzyme that controls the switch between aerobic and anaerobic metabolism without harming non-cancerous cells. Even better, DCA had already been FDA-approved for mitochondrial disorders, meaning that using it in humans would be an “off-label” use of an already existing drug to test it in humans. Thus, the regulatory requirements were considerably easier to meet for early drug trials in cancer.

Déjà vu all over again

Over the last couple of years, my biggest fear was that the activities of “entrepreneurs” like Jim Tassano would taint what is a scientifically fascinating and potentially very useful new cancer therapy with the indelible stain of quackery. DCA is most definitely not quackery. It is, however, unproven in humans and thus may not be effective, which is why self-treatment and treatment by doctors who have no clue what they are doing are not advisable. Fortunately, while ignorant businessmen like Tassano and opportunistic doctors were selling DCA to desperate cancer patients, a clinical trial was beginning by Michelakis and his team, and last week the results were reported in Science Translational Medicine entitled Metabolic Modulation of Glioblastoma with Dichloroacetate.

The first part of the study was something quite fascinating that I don’t recall ever having seen before in a clinical trial. Michelakis and colleagues studied 49 consecutive surgically excised glioblastomas. Glioblastoma is an aggressive form of brain cancer known to exhibit the Warburg effect and thus a good candidate for the first attempts at testing DCA in humans. These tumors were then tested in vitro with DCA. The excised tumors and cells derived from them did demonstrate evidence of the Warburg effect, and treatment of the cells in vitro and in vivo with DCA resulted in significant reversal of some of these features in the excised tumors, particularly mitochondrial hyperpolarization, while not having any effect on normal tissues excised with the cancers. This is illustrated in Figure 1:

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Michelakis also reported other indications that, in these glioblastoma tumor cells, DCA appeared to be having biochemical effects consistent with reversing the Warburg effect and killing glioblastoma cells, including increasing apoptosis (programmed cell death) and modulating the levels of a mitochondrial enzyme.

The second part of the study is what most media and blog reports focused on, probably because it is the clinical trial part of the study. Michelakis and colleagues treated five patients with neuroblastoma with oral DCA. However–and this needs to be emphasized–patients were also treated with a chemotherapeutic agent (temozolomide, abbreviated TMZ) and radiation, with DCA added to the mix at different times and in different combination. (I’ll go into more detail about this later.) The DCA dose started at 12.5 mg/kg orally twice a day for 1 month, and then the dose was increased to 25mg/kg orally twice a day. Michelakis then followed a dose de-escalation protocol, decreasing the dose by 50% when dose-limiting toxicity occurred. The patients were followed clinically for up to 15 months. In other words, this appeared to be a combined phase 0/phase I clinical trial, with a dose escalation. Michelakis went one further in that he isolated tumor cells from the pretreatment biopsies and produced glioblastoma cell lines. He could do this in three of the patients because he had tissue from their first debulking surgery, and these patients had recurrent glioblastoma that had failed additional chemotherapy

For those not familiar with the various types of clinical trials, phase I clinical trials are not trials of efficacy. They are designed to determine two things: dose and dose-limiting side effects. They generally use a few patients (although five patients represent a rather small number, even for a phase I trial, which usually requires around 10 or 20), and it is not uncommon to perform a dose escalation. Researchers don’t expect necessarily to see tumor response in a phase I trial, as that is not the purpose of the trial, but it is heartening when tumor shrinkage is observed, for obvious reasons. Phase 0 trials similarly are not therapeutic trials but rather seek to determine if the drug is doing biochemically what it is expected to do based on preclinical studies. The usual design is to take a biopsy of the tumor, test it for biochemical markers in the laboratory, treat the patient with experimental drug, and then resect the tumor. The biochemical markers in the resected tumor are then compared with those measured in the pre-treatment biopsy. The idea is to see whether the drug can recapitulate biochemical changes in actual living tumors in human patients, the idea being that, if it can, then the drug is “hitting the target” (i.e., its molecular target) and therefore “working.” Whether its “working” actually shrinks tumors or results in prolonged patient survival is then the next question that has to be tested.

So, how did the patients fare?

Patients #1-3 were patients with recurrent glioblastoma who had had multiple different forms of therapy. Patient #1 completed standard therapy, including debulking surgery, radiation, and TMZ. He then received DCA therapy and remained clinically stable for 15 months. He even had some regression of paraventricular masses, as shown in these MRIs:

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Patient #2 had had several glioblastoma recurrences despite surgery, radiation, TMZ and several palliative chemotherapy protocols, including etoposide, CCNU (Lomustine) and tamoxifen. She underwent another debulking surgery followed by DCA. Fifteen months later, she was doing well with stable disease (disease that hasn’t progressed).

Patient #3 died after three months.

Patients #4 and #5 were patients with a diagnosis of new, as opposed to recurrent, glioblastoma. Patient #4 underwent surgical resection and then entered a protocol of a three-month DCA pre-treatment followed by DCA plus standard therapy, a strategy based on the speculation that DCA might sensitize the tumor to subsequent chemotherapy. By the end of the third month however the patient showed radiologic evidence of disease progression and a second debulking surgery was performed. Following the surgery he continued with DCA and standard therapy (radiation and TMZ). His TMZ treatment was extended to nine months, because he was showing ongoing regression. After the combination phase, he continued with DCA alone for six more months. At that time (eighteen months of DCA therapy, 15 months after the 5 combination therapy was initiated), he remained asymptomatic, with no radiologic evidence of tumor growth or recurrence. Patient #5 underwent debulking surgery for GBM and then was started on DCA. along with radiation and TMZ therapy. The patient completed the TMZ regimen 6 months later and remained on DCA alone for 9 additional months. Michelakis reported that there was evidence of ongoing regression after TMZ was completed and 15 months after enrollment (15 months on DCA) the patient showed complete resolution of the tumor (Fig. S4), remaining asymptomatic. Patient #5’s MRI is shown below:

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The reason I went into such detail about these five patients this is because not only were there only five patients, but they were not all even treated the same way. They were treated with varying regimens of surgery, with drug therapies combining DCA and chemotherapy (mostly TMZ), some with and some without radiation. Even so, the tissue from these tumors showed signs of metabolic reversion to an oxidative phosphorylation phenotype. They also showed signs of decreased angiogenesis, suggesting that DCA also inhibits angiogenesis, resulting in decreased vascularity of the tumors. In fact, normal cells (namely the endothelial cells that line blood vessels in the tumor) also showed increased apoptosis. This result is somewhat anomalous in that DCA is not supposed to affect normal cells. On the other hand, there is copious evidence that microvessel endothelial cells are not entirely “normal,” although I’ve never seen any evidence that they exhibit the Warburg effect before.

Perhaps the weakest part of the study was Michelakis’ attempt to link DCA to cancer stem cells in glioblastoma. The concept of cancer stem cells is something I should do a full post sometime; in the meantime, though, my “blog buddy” has written a bit about them elsewhere. Suffice it to say that stem cells are hot; they’re sexy. They’re a fad right now. Don’t get me wrong; I think cancer stem cells are important in cancer pathogenesis and therapy. It’s just that, if you peruse the medical literature these days, pretty much every researcher is desperately trying somehow to link his results to cancer stem cells. The data presented by Michelakis to try to indicate that DCA was targeting cancer stem cells struck me as fairly unconvincing and “tacked on.” The study would have been just as strong without it.

So what does this all mean?

The problem is, as both our very own David Kroll pointed out, we don’t know for sure if the DCA was responsible for this effect. As a cancer researcher, I can’t say whether the regressions observed were due to DCA, although the regression of paraventricular masses in patient #1 and the regression observed in patient #5 are certainly fairly suggestive (at least to me) of an anti-tumor effect due to DCA alone. The only side effect Michelakis reported was a reversible change in peripheral nerve function.

I’m frequently asked why we shouldn’t just use DCA now–or even let people use it the way that they were using Jim Tassano’s homemade DCA? What’s the harm? That’s a rather difficult question, because there is always a conflict between wanting to do something now for suffering patients, damn the consequences, and following the scientific method to demonstrate efficacy and safety. Our nation has been at both extremes. Indeed, until 1906, pharmaceutical companies could make essentially any claims and sell essentially anything to the public as a drug without regulation. We all know how well that worked out. Early in the history of the FDA, as Dr Jerome Groopman points out, companies often tested new drugs by sending them to doctors to offer to their patients, asked for little information regarding side effects and complications, and had no standard criteria for efficacy. There was a reason we moved away from such a system.

I think Dr. J. Leonard Lichtenfeld, Deputy Chief Medical Officer for the national office of the American Cancer Society, put it well in writing about this latest DCA study on his blog, Dr. Len’s Cancer Blog:

This research still needs lots of work before we know whether it works or doesn’t work, and whether it is really safe or not when given to patients with cancer under a variety of circumstances.

If that sounds overly cautious, so be it. I have seen too many dashed hopes in my medical career which make me a bit cautious about reports like this. That’s not to say I don’t think it could work–it could, as I mentioned above–but I want to see evidence in well done trials that prove the point that DCA is effective in the treatment of which cancers under what circumstances.

Early in my cancer training there was a substance isolated by a researcher that was supposedly non-toxic and would cure leukemia. The research center where I was working was inundated from people around the globe who wanted this treatment, especially after the lead researcher injected himself on a nationwide morning show to demonstrate its apparent lack of toxicity.

Only grams of this medicine existed. Fortunes were offered in return for getting this miracle drug.

But the miracle drug–after reasonable clinical trials were done–didn’t work after all.

Many are the lists of new “miracle cures” that have met this same fate. The difference today is that the Internet has allowed news of these drugs to be disseminated to more people than ever before–and faster than every before. Moreover, it has linked patients and activists into mutually supportive disease-specific communities, who can inform and educate each other, as well as publicizing research about their disease and lobbying legislators. The dark side of this power, however, is that it can facilitate the spread of false hope and the demand for a drug after only cell culture and animal work, before it even makes it to human trials. Add unscrupulous “entrepreneurs” into the mix, and the potential for harm is great. I like to echo the words of Fran Visco, President of the National Breast Cancer Coalition, who said:

…this isn’t about emotion, it’s about saving as many lives as possible and not about getting as many drugs out as possible. It’s about doing the right research and making sure we have patient protections in place and making drugs available that are truly helpful.

Exactly. Emotion is easy. Conspiracy mongering is even easier. (Are you listening, DaveScot?) Balancing harms versus benefits, risks and rewards, all the while doing the best for each patient that we can is very, very hard. One has to remember that cancer is not just one disease. Not only that, but even a single type cancer is often not just one disease. As I have written extensively about before, cancer is incredibly complex. Because of that complexity, it’s incredibly unlikely that any one drug will be any sort of “magic bullet” to cure cancer. Worse, simply using a drug like DCA outside the auspices of well-designed clinical trials will virtually guarantee that we will never know for sure whether the drug actually works. Because of that, as frustrating as it is, as slow as it is, letting science take its course to determine if DCA works, how it works, and for what cancers it works is the best method to make sure that the most patients are helped and the fewest are harmed. I don’t say this because I want DCA to fail; I say it because I want DCA to be shown to be an efficacious treatment for cancer.

We need all the good treatments we can get.

REFERENCE:

Michelakis, E., Sutendra, G., Dromparis, P., Webster, L., Haromy, A., Niven, E., Maguire, C., Gammer, T., Mackey, J., Fulton, D., Abdulkarim, B., McMurtry, M., & Petruk, K. (2010). Metabolic Modulation of Glioblastoma with Dichloroacetate Science Translational Medicine, 2 (31), 31-31 DOI: 10.1126/scitranslmed.3000677

Other good posts about DCA:

For the record, 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