Respectful Insolence

I would have written about this one on Friday, except that Your Friday Dose of Woo had to be served up. (You did read last week's YFDoW, didn't you? It was a particularly loopy bit of woo, with a bad computer interface grafted on to it, to boot!) The reason I wanted to write about it is because the responses to this particular bit of news in the blogosphere grated on me, for reasons that will become apparent soon.

It's about a new cancer drug that I learned about from both fellow ScienceBlogger Jonah and readers who forwarded articles about it to me. If you believe some other bloggers (one of whom, Ezra Klein, who really should know better, even gave his article the utterly ridiculous title Objectively Pro-cancer), it sounds a lot like a "miracle cure" that "they" don't want you to know about, if you know what I mean. Yes, if you believe blogs like Daily Kos (especially the comments, many of which sound as though they come from Kevin Trudeau wannabes), it's one more bit of evidence of big pharma supposedly "suppressing" yet another cheap near-miraculous cure for cancer. Here's the story:

It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their "immortality". The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe.

It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs.

Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.

DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar.

Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis's experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020).

Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump don't get enough oxygen for their mitochondria to work properly (see diagram). In order to survive, they switch off their mitochondria and start producing energy through glycolysis.

I looked up the paper and read it, although not yet in as much depth as I would like to. I also have to point out that my memory of the finer points of glycolysis and mitochondrial aerobic energy production is a little shaky. Even so, whether it is the cause of cancer (less likely) or a consequence of the genetic derangements in cancer cells (more likely), I have to admit, targeting the Warburg effect is a way cool idea, and the experiments are pretty convincing in cell culture and in rats. Basically, 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 having to use aerobic metabolism. It's been well 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 sufficient oxygen present to switch on the aerobic process of oxidative phosphorylation in noncancer cells, a process that takes place in tiny structures called mitochondria. The concept behind this drug was to target this difference, as the article explains:

Crucially, though, mitochondria do another job in cells: they activate apoptosis, the process by which abnormal cells self-destruct. When cells switch mitochondria off, they become "immortal", outliving other cells in the tumour and so becoming dominant. Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die.

"The results are intriguing because they point to a critical role that mitochondria play: they impart a unique trait to cancer cells that can be exploited for cancer therapy," says Dario Altieri, director of the University of Massachusetts Cancer Center in Worcester.

Indeed they appear to. In rats, tumor weights in the treated animals were approximatel 60% lower than the tumors in the untreated control groups (my reading of the data in the paper, figure 8). The drug increase apoptosis, decreases proliferation, and inhibits tumor growth by acting on a critical enzyme that controls the switch between aerobic and anaerobic metabolism. The results of this study are likely to result in new targeted therapies aimed at mitochondria and, even better from an intellectual and scientific standpoint, rekindle the old argument about the metabolic changes in cancer cells, specifically: Which comes first, the metabolic or genetic derangements in tumor cells?

So where do I put on my pharma shill hat? Patience, dear readers. First, you must read this from the investigators in a different news story:

It is expected there would be no problems securing funding to explore a drug that could shrink cancerous tumors and has no side-effects in humans, but University of Alberta researcher Evangelos Michelakis has hit a stalemate with the private sector who would normally fund such a venture. Michelakis' drug is none other than dichloroacetate (DCA), a drug which cannot be patented and costs pennies to make.

It's no wonder he can't secure the $400-600 million needed to conduct human trials with the medicine - the drug doesn't have the potential to make enough money.

Michelakis told reporters they will be applying to public agencies for funding, as pharmaceuticals are reluctant to pick up the drug.

At roughly $2 a dose, there isn't much chance to make a billion on the cancer treatment over the long term.

And now the responses from bloggers that irritated me. First, Daily Kos:

It seems to good to be true. A cheap, effective cancer cure that BigPharma doesn't own. If further research proves effective in humans, it could be the answer to many peoples prayers. I've always thought something simple, rather than the current convoluted regimen of surgery, radiation and chemicals would be the cure for cancer.

Again, if proven effective, will we ever see it in use in this country? Will patients have to take 'DCA tours' to Canada for treatment?

Yes, you spotted some real ignorance right there when this Randular character claimed DCA is likely a "cure" for cancer and that the cure for cancer would likely be "simple" (as if cancer were one disease!), but what I'm more interested in is the spin being put on this story. Spin like this, from Digby:

And here I thought the pharmaceutical companies had to charge such high prices because of all the research they were doing. Seems without the possibility of future revenue they can't be bothered. Of course, a cheap cure for cancer would cut into profits in so many ways, wouldn't it?

Yet another claim that this might be a "cure" for cancer and that pharmaceutical companies are being downright evil for not being immediately interested in it. And here's a guy blogging under the 'nym akaoni opining:

Big Pharma won't put up the dough to fund human research and enable this drug to come to market, there's no money in it. In fact, it wouldn't surprise me to discover that they had an interest in actively preventing the research so as to maintain demand for more expensive less effective drugs. This drug looks to be extremely promising, and I can't imagine that it won't get government funding for human trials, but that said, it doesn't pay to underestimate the power of Big Pharma...

Time for a reality check, and to lay down some Respectful Insolence™ on these guys, who sound disturbingly like alties in many ways, so much so that perhaps I should get them Kevin Trudeau's contact information:

1. This drug has only been tested in cell culture and rats. Yes, the results were promising there, but that does not--I repeat, does not-- mean the results will translate to humans. In fact, most likely, they will not. Those of us who've been in the cancer field a while know that all too common are drugs that kill tumors in the Petrie dish and in mice or rats but fail to be nearly as impressive when tested in humans. In the 1980's it was immunotherapy. Man, some immunotherapies totally melted tumors away but, sadly, didn't do nearly as well in human trials. The same is true of antiangiogenic therapy, pioneered by my surgical and scientific hero Judah Folkman. In 1998, it was all over the media (see pictures below) that antiangiogenic therapy would be the "cure" (or at least would turn cancer into a manageable chronic disease). These drugs dramatically shrank tumors in mice in two major studies published in Cell and even induced tumor dormancy, as described in Nature. Guess what? They didn't do the same thing in humans. Don't get me wrong, antiangiogenic drugs have proven to be a useful addition to our anticancer armamentarium (not to mention an area of research interest for me). However, remember the saying: "If it sounds too good to be true, it probably is." Well, it probably is in the case of DCA.

2. Cancer is not a single disease. It is many diseases, and requires many different approaches. This drug showed activity against several cancers in vitro, but there are conventional chemotherapeutic drugs that also show activity against lots of cancers. In fact, the comparison to antiangiogenics becomes even more relevant here, because antiangiogenic drugs theoretically could act against any cancer. That's because they target normal cells lining blood vessels, which are needed to grow new blood vessels to supply tumors with blood and oxygen. These cells are very stable, and much less prone to the mutations that cancer cells undergo with such frequency that can lead to resistance. In contrast. DCA targets the tumor cells themselves, which are far more likely to develop resistance. Bloggers ranting against big pharma are showing magical thinking in assuming that this drug will work against nearly all tumors, given that at best only 60-90% of cancers even demonstrate the Warburg effect. Indeed, remember how I mentioned that in this study DCA inhibited tumor growth by 60% or more in rats? Pretty impressive, yes? Compare this result to that obtained by angiostatin and endostatin, both of which melted experimental mouse tumors away to a few dormant cells. Neither were anywhere as impressive against human tumors. That doesn't mean antiangiogenics aren't useful cancer drugs (Bevicuzimab, in particular is quite effective at potentiating the effect of chemotherapy in colorectal cancer, for example), but they are useful in the same way that a number of chemotherapeutic agents are usefu: as an additional weapon. They are not miracle cures, and I'd be willing to bet that DCA isn't, either.

3. Here's where the worst misinformation is being spread about this story. It will not cost $600-800 million to do clinical trials to test this drug, yet certain bloggers are acting as if that much money will be needed to to see if this drug works in humans. That's just a load of crap. That figure refers to the total cost of bringing a new drug to market, from idea to research and development, to synthesis, to cell culture and animal studies, to patent applications, to all the clinical trials needed, to filing the regulatory documentation, all of which together can sometimes approach $1 billion. It does not refer to the amount of money required to do a clinical trial to see if there is efficacy in humans, the logical next step after what has been published thus far. In contrast to what's being spewed into the blogosphere, to run a preliminary trial to determine if there is evidence of efficacy in humans could be done for costs that are well within the means of an investigator, if he's willing to apply for grants. All he would require is a few hundred thousand dollars for a small preliminary trial (less ideal) or probably between $1 and $5 million for an intermediate-sized Phase II study against one tumor (it's the Phase III trials, with thousands of patients, that cost tens of millions of dollars). Most NIH R01 grants are funded for between $1 and $2 million (mine's for a little more than $1.3 million over 5 years), and clinical R01 grants can be funded for up to a few million dollars. Thus, this is not by any means an unreasonable amount of money to be trying raise to do the trial to confirm in humans the preclinical data and, if the effect is as great in humans as it is in animals, should be adequate to detect the drug's promise. If that turns out not to be a big enough sample, then that would imply either that (1) this drug isn't effective at all in humans or (2) isn't any more effective than many other conventional chemotherapeutics that we already have. True, the funding climate sucks these days, but Michelakis is funded by grants from the Canadian Institutes for Health Research (CIHR), Alberta Heritage Foundation for Medical Research (AHFMR), and Canadian Foundation for Innovation. He's perfectly free to apply to the NIH and other organizations for funding. Given such compelling preclinical data, hewould stand a very good chance of being funded.

4. Lastly, there was nothing stopping the investigator from patenting the idea of using DCA to treat cancer. I know someone who is doing just that for a use of a drug that's FDA-approved for treating something totally unrelated to cancer. indeed, I sincerely hope that Michelakis has, in fact, done this, because now that his results have published it's too late; the cat's out of the bag. If he had done that, he could then have licensed his idea to whatever pharmaceutical company was interested, and that pharmaceutical company would then have had a patent on the use of this drug to treat cancer. If Michelakis hasn't done that, well, I applaud his idealism (or curse his naïveté); he shot himself in the foot and made his idea less appealing to industry.

I'm not in any way saying that it isn't a problem that drug companies show little or no interest in potentially promising new compounds that they can't patent. It can be a problem, just as "orphan" drugs often don't make it to market because there aren't enough patients who could benefit from the them to make it profitable for drug companies to invest in developing and marketing them. In those cases, there are government programs to encourage the manufacture of these drugs. Perhaps a similar sort of program should be in place for situations like this or perhaps tax incentives to encourage pharmaceutical companies to manufacture drugs like this. Also, if this drug were truly the miracle cure that it's being represented as, believe me, pharmaceutical companies would find a way to make money off of it, either by trying to modify it to make it more effective or adding a molecule to target it more closely to the cancer cell.

What irritates me about the hysteria some bloggers are whipping up over this is that it is at its heart basically paranoid conspiracy mongering, and the reason this story has any legs at all is because people are inherently distrustful of big pharma. There are some good reasons for this and many reasons that boil down to little more than an inherent distrust of big corporations. Even now, for example, our old "friend" Dean Esmay is likening big pharma's disinterest in DCA to its disinterest in the use of high dose vitamin C against cancer. Never mind that Dean doesn't know what he is talking about when it comes to the alleged efficacy of vitamin C against cancer. Never mind that vitamin C never in even Linus Pauling's hands showed anywhere near the efficacy against cacncer cells in vitro and in animal models that DCA has. Never mind that even high dose vitamin C has shown in essence no evidence of efficacy against cancer in humans. Given those facts, it's not surprising that pharmaceutical companies aren't interested in vitamin C as a treatment for cancer, regardless of its cost or patentability.

What is most pernicious about the conspiracy-mongering stories being spread about DCA is that it builds false hope. People with cancer hear about this drug, and they think there's an amazing cure out there that's being withheld from them because of the greed of big pharma. Big pharma may show a lot of greed at various times, but that's nonetheless a very distorted version of the true situation. I agree with a a blogger going under the 'nym of Walnut (the only blogger I've yet found thus far who knows enough to refrain from the usual pharma bashing over this):

But this all plays into people's yen for conspiracy theories. Big Pharma hates us. And yes, I've indulged in this on my blog, I know, I know. Big Pharma is bad. But they also make money off of healing people.

You know what the worst part of this DCA flap is? It builds false hope. And when it comes to cancer, I think there are fewer things crueler than building false hope. It's sadism, as far as I'm concerned.

Yes, it's very easy and satisfying to take this promising preliminary study and build from it a conspiracy theory of evil big pharma "keeping cures from the people." It's just not very accurate and it adds too much heat and noise to the debate over the real shortcomings in our system of developing new drugs that make drug companies reluctant to pursue research on drugs that show promise but little profit potential. There are real, systemic problems with the financing of drug development and how drugs are marketed, but hyperbole and conspiracy theories don't address these problems; they obscure them.

Look for DCA to be featured as yet another cure "they" don't want you to know about in Kevin Trudeau's next book.

ADDENDUM: Walnut has posted his critique on Daily Kos as well.

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)

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)