possible "Cheap, safe drug kills most cancers"

[Stonebraker]

http://www.newscientist.com/channel/hea ... ncers.html

Just heard this on the radio, and decided to check out the online story! The story doesn't list any drawbacks, so I'm wondering if anyone with information on this can post what they know.

[BWV 1080]

The blog of an oncologist addressed some of the promise and hype over DCA here:


http://scienceblogs.com/insolence/2007/ ... preted.php

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.

...

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.

Mouse.jpgCancer.jpg

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.