I’m surprised to find that I’m moving to a topic that may actually be more controversial than a Michael Moore movie, but in fact, I think that’s where I’m headed.
Several months ago, I wrote a post about dichloroacetate, or DCA, which is a chemical used to treat a childhood disease called congenital lactic acidosis, and which has been the study of some more recent study by Dr. Evangelos Michelakis at the University of Alberta in Edmonton, Alberta in Canada. DCA can increase the activity of mitochondria, which produce energe in the cell and can be suppressed in cancer cells; restoring that function can lead the cells to undergo programmed cell death, or apoptosis, that is supposed to occur when a cell recognizes that it has dysfunctional mutations. Recent work by the group in Edmonton (summary here) suggested that DCA was effective in killing tumor cells in test tubes and some animal models, and the authors suggested that DCA should move readily into clinical trials for cancer. One problem is that DCA is a generically available product that no pharmaceutical company stands to profit from, so it does not have a readily available source of funding for the millions of dollars needed to run clinical trials that might lead to a proper demonstration of effectiveness of not. The University of Alberta has established a charitable fund that has thus far raised signficant financial support in order to test DCA in clinical trials despite the absence of a big pharma beneficiary. Trials are reportedly in development.
At the time that this came out, in a real media frenzy, my post covered some of the news and used the occasion to temper some of the extreme enthusiasm about this agent being a likely miracle for the broad treatment of cancer. I described the huge gap between promising preclinical drug that kills cancer cells in test tubes and rodents and the demonstration of clinical benefit in large trials with real patients. The majority of drugs are abandoned along the way for being too toxic or not living up to the early promise of efficacy. We would do well to remember that back in 1998, when emerging work on angiogenesis by Dr. Judah Folkman was hailed as a certain miracle, again based on very promising work in mice. Dr. Folkman was very circumspect and avoided overpromising what his research could accomplish in humans: “if you’re a mouse and you have cancer, we can take good care of you” and, “Going from mice to people is a big jump, with lots of failures” (basically summarizing my first DCA post in one sentence). In contrast, in that same front-page article in the New York Times that featured this reported breakthrough, Dr. James Watson (who along with Francis Crick discovered the molecular structure of DNA and was awarded the 1962 Nobel Prize in Physiology and Medicine) was quoted as saying, “Judah is going to cure cancer in two years”. I cringed when I heard that, fearing that it would feed a media machine and lead to incredible hype, and it did. But nearly ten years later, we have not cured cancer, at least not nearly enough, even though a few antiangiogenic drugs like Avastin (bevacizumab) have recently been shown to improve outcomes for colon, lung, breast, and some other cancers.
I’ll also mention that Dr. Len Lichtenfeld of the American Cancer Society and writer of Dr. Len’s Cancer Blog (a fine resource that should be added to my list of links), expressed similar skepticism, in more detail and more eloquently, I’d say, at his own site. Widely disseminated through an ABC news website, his story was entitled “DCA: Cancer Breakthrough or Urban Legend?” and expressed a similar skepticism about early lab work necessarily translating to a true clinical miracle. And we both hoped that our skepticism was misplaced and that DCA will emerge as a significant contribution for a wide range of cancers.
What’s happened since then? The University of Alberta is widely publicizing their work and soliciting funding support from individual contributors, as noted above, and clinical trials are planned. Great. In the meantime, there’s a pretty heavily trafficked website, www.thedcasite.com, which provides information and a forum for reviews of outcomes by patients who have obtained and tried DCA on their own. DCA is not widely available, but there are a few physicians prescribing it in their clinics, including Dr. Akbar Khan, Director of the Medicor Cancer Center in Ontario, Canada. I am not going to pass judgment, but I did find him through another website, Canadian Quackery Watch, which is not where I would hope to be featured. The person who runs www.thedcasite.com also has a website that sells DCA online directly to consumers;www.buydca.com (although I just saw that the site and operation have just been shut down by the FDA, since it is illegal to sell substances suggested to have anti-cancer activity without FDA approval). Regardless, the approach of taking DCA based on preclinical work is not being endorsed and is actually being strongly advised against by the pioneering investigators from the University of Alberta in their Frequently Asked Questions page:
Should I take DCA on my own?
Absolutely not! This can actually be dangerous. For example, DCA can be found in stores selling chemicals to scientific laboratories. Often, DCA is sold in a form that is very acidic and if consumed could cause serious or catastrophic complications. Even for use in animals DCA often has to be processed with chemicals to correct its acidity etc. In addition, the dose in patients with cancer, or its interactions with other medications that cancer patients might be on, are completely unknown.
Often, patients with terminal cancer might feel they are in a desperate situation and might be “willing to try anything”. It needs to be remembered that the inappropriate use of these drugs might cause catastrophic complications and make the situation even worse. In addition, if complications occur, because this was not done under the supervision of a physician, this problem will not become known and other patients might be exposed to a risk that could have been prevented.
I’ll just say that I do agree with this recommendation. Another important factor is that if pursue investigational approaches themselves, inside or outside of their doctor’s plan, it can short-circuit the process of actually clarifying the value of these approaches in proper clinical trials. In the US, we are particularly bad at having patients be randomized (we want what we want), but we need to be reminded that sometimes the new approach can be significantly detrimental (as described in a prior post), and we might never learn this if the proper trials aren’t completed. Anything that can treat cancer can also potentially cause harmful effects, I assure you. We need to evaluate carefully with clinical trials that may be undermined by people doing what they intuit may be better.
Reading through many stories on the DCA site, there is certainly a lot of desperate hope, but there are a significant number that I read that sound like the DCA is not providing an obvious benefit. While there has been an occasional report of favorable results with DCA in cancer, specifically lung cancer (such as here), and I would certainly like to learn more about the favorable cases, which may represent true responses, but there are still several outstanding questions. In the report I cite, this woman is reported to have “lung cancer lymphoma”, but that doesn’t make sense, since it should be either lung cancer or lymphoma. Sure, it’s semantics, because if a cancer responded, it’s still worth noting, but I’d be inclined to do more fact-checking before drawing conclusions. Perhaps more importantly, I haven’t read that the favorable results have been shown in the setting of objective CT scan findings before or after DCA, nor that DCA was the only agent. If a person is on a new drug plus many other potentially active agents, how can we really know if the drug we’re focusing on is the breakthrough? I’m not singling out DCA here; I said the same thing in a post earlier this week when I described a promising trial of standard chemo with a new drug named vorinostat that looked provocative, but was it vorinostat, just the chemo, or a good combination?
The only way we really move forward is by isolating one variable as best we can in a clinical trial, in as uniform of a population as we can study, and then check the differences between new treatment and what we’ve got now. I understand the desperation of facing a cancer diagnosis and having limited or no attractive anti-cancer options. I don’t want to dispel hope. But my provisional conclusion about DCA is that it definitely merits further study, and I’d be very enthused to participate in clinical trials with it, but we won’t improve our treatments for cancel from off-label use of DCA or other investigational drugs, particularly in a buckshot approach of trying multiple different things at once. Importantly, widespread use of such agents outside of trials may prevent these trials from being completed and translating to new and unquestionably needed anti-cancer options.
As always, I’d welcome people’s comments.
posted by Dr. West @ 8:27 pm link to this post
Loading ...
August 1st, 2007 at 7:21 am
[…] We’ll see how this plays out in the courts. I am certainly sympathetic to patients with few options, but I think it’s unfortunate to see factions developing that are moving toward guerilla warfare of patients against the FDA and/or doctors weighing evidence about the value of a treatment. It’s not very different from the recent issues about the drug DCA or the hot debate about CT screening for lung cancer. Perhaps I seem dry and overly clinical in wanting to carefull weigh the facts. Perhaps evidence is a luxury when you’re desperate for options. But I’m saddended to see claws come out, because it shouldn’t be an “us and them” situation. The cancer experts don’t want to keep their patients from getting effective treatments, and I don’t think the FDA does either. They’re trying to walk a fine line between offering useful therapies and not approving harmful and ineffective treatments that need to be recalled later (it’s not like this hasn’t happened in the recent past). […]
July 31st, 2007 at 11:26 pm
Willis–Thanks for the cites (though I still can’t understand most of them). The more I think about it, I’m not sure what the controversy is in this particular instance (as opposed to the more general case that Dr. West discusses in his post on the FDA being sued).
The articles you cite certainly point to a strong possibility that DCA will be effective in treating NSCLC. Together with the pre-clinical findings reported by Michelakis et.al., they certainly support clinical trials of DCA (and expedited ones at that; I think the argument you made earlier about DCA already being shown to be safe in other settings is a strong one). So, I would hope that clinical trials (basically starting with phase II) could happen on an expedited basis. The whole issue of nobody making a ton of money off DCA takes us back to the discussion about national health care. In Canada, the government should be able to fund such trials. Even in the US, while the amount of money needed to support a clinical trial is relatively large, it is also small for a entity like the federal government. There would seem to be a role for the government to fund clinical trials for substances like DCA.
So, it sounds promising, there should be clinical trials (and pronto). Then, let’s see what happens. Meanwhile, while the sales site has been shut down, it seems that anyone who wants to get DCA can find a way. Why clinical trials? For all the reasons discussed before, but also because otherwise we’d only have ad hoc testimony and anecdotal evidence on the Internet.
I want what’s best for me now, but I also feel at least some obligation to the next generation of patients. In this instance, it may be that everyone can be happy.–Neil
July 31st, 2007 at 10:10 pm
Editor’s note:
Willis123 left the full web addresses for the pubmed listings for each of these articles. They were very long and messed up the page formatting, so I ran each through the application at www.tinyurl.com to shrink them down. They should all work as functional links, but if they don’t, it’s MY fault.
-Dr. West
July 31st, 2007 at 8:45 am
Sorry it has taken me so long to get this posted. I have been a little busy. Here is a list of cites that I think support the effectiveness of a mechanism like that described by Michelakis, et al. for DCA. To be clear, I am not saying this proves it will work. What I am saying is that, as someone with a fairly sophisticated understanding of what these papers discuss, I think that they are consistent with the metabolic-electrical remodeling proposed by Michelakis, et al. Moreover, I think they are consistent with something like DCA being an effective cancer treatment. I say this because I think that they support either (1) the inherent relationship between apoptosis resistance and glycolysis or (2) the relationship between the mitochondrial membrane potential and apoptosis resistance. All I would ask is that any cancer researchers out there who haven’t looked into this closely, please do. As I said, I am not guaranteeing this will work, but I think that there are real reasons to think that this cancer breakthrough may be a big one. There are other papers that I think are relevant, but I think these are probably the most important.
Pelicano from the December issue of Journal of Cell Biology regarding mitochondrial respiration defects activating Akt survival pathway. This is important because it supports the idea that alterations in mitochondrial function are inherently related to apoptosis resistance.
http://tinyurl.com/29j9n8
Two papers by Heerdt regarding colon carcinoma aggressiveness correlated with mitochondrial membrane potential. This is important because it is consistent with the metabolic-electrical remodeling proposed by Michelakis, et al.
http://tinyurl.com/2ezdtq
http://tinyurl.com/22khxt
This is the paper by Fantin, et al. from the June 2006 issue of Cancer Cell. In this paper they report results from their experiments knocking down a protein called LDH (lactate dehydrogenase). LDH is a different component of the glycolysis pathway, but like DCA’s inhibition of PDK, inhibition of LDH also had the effect of promoting the conversion of pyruvate into acetyl coA. As with DCA, this increase in acetyl coA was accompanied by increased apoptosis and reduction of human cancer implanted in mice.
http://tinyurl.com/2epnkz
Two papers by Pedersen. The first is an introduction for the February 2007 Journal of Bioenergetics and Biomembranes. This article discusses more recent research discussing the critical importance of the mitochondria to the cancer problem, and the promise of therapies targeting the metabolic features of cancer (he mentions the Michelakis paper briefly). The second paper is by Pedersen, et al. and discusses hexokinase, the enzyme that catalyzes the first step of glycolysis (the conversion of glucose to glucose-6-phosphate). Pedersen has been researching hexokinase and its critical function in apoptosis resistance since the late 1970s. Akt’s anti-apoptotic effects are rely on the fact that it encourages the binding of hexokinase to the mitochondrial outer membrane.
http://tinyurl.com/2cxhkj
Pedersen, et al., Hexokinase: cancers double-edged sword:
http://tinyurl.com/2z6ppq
Pastorino, et al. In this paper the authors discuss hexokinase and its relationship with the cells apoptosis mechanisms, and also with the Akt survival pathway.
http://tinyurl.com/29j9n8
July 27th, 2007 at 6:37 am
Sarcomas are a different kind of cancer than carcinomas, including SCLC and NSCLC. Large cell NSCLC represents about 10-15% of NSCLC cases, with adenocarcinomas (40-50% in the US) and squamous cell carcinomas (20-30%) being more common. Because sarcomas are so different and are resistant to many chemo agents and other anti-cancer drugs, I would not consider responses or lack of responses in sarcomas to speak directly to how lung cancers might respond.
I’m definitely aware that Medicor Cancer Center in Toronto is administering DCA; I mentioned this in the post above. I hope that Dr. Khan provides a report of how these patients are responding on DCA and not just a rare anecdotal “miracle patient”, with no denominator to tell us how common or rare good responses are. Without that, I fear that this is going to just feed the hype and not allow us to learn anything about whether DCA really offers meaningful benefit for cancer patients.
-Dr. West
July 26th, 2007 at 7:34 pm
I’m pretty sure that Willis was saying that DCA was a more likely candidate against many forms of non-small-cell lung cancer (NSCLC) than against small-cell lung cancer (SCLC). It’s my understanding that “large-cell lung cancer” is a relatively small subset of NSCLC (the largest subsets being adenocarcinoma and squamous cell).–Neil
July 26th, 2007 at 6:34 pm
Question for Willis123
I read all your posts carefully but don’t pretend to understand a lot of the information you provided. In one part you stated:
“according to the Chen data, sarcomas do not appear to exhibit hyperpolarized mitochondrial inner membrane potential. In light of that fact, and given the mechanism by which DCA is described as working, I do not think this is surprising or discouraging. In addition to sarcomas, the other cancers described by Chen as not exhibiting hyperpolarized mitochondrial inner membranes include large-cell lung cancer, small-cell lung cancer… “
I’m confused. Are you saying it’s unlikely DCA would be effective against non small cell lung cancer (NSCLC) and small cell? I thought all the excitement over DCA was due to the results of DCA on lung cancer in rats?
Could you please clarify.
Not sure if you or Dr. West are aware of this, but there is a private clinic in Toronto, Canada treating cancer patients with DCA. The government is allowing it on the basis that DCA is already approved, albeit for a different illness, so the clinic is basically using DCA “off-label” which is not illegal.
Salina
July 25th, 2007 at 8:43 pm
Neil and Willis123,
I appreciate this high-level discourse, and I don’t have much to add, except that I really wait to see the results in humans before drawing conclusions about the utility of a drug. There are so many drugs that have anti-cancer activity in the lab that this raises my hopes almost not at all. So Neil, I really would put no weight at all on comparing different drugs in different preclinical settings — it’s really comparing apples and oranges. We’ve also seen many drugs that are developed with presumed targeted effects that may have little or nothing to do with the real mechanism of the drugs.
This may be because I’m a lapsed scientist, but I’ve long felt that you can find basic science results to support just about any point you’d want to make, and that a suspiciously broad array of drugs have anti-angiogenic activity. So I view the basic science much the way I view the inner workings of the television. I just need to see if it really works (in people). This isn’t the mosst sophisticated view of the world, but I care more about the end result in the clinic than the lab-based studies. That’s my admitted bias.
-Dr. West