Potential cancer drug DCA tested in early trials

DCA has been tested in a small trial

• Updated below

The controversial drug DCA (dichloroacetate) is in the headlines again, after researchers in Canada carried out a small-scale clinical trial of the drug in five patients with advanced brain tumours.

Over the past year or two there have been several articles in the news and on the internet about DCA, which was claimed to be cheap, safe and “kill most cancers”.

Understandably this caused a great deal of interest, especially as DCA is an off-patent drug and appears to be non-toxic to humans (although it can cause significant side effects, as we’ll see later).

But before we jump to conclusions and hail DCA as a ‘wonder drug’, we need to look at the science behind the headlines.

What is DCA and how does it work?

All our cells need energy to grow and function, including cancer cells. Simply put, our cells usually generate energy by breaking down sugar (glucose). To do this, they use a process known as the Krebs cycle, which takes place in tiny structures within the cell called mitochondria (the ‘power stations’ of the cell).

But cancer cells bypass this cycle and produce energy using a simpler process, known as glycolysis, which takes place outside the mitochondria in the cell’s cytoplasm (the main part of the cell). This was first noticed by Nobel prize-winning German scientist Otto Warburg back in the 1920s.

Mitochondria are the ‘power stations’ in our cells

Mitochondria play a crucial role in cells. As well as generating energy for the cell, they can also trigger the cell to die if it is faulty – a process that helps stop cancers from forming in the first place.

Because cancer cells seem to switch off their mitochondria, scientists think this is one way in which cancer cells are able to evade death and remain immortal.

DCA, or dichloroacetate, is a very simple chemical and is similar to some of the chemicals involved in the Krebs cycle. In 2007, researchers at the University of Alberta (led by Evangelos Michelakis) found that adding DCA to cancer cells grown in the lab kick-starts the Krebs cycle, turning the mitochondria back on again. This caused the cancer cells to stop multiplying and die. The team discovered that DCA didn’t affect healthy cells, because their mitochondria were functioning normally.

DCA has been tested as a treatment for children and adults with certain rare metabolic disorders. This means that, at the doses needed to treat these diseases at least, DCA has been through clinical trials aimed at assessing its safety. Based on their results, the researchers have proposed that DCA could also be useful in treating cancer.

To begin to investigate if this is indeed the case, Michelakis and his team started by carrying out experiments on cancer cells grown in the lab. The team also studied rats that had been injected with cancer cells. They found that DCA could slow the growth of the rats’ tumours, and reduce their size. This did not prove that the cancers were completely cured, or that DCA could prevent cancers from growing.

It is important to stress that DCA had not then been tested as a cancer treatment in humans, despite the implication in news headlines that it “kills most cancers”. There are many research papers produced by scientists around the world every year that reveal potential new treatments for cancer. But it is important that every discovery is carefully investigated to make sure that it is effective and safe for use in patients, and DCA is no exception.

The University of Alberta researchers received approval for a human cancer trial in September 2007, involving 50 patients. Now they have published the first results from five of those patients in the journal Science Translational Medicine.

The new trial

In this study, Michelakis and his team gave DCA to five patients with advanced glioblastoma, a type of brain tumour, in combination with surgery, radiotherapy and a drug called temozolomide. It’s important to point out that the aim of this study was not to find out whether DCA could treat glioblastoma, but to figure out the safest dose to use for cancer patients. We already know that the drug can be safely given to humans – although it can cause side effects – but this is the first time it has been tested in people with cancer.

The study shed light on the dose that could be given to patients without causing nerve problems or other serious side effects. Four patients were still alive after 18 months, and three showed some shrinkage of their tumour, but it is impossible to tell with such a small study whether this is longer than might be expected. And, given that they were also receiving other treatment, it’s hard to know if it was due to DCA at all.

As well as this small trial, the researchers also looked at the effect of DCA on tumour samples from 49 other glioblastoma patients. They found that DCA could switch mitochondria back on in the cancer cells, although – crucially – it’s still not clear exactly how it’s doing this.

Finally, the team looked at tumour samples taken from the five patients on the trial, both before and after treatment with DCA, and found that the drug was again helping to switch mitochondria on. They also discovered other differences in the cancer cells’ metabolism before and after treatment.

A key gap in this trial is that, as we’ve mentioned above, it’s not clear exactly how DCA is working. The researchers suggest that the drug may target cancer stem cells and prevent the growth of blood vessels into tumour, although they didn’t actually prove this.

Is it safe?

These results show that lower doses of DCA could, at least in theory, be given to cancer patients while avoiding some of the damaging side effects seen at higher doses. For example, a clinical trial of DCA for a childhood disease found that the drug caused significant side effects, affecting the nervous system. It is also known to be an environmental pollutant. And researchers have found that DCA can actually cause cancer in animals.

This is not necessarily a barrier to the use of DCA as a treatment for cancer – there are a number of powerful cancer drugs that are carcinogens themselves. And this is why we need to test them in clinical trials (as Michelakis and his team have begun to do here) to discover how they can be safely used to treat patients while minimising any harmful effects.

Why can’t we use it now?

It is understandable that people with cancer will want to try everything possible to help treat their disease. However, there is still no evidence – yet – to support the immediate use of DCA to treat cancer patients.

The trial in Canada is being conducted under stringent conditions both to ensure the validity of the results and to protect the participants from any unforeseen effects. Further clinical trials of DCA using more patients will help determine whether the treatment is more effective than the cancer therapies that are currently available.

There are reports that people are buying personal supplies of DCA from sources such as the internet. Cancer Research UK would strongly advise against this, as DCA still has not been shown to actually treat tumours successfully in patients. And it may be harmful when given to cancer patients without accurate dosing and medical supervision.

What will happen in the future?

It is clear that DCA is an intriguing drug – one of many currently being investigated by scientists around the world. It will be interesting to see the results of more extensive lab-based experiments and larger clinical trials of DCA. And cancer cell metabolism is certainly a productive area of research that we’re actively funding.

The fact that DCA is off-patent is no barrier to its development as a treatment for cancer. For example, Cancer Research UK has secured a licence for an off-patent drug called fenretinide, which could be used to treat rare childhood cancers. And there is certainly no “conspiracy” by pharmaceutical companies to prevent research into DCA – there is just not enough evidence at the moment to support its widespread use to treat patients.

While these results are intriguing, it is unlikely that this one compound represents “the cure” for cancer – and it is also unlikely that DCA is the “wonder drug” that the headlines portray. Cancer is a complex and multi-faceted disease, and it can be caused by a range of different faults within the cell. It is unlikely that any single drug could ever treat all forms of the disease.

There are many promising new treatments for cancer currently in development, funded by organisations across the globe – including Cancer Research UK. If anything, these new results show why research is so important in bringing safe and effective treatments to people with cancer – they don’t provide definitive answers, but they support further investigations which may yield benefits for patients in the future.

Kat

Further reading:

• A more detailed analysis of the research can be found at Respectful Insolence – DCA and cancer: Deja vu all over again

Updates

16th May 2011: Several websites are reporting that last week ‘cancer was cured without anyone reporting on it’. This is not true and seems, we think, to have arisen from a misreading of the date on the most recent paper on DCA (which was published on May 12th 2010 – i.e. this time last year).

Everything we wrote in the post and comments below stands – DCA is still only a ‘potential’ cancer treatment, and more research is needed to find out whether it’s safer or more effective than existing therapies.

Henry

17th January 2012/ongoing: A number of scientific papers investigating DCA have been published over the past year or so by researchers around the world – we thought we would highlight some of them here for people who are interested in the current state of DCA research. However, it’s important to remember that most of these studies have only been done using cancer cells grown in the lab, and we still don’t have solid evidence from clinical trials that DCA is effective at treating cancer in patients.

• Lab research on liver cancer cells grown in the lab shows that a combination of DCA and a drug called sorafenib is more effective than DCA alone. (2013)
• Researchers have tested DCA and other inhibitors of cancer cell metabolism in multiple myeloma cells grown in the lab. (2013)
• A combination of DCA and a drug called sulindac can kill non-small cell lung cancer cells and squamous cell cancer cells grown in the lab. (2012)
• DCA can encourage the death of glioma (brain tumour) stem cells grown in the lab. (2012)
• A combination of DCA and the drug omeprazole can slow the growth of bowel cancer cells and fibrosarcoma cells grown in the lab. (2012)
• A combination of omeprazole, tamoxifen and DCA was given to a woman with cholangiocarcinoma that was no longer responding to treatment – it slowed the growth of her cancer for three months. (2012)
• Researchers are testing a new way of delivering DCA more directly to cervical cancer – so far these experiments have only been done using mice. (2012)
• A combination of arsenic trioxide and DCA is more effective than either drug alone at killing cancer cells grown in the lab or slowing their growth. (2011)
• DCA has an effect on aggressive neuroblastoma cells grown in the lab, but not on less aggressive cells. (2012)
• Lab experiments show that DCA can suppress the production of a molecule called HIF1alpha, produced by cancer cells to help them grow a blood supply. Tests in rats show that DCA can reduce the growth of blood vessels in tumours. (2012)
• Cancer Research UK-funded scientists show that combining DCA with a drug called bevacizumab, which blocks the growth of blood vessels into tumours, can have enhanced anti-tumour effects in mice. (2013)
• Scientists in the US are testing a more potent form of DCA, called Mito-DCA, that seems to target mitochondria more effectively. (2014)
• In tests on cells grown in the lab and tumours transplanted into animals, Cancer Research UK-funded scientists show that DCA seems to switch on a response called autophagy in cancer cells, where they start to break down and ‘recycle’ parts of themselves, which could affect how patients respond to DCA treatment. (2014)
• PubMed search for “DCA cancer” – see the latest scientific publications

It’s clear from these papers – and others that we don’t have room to highlight – that DCA and cancer metabolism is an active and exciting research area at the moment. Right now, Cancer Research UK isn’t directly funding research specifically into DCA, but we are funding projects investigating various aspects of cancer metabolism, which may touch on it.

As we’ve previously explained, we give out funding in response to applications from researchers, and only fund the very best science that will benefit cancer patients. So if a researcher applied to us for funding to study DCA, their application would be judged on its scientific merits like all the rest.

Kat

Key references:

• P. Kaufmann, et al (2006). Dichloroacetate causes toxic neuropathy in MELAS Neurology, 66, 324-330
• Michelakis ED, et al (2010). Metabolic modulation of glioblastoma with dichloroacetate. Science translational medicine, 2 (31) PMID: 20463368
• S Bonnet et al, (2007). A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth Cancer Cell, 11 (1), 37-51 DOI: 10.1016/j.ccr.2006.10.020