Potential cancer drug DCA tested in early trials
Posted on May 12, 2010 by Kat Arney
    
 "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


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 asglycolysis, which takes place outside the mitochondria in the cell’s cytoplasm (the main part of the cell).

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.

Further reading:  A more detailed analysis of the new research can be found at Respectful Insolence – DCA and cancer: Deja vu all over again
    
Metabolic modulation of glioblastoma with dichloroacetate.  
Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC.SourceDepartment of Medicine, University of Alberta, Edmonton, Alberta, Canada. em2@ualberta.ca

Abstract Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.
http://www.ncbi.nlm.nih.gov/pubmed/20463368 

What is a Glioblastoma?

Brain tumors belong to a group of diverse tumors that affect the brain and spinal cord known ascentral nervous system neoplasms. A brain tumor is a mass of abnormal cells in the brain that have grown and multiplied in an uncontrolled fashion. Brain tumors that develop from various types of cells that make up the brain are called primary brain tumors. These types of brain tumors are usually localized (confined) to the brain itself and only rarely spread to other parts of the body. Metastatic brain tumors, also know as secondary brain tumors, originate from cancer cells in another part of the body (e.g., lung, breast) and spread to the brain through the bloodstream. The distinction between primary and secondary brain tumors is important from a clinical perspective because they are usually treated differently.

Approximately 50% of all primary brain tumors originate from specialized nerve cells in the brain called glial cells. Brain tumors that arise from glial cells are called gliomas. There are many different types of gliomas but the most common gliomas develop from glial cells called astrocytes. Primary brain tumors that develop from astrocytes are referred to as astrocytomas.

The World Health Organization (WHO) classifies astrocytomas into four distinct grades designated as Grade I, II, III, and IV (discussed in detail below) on the basis of how quickly the cells grow and spread and how the cells appear under a microscope. A glioblastoma, technically know as glioblastoma multiforme, is the fastest growing type of astrocytoma (Grade IV astrocytoma) that quickly spreads and invades nearby normal brain tissue and contains areas of dead cells (necrosis) in the center of the tumor.

Approximately 18,000 people in the United States are diagnosed each year with a malignant (cancerous) primary brain tumor. Glioblastoma multiforme (GM) is the most common type of primary malignant brain tumor in adults and accounts for about 50% to 60% of cases. Although GM can occur in all age groups, it is most commonly observed in adults 50 to 70 years in age. Less than 10% of childhood brain tumors are glioblastomas. Glioblastoma multiforme tends to occur more frequently in males than females by a ratio of about 3:2. According to the American Cancer Society, about 13,000 in the United States die each year from primary brain tumors.
 
http://www.glioblastoma-guidebook.com/2009/landinge.php?gid=OC009&?=a&assoc=Google&keyword=glioblastoma 

Coca-Cola Co. and PepsiCo Inc. are changing the way they make the caramel coloring used in their sodas as a result of a California law that mandates drinks containing a certain level of carcinogens bear a cancer warning label.

The companies said the changes will be expanded nationally to streamline their manufacturing processes. They've already been made for drinks sold in California.

Coca-Cola and PepsiCo account for almost 90 percent of the soda market, according to industry tracker Beverage Digest. A representative for Dr Pepper Snapple Group Inc. was not immediately available for comment.

The American Beverage Association, which represents the broader industry, said its member companies will continue to use caramel coloring in certain products but that adjustments were made to meet California's new standard.

"Consumers will notice no difference in our products and have no reason at all for any health concerns," the association said in a statement.

A representative for Coca-Cola, Diana Garza-Ciarlante, said the company directed its caramel suppliers to modify their manufacturing processes to reduce the levels of the chemical 4-methylimidazole, which can be formed during the cooking process and as a result may be found in trace amounts in many foods.

"While we believe that there is no public health risk that justifies any such change, we did ask our caramel suppliers to take this step so that our products would not be subject to the requirement of a scientifically unfounded warning," Garza-Giarlante said in an email.

The Center for Science in the Public Interest, a consumer advocacy group, in February filed a petition with the Food and Drug Administration to ban the use of ammonia-sulfite caramel coloring.

A spokesman for the Food and Drug Administration said the petition is being reviewed.

But he noted that a consumer would have to drink more than 1,000 cans of soda a day to reach the doses administered that have shown links to cancer in rodents.

The American Beverage Association also noted that California added the coloring to its list of carcinogens with no studies showing that it causes cancer in humans. It noted that the listing was based on a single study in lab mice and rats.

Read more: http://www.abc15.com/dpp/news/national/coke-pepsi-make-changes-to-avoid-cancer-warning?utm_source=dlvr.it&utm_medium=twitter#ixzz1oovzUIYB