Arthritis drug could also help combat ovarian cancer

Monday January 11 2016

Ovarian cancer can cause persistent bloating and pelvic pain

“A rheumatoid arthritis drug can kill off ovarian cancer cells in women with the BRCA1 mutation,” the Mail Online reports. The drug, auranofin, was found to be effective against ovarian cancer cells associated with the BRCA1 mutation.

The BRCA1 gene – along with a similar gene called BRCA2 – is designed to repair damage to DNA as cells divide. The absence of this ability increases the risk of cells developing abnormalities that can trigger ovarian cancer, as well as breast cancer.

This study was laboratory research examining the effect of the arthritis drug, auranofin, on ovarian cancer cells with and without BRCA1 mutation. Auranofin is not currently licensed in the UK.

When ovarian cancer cells were treated with auranofin in the lab, researchers found the drug’s cancer-killing properties were most effective at treating ovarian cancer cells lacking a “healthy” version of the BRCA1 gene.

It seemed auranofin caused damage to the DNA of cancerous cells with BRCA1 mutations, helping to kill them. The results suggest there may be promise for this drug in the treatment of ovarian cancers associated with BRCA1 mutations.

Although auranofin is currently used in the treatment of rheumatoid arthritis in the US, and has been tested in early-stage ovarian cancer studies in humans, much more study is needed looking into its effectiveness and safety before it could be approved for use in the treatment of ovarian cancer.  

Ovarian cancer warning signs

There are three main symptoms of ovarian cancer:

• increased abdominal size and persistent bloating (not bloating that comes and goes)
• persistent pelvic and abdominal pain
• difficulty eating and feeling full quickly, or feeling nauseous

See your GP if you have these symptoms regularly, on most days for three weeks or more.

 

Find out more about the symptoms of ovarian cancer

Where did the story come from?

The study was carried out by researchers from Plymouth University in the UK, and was funded by Plymouth Hospitals NHS Trust and Plymouth University.

It was published in the peer-reviewed journal, Mutation Research.

The body of the Mail’s coverage is generally accurate, though the headlines are slightly premature for this stage of research.

And dubbing the BRCA1 gene the “Angelina Jolie gene” – who announced she had preventative surgery because she has a high risk of developing the cancer – is arguably in bad taste.

What kind of research was this?

This laboratory research aimed to investigate the effect of a drug normally used in the treatment of rheumatoid arthritis in women with ovarian cancer and the BRCA1 mutation. Ovarian cancer is often diagnosed at a late stage, when the outlook is poor.

Women with mutations of the BRCA1 (breast cancer 1 early onset) gene are known to be at increased risk of developing both ovarian and breast cancer. Around 1 in 10 cases of ovarian cancer are associated with a BRCA1 mutation.

Normally, BRCA1 plays a major role in DNA repair. The mutation means cells are less able to repair DNA damage and are therefore more likely to become cancerous. This leads to the increased risk of cancer seen in women with a fault in this gene.

There is a need for improved treatments for ovarian cancer, which has seen ongoing research, even using drugs normally used for other purposes.

One such candidate is auranofin, a drug approved in the US for the treatment of rheumatoid arthritis. The drug is not available in the UK, however.

Auranofin disrupts an enzyme (thioredoxin reductase) and increases the production of reactive oxygen species (ROS). ROS are molecules that contain oxygen and are capable of damaging cells, leading to cell death. The combination of these two effects may have cancer-killing properties.

Though other studies have examined the use of auranofin in the treatment of ovarian cancer, none looked specifically at the effect in women with BRCA1 mutations. This is what this study aimed to do.  

What did the research involve?

The research involved human ovarian cancer cells treated with auranofin. In some of the cells, the researchers first used a special method to stop the activity of the BRCA1 gene to mimic the effect of a mutation. They then treated the cells with different concentrations of auranofin for 10 days.

After 10 days, the researchers looked at how well the cells were surviving by counting the cell clumps and examining DNA damage. They compared the results in cells that had BRCA1 depletion and those that did not.

The researchers also looked at proteins that might be responsible for the cancer-killing properties in BRCA1-depleted ovarian cells treated with auranofin. 

What were the basic results?

The researchers found BRCA1-depleted cells – in effect, those mimicking a BRCA1 mutation – were more sensitive to auranofin. At all concentrations of auranofin tested, around a third up to half fewer cells survived.

BRCA1 is known to play a key role in the repair of breaks in DNA. As expected, further laboratory examination revealed the BRCA1-depleted cells had increased number of breaks in their DNA. Those without BRCA1 depletion had only a slight increase in the number of DNA breaks after being treated with auranofin.

Further experiments suggested auranofin increased DNA damage by increasing the production of reactive oxygen species. In the BRCA1-depleted cells, because this damage was not being repaired, enough damage accumulated to trigger the cells to self-destruct. 

How did the researchers interpret the results?

The researchers concluded that, “Accumulated lethal double-strand breaks resulting from oxidative damage render BRCA1-deficient cells more sensitive to auranofin.”

Conclusion

There is an ongoing need for the development of new and more effective treatments for ovarian cancer, a cancer that is notoriously detected at a late stage and often has a poor outlook as a result.

Women with mutations in the DNA repair gene, BRCA1, are known to have an increased risk of developing ovarian cancer.

This laboratory study investigated the potential of the drug auranofin, which is approved in the US for the treatment of rheumatoid arthritis. The researchers found auranofin had superior cancer-killing properties in ovarian cancer cells lacking BRCA1.

It seems depletion of BRCA1 makes the cancer cells more susceptible to the oxidative DNA damage caused by auranofin treatment, causing the cells to self-destruct.

The results suggest there may be promise for this drug in the treatment of ovarian cancers with BRCA1 mutations.

However, this research is in the very early stages – the researchers only incubated auranofin with ovarian cancer cells in the laboratory, they did not give the drug directly to women with ovarian cancer.

Auranofin is currently approved for the treatment of rheumatoid arthritis in the US and has therefore been tested in humans already, which can make the path to human trials quicker.

In fact, the drug has already been used in early-stage (phase II) ovarian cancer trials in humans, but not specifically women with BRCA1 mutations. The results of these trials are needed to give an indication of whether the drug does indeed have potential for treating ovarian cancer.

Given the results of the current study, the researchers may want to start trials specifically in women with ovarian cancer who have BRCA1 mutations. We need to await the results of these studies before we know how effective and safe it is for treating ovarian cancer.

This research is encouraging and does show promise, but the Mail Online’s headline is premature by saying the drug will “give hope to millions”. 

If you have a strong family history of ovarian or breast cancer, you may want to ask your GP about being tested for any BRCA mutations. You should bear in mind that testing cannot guarantee you will or won’t develop cancer, and a positive result can cause considerable emotional distress.

Read more about predictive genetic tests for cancer risk genes.