The promise of antidepressants in brain cancer fight

By Tom Espiner
Health reporter

Image source, Science Photo Library
Image caption,
Research indicates that tricyclic antidepressants can effectively target brain tumours.

Brain cancer is one of the least-funded types of cancer in the UK, according to cancer charities, but kills more children and adults under 40 than any other cancer.

It accounts for around 2% of total cases of cancer in the UK per year, but attracts only 1% of the funding, according to charity Brain Tumour Research.

In some cases, parents in the UK have looked abroad for brain cancer treatment. The parents of five-year-old Ashya King, who were briefly detained for taking him out of the country, recently received NHS funding for proton beam treatment in Prague.

Nevertheless, brain cancer research could be entering an exciting and productive period, according to veteran cancer researcher Professor Geoff Pilkington.

One promising avenue of research is repurposing drugs to target brain tumours.

Old drugs could be used for new purposes, Prof Pilkington says.

"There are huge numbers of drugs which are being looked at," he says, including diabetes drugs.

Targeted treatment

Some of the most effective repurposed drugs could be types of antidepressants, says Prof Pilkington.

Antidepressants that kill cancer cells could be very effective, because they can get through the blood-brain barrier - a natural defence designed to stop toxins entering the brain.

Prof Pilkington has been researching drugs called tricyclic antidepressants at the University of Portsmouth since 2003.

Researchers at the university have found that not all tricyclic drugs are effective - only four out of the 20 they tested had any effect.

Nevertheless, they found that tricyclics such as clomipramine selectively killed brain cancer cells.

In the lab, clomipramine attacks the mitochondria of cancerous cells - the parts of cells that release energy from glucose, and power the growth of a tumour.

Many cancer drugs focus on damaging DNA in the nucleus of cancer cells, which can affect the surrounding tissue.

Tricyclic drugs including clomipramine, nortriptyline and doxepin were effective in the lab against types of brain, blood and skin cancers, Prof Pilkington says.

Separate research indicates that tricyclics, which are commonly used to treat depression and other psychiatric illnesses, can cut the risk of certain types of bowel and brain cancer.

Side effects

Prof Pilkington warns that antidepressant drugs probably only work for a limited number of patients, in part due to the nature of cancer treatment.

Patients can be on a cocktail of different treatments, including chemotherapy and radiotherapy.

Antidepressants can upset brain chemistry and cause convulsions in patients who are already prone to seizures, and can otherwise affect quality of life by making patients very tired, he says.

"They [tricyclics] lower the threshold at which seizures take place," Prof Pilkington says. "Quite a lot of brain cancer patients suffer from seizures, so you have to make sure that anticonvulsant medication is absolutely correct."

One of the problems with patients treating themselves "willy-nilly" is that they are very unlikely to give themselves the correct dose, he adds.

'Cheap as chips'

There is "not a shred" of clinical evidence that antidepressants kill brain cancer outside of a laboratory, he says.

However, there is "lots and lots" of anecdotal evidence that tricyclics work, Prof Pilkington says.

"A lot of patients I know have survived for very long periods of time on that drug [clomipramine], but there's not a shred of evidence from a controlled clinical trial," he says.

Even patients with malignant brain cancers such as glioblastoma have survived "well beyond" the mean survival time, he says.

Antidepressants like clomipramine are well-established - but the fact they are old is a barrier to getting the drugs to clinical trial, Prof Pilkington says.

Clinical trials are necessary to establish that treatments are safe for humans.

"It's been a nightmare trying to get it [clomipramine] into clinical trial," he says. "The big problem is it's as cheap as chips, so the drugs companies don't get their quid pro quo out of this.

"There's no money for clinical trials to be run. We've tried time and time again," he adds.

'Vicious' trial problems

Clomipramine has been in use for mental health since the early 1960's, Prof Pilkington says.

But drugs companies have no incentive to fund clinical trials for new uses, as the drug sells too cheaply, he says.

"It's as cheap as aspirin, almost. No-one's going to make a fortune from this," he says.

Even if funding were found, for example from the charity sector, brain cancer is often very debilitating.

It could be difficult to find a group of patients who were healthy enough to undergo a five year trial, he added.

In addition, there's a design problem. According to Dr Matt Williams, an Imperial College consultant oncologist, there is only a small group of people in the UK who would be qualified to design a trial.

"You get this really vicious carousel," Dr Williams says. "There aren't many trials in brain tumours, so therefore the number of people who can treat brain tumours and have experience in designing trials isn't very large, so therefore the number of people who are available to help you design trials in brain tumours isn't very large, and the amount of work you have is huge."

"The issue is there's a huge amount of work, and there's not a huge amount of us to do it," he says.

Counting the cost

Clinical trials on average cost around £4,000 per patient in administrative costs alone, quite aside from the costs of the drugs, Dr Williams adds.

Cancer charity Cancer Research UK said that clinical trials can cost between £100,000 and many millions of pounds.

The charity said it would be unlikely to fund a full clinical trial for brain cancer, but says that it has increased its funding for brain cancer research from £4m to £6m per year.

"Not enough progress has been made in targeting brain tumours," a Cancer Research UK spokeswoman says.

Nevertheless, Prof Pilkington has "no doubt that significant advances will be made".

Using old drugs for new purposes has the blessing of experts such as Plymouth University clinical neurobiology professor Oliver Hanemann.

"Repurposing is a fast way of [targeting] new drugs at brain tumours," he says.

However, the problems of funding and staffing clinical trials have to be overcome before the drugs can be sanctioned for safe use.

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