How an old antidepressant could provide the next brain cancer breakthrough
In 1998, I received an intriguing handwritten note. It came from David Wilkie, emeritus professor at University College London, and asked if I thought the antidepressant drug clomipramine could affect brain tumours. I had been investigating how brain cancer spreads and Wilkie wondered if his own work on how clomipramine could kill cells might be of relevance.
This sparked a series of investigations over the last 18 years into how this old drug that was once commonly used as an antidepressant might find a new purpose in cancer treatment. Research has now linked it to increased survival rates for brain tumour patients and, because its patent has expired, it is cheaply available at less than 10p a tablet. Clomipramine (sold under the brand name Anafranil) has been used for decades to treat patients with depression. Yet surprisingly – some might say scandalously – it has still not been through the clinical trials that would allow it to be prescribed for brain tumour patients.
Clomipramine's use as an antidepressant has somewhat declined since it was first introduced in the 1950s, due to the development of selective serotonin reuptake inhibitor (SSRI) drugs such as Prozac. But its potential use as a brain cancer drug comes from the fact that it can cross the blood-brain barrier, which protects the brain from toxins in the blood but can also prevent drugs from entering.
The first piece of research, carried out by a PhD student in my lab, made the important discovery that clomipramine specifically targeted brain tumour cells – but not healthy brain cells. Additional studies confirmed that clomipramine worked by targeting these cells' energy source (mitochondria). Depending on the dose used, this would set up cell death in a way that was reversible after 24 hours but irreversible after 48 hours, even at a relatively low dose.
This is very different from the way that current gold-standard brain tumour therapy works, which typically involves killing both cancer and normal cells by targeting their nuclei.
Research has shown that clomipramine is linked to a reduction in the likelihood of developing a tumour by 40%-50% depending on the dose, and 64% for patients taking the drug long-term. We (and others) have also shown that using other repurposed drugs as well can make cancer cells more sensitive to clomipramine and enhance its anti-tumour effect.
But the evidence needed to change a drug's licence so it can be prescribed for a specific condition can only be obtained with a robust clinical trial. The trials that have so far been carried out with brain tumour patients unfortunately are not enough. One was a pilot with a small sample size (50 patients) and the second was halted because it had too few patients who complied with the trial rules after the initial 12 months.
Publicity for the drug has resulted in many doctors giving their brain tumour patients clomipramine anyway. In these anecdotal cases, some patients have gone on to survive for periods of up to ten years – and even 17 years in a couple of instances.
But because these patients were not controlled by a clinical trial – for example taking recorded doses and consistent biological measurements – any results can't be used to change the licence. So even with compelling laboratory and anecdotal evidence, many doctors still only prescribe within the existing guidelines. This helps them to avoid being liable for negligence if a patient is harmed.
Some politicians in the UK have tried to alter the law to make it easier to for promising off-patent drugs to be used for cancer treatment within the regulations. But the latest law, which came into effect in March 2016, was very watered down. Its main outcome was a searchable database that will record doctor's medical innovations. This could be a useful reference but doesn't provide any protection against negligence to encourage more doctors to trial drugs like clomipramine.
So this brings us back to the need for a robust clinical trial. Our laboratory research aims to find partner drugs that can target multiple specific biological pathways and to personalise patient therapies. But finding the funds for a clinical trial is difficult, especially less than 2% of national cancer research money may be spent on brain tumour research. But without this funding, we won't be able to reveal the full potential of clomipramine to save the lives of brain cancer patients.