Researchers have had promising results treating tumours with everyday medicines. So why arent the big pharma companies investing in trials?

Helen Hewitt lost her mother, her younger brother and her baby son to cancer. Having successfully overcome breast cancer herself, she is currently battling several tumours in her lungs, and thanks to an inherited mutation in her DNA is at high risk of developing other cancers as well. Yet Helen, 41, is pioneering an unfamiliar approach against this all too familiar foe. Alongside conventional chemotherapy, surgery, and radiotherapy, she is taking a cocktail of experimental yet well-known medicines. Some of them might even be in your bathroom cabinet.

One is the diabetes drug metformin, which besides making healthy cells more sensitive to the effects of the hormone insulin may also help to starve sugar-hungry cancer cells. The cholesterol-lowering statin and the antibiotic shes been prescribed have the added benefit of dampening inflammation a process cancer cells use to help them grow. Then theres mebendazole, a common treatment for threadworm, which may also inhibit the growth of the blood vessels to her tumours.

Helen sought out these drugs after undergoing surgery to remove one tumour from her lung, only to discover that a different tumour had set up offshoots there as well. It just made sense to try something that might weaken the tumours but wasnt going to have a big impact on me in terms of side effects, says Helen, an NHS podiatrist who lives inWolverhampton.

Although the jury is still out on whether such drugs really make a difference, these arent the only medicine cabinet stalwarts undergoing a makeover. From aspirin to antacids, beta blockers to ibuprofen, all are being reinvestigated and utilised as potential anti-cancer drugs.

Unlike older therapies, which directly target and destroy dividing cancer cells, many of these repurposed drugs appear to work by targeting the healthy cells that cancers team up with to support their growth. Though widely accepted, this view of cancer as a mixture of deranged and healthy cells is still relatively new which in part explains why the anti-cancer properties of drugs like aspirin may have been missed the first time around. When many of these drugs were developed, we had a very simplistic view of cancer and all the focus was on finding ways of killing cancer cells, says Pan Pantziarka, joint coordinator of the Repurposing Drugs in Oncology project, which aims to identify the most promising medicines for adaptation and get them into clinical trials. But the whole system depends on developing a supporting blood supply, subverting the immune system, and producing certain growth factors. A lot of these repurposed drugs address these other things that cancer is dependent on to survive.

An early success story is the controversial drug thalidomide. Originally developed as a sedative during the 1950s, it was later used to curb morning sickness during pregnancy, until it was found to increase the risk of severe birth defects and confined to the scrapheap. Thalidomides resurrection as a cancer drug began in the 90s, following the discovery that it inhibited the growth of new blood vessels. A series of case reports also indicated that it might suppress the immune system. Angus Dalgleish, a professor of oncology at St Georges hospital in Tooting, London, became interested in the drug after witnessing the dramatic turnaround of a patient with autoimmune disease who was treated with thalidomide. I started doing some more reading and it struck me that here was a gem that had been thrown out with the rubbish, he says. At around the same time, the results of a small trial of thalidomide in patients with the bone marrow cancer myeloma were published. The patients had failed to respond to standard therapy and were given thalidomide as a last resort; a quarter of them saw a reduction in their cancer as a result. But thalidomide had other side effects besides the awful deformities it generated in foetuses. So working with a startup company called Celgene, Dalgleish helped to develop several less toxic analogues, which were put into clinical trials. One of them was lenalidomide, today a blockbuster myeloma drug, which generates around $4bn in worldwide sales per year.

thalidomide
The controversial drug thalidomide, now repurposed an an anti-cancer drug. Photograph: AP

For now at least, thalidomide stands alone as a successfully repurposed anti-cancer drug. But it could soon be joined by aspirin, which has already taken on a new guise as a treatment for heart attacks and stroke. Theres now some very interesting evidence suggesting that it might be a useful anti-cancer drug as well, says Ruth Langley, a medical oncologist at the MRC Clinical Trials Unit in London. She is currently recruiting for a clinical trial of aspirin in around 11,000 patients who have already undergone the best available treatment for breast, colorectal, gastro-oesophageal or prostate cancer. We are trying to see if, by giving aspirin, we can either delay the cancers coming back or even prevent them coming back altogether, Langley says.

The idea comes from previous observations that people who take aspirin to prevent heart attacks seem to have lower rates of cancer than the general population, and if they do develop cancer its less likely to spread to other organs. Aspirin acts on particles in the blood called platelets and makes them less sticky. This reduces the likelihood of blood clots, which is why its used to treat cardiova scular disease. One theory is that platelets also surround cancer cells as they travel around the body, making them less visible to the immune system, but they do this less efficiently if someone is taking aspirin. Another theory is that platelets help cancer cells to anchor in new sites and set up new tumours.

Several trials are under way around the world, investigating the use of the beta-blocker propranolol (more commonly used to treat high blood pressure) in breast, ovarian and other cancers. These follow the discovery that propranolol can be used to treat non-cancerous birthmarks called haemangiomas also known as strawberry marks in children. We said to ourselves, if it works in haemangioma, these drugs must inhibit the growth of blood vessels, so they could be useful to treat cancer too, says Nicolas Andr, a paediatric oncologist at Hpital de La Timone Enfants in Marseilles, France, who is about to start a trial of propranolol in angiosarcoma a cancer of the lining of blood vessels.

And there are other candidates. The ReDo project has drawn up a list of the six most promising drugs based on their low toxicity, plausible mechanism of action and strong evidence of potential efficacy in humans. They are: the aforementioned anti-worm drug mebendazole; an antacid used to treat stomach ulcers called cimetidine; the angina drug nitroglycerin; a broad-spectrum anti-fungal called itraconazole; an antibiotic used to treat chest infections called clarithromycin; the anti-inflammatory painkiller diclofenac.

Yet despite the excitement surrounding these drugs, getting them into clinical trials is a long and arduous process. Unlike thalidomide, whose anti-cancer properties were spotted relatively early by someone with the clinical contacts to quickly move things forward, many of these drugs have been ignored, despite preliminary human trials with encouraging results.

Why is this? Surely pharma companies should be jumping up and down at the prospect of an effective, low toxicity cancer drug particularly when the number of new cancer cases is projected to increase by 70% worldwide over the next two decades. In the UK alone, the number of people living with cancer is predicted to rise to 4 million by 2030, compared with 2.5 million currently. The trouble is that many of the existing drugs showing promise as anti-cancer agents have already lost their patents. A drug company that invests money in supporting a clinical trial is not guaranteed to recoup that money if the trial is successful because some other manufacturer could come in and sell the same drug at a lower price, says Pantziarka. Its a return-on-investment question. Where clinical trials of these drugs have been done, theyve generally been conducted by doctors and small groups of investigators. They dont have the time, experience or the money to take their positive results and change practice, Pantziarka adds.

Ironically, their low cost is one reason repurposed drugs are such an attractive prospect. The average cost of new cancer drugs has increased from around 70 per month in the 1990s to more than 7,000 per month today; if this trajectory continues then we can expect the first 70,000 a month cancer drug by 2035, says Paul Cornes, an oncologist at the Bristol Oncology Centre. Part of the reason theyre so expensive is because it takes years of testing to ensure that any new treatment is safe and effective. But with repurposed drugs, many of these questions have already been answered. We know theyre relatively safe, because theyre widely used, says Andr. Even so, we need sound, state-of-the-art clinical trials to confirm they work in cancer, and in order to get those we need funding.

With investment from big pharma lacking, some groups are coming up with creative ways of getting these drugs into clinical trials. In November, doctors at St Georges hospital used crowdfunding to raise 50,000 to test the benefits of the anti-malarial drug artesunate on 140 patients with colorectal cancer. In an earlier pilot study of 20 patients, the cancer spread in six of the 11 given a placebo, compared with just one of the nine given artesunate. In this case, the drug appears to kill cancer cells directly, and it costs just 70p per day.

Despite promising results like these, it could still be years before we know for sure if repurposed drugs work against cancer, and if so, how best to use them. But unfortunately, time is a luxury many cancer patients cant afford. This has prompted some to take matters into their own hands.

One of them is Ben Williams, an experimental psychologist at the University of California in San Diego, who was diagnosed with an extremely aggressive brain cancer called a glioblastoma in 1995, aged 50. He immediately underwent surgery, and then radiotherapy, but his prospects looked bleak: the average life expectancy for patients with glioblastoma is just 15 months, with younger people more likely to survive. Williams expected to die within the year.

With little left to lose, he started searching for other drugs that might complement the chemotherapy he was about to start, using the biomedical literature database PubMed. This provided published studies of alternative glioblastoma treatments, many of which were repurposed drugs. When he identified a relevant-looking drug, hed contact the researchers directly, asking for further information and advice about taking it. Part of my strategy was that I needed to make the chemotherapy more effective, because it didnt work most of the time, says Williams. If youve got a lethal diagnosis, then youre going to have to take some risks to beat it.

As a result, he started taking a cocktail of drugs more commonly prescribed for acne, insomnia and high blood pressure, as well as the breast cancer drug tamoxifen, which early studies had suggested might help to overcome resistance to chemotherapy. His oncologist was unimpressed. He said, youre going to hurt yourself, but I knew that I was less likely to hurt myself doing this than taking some of the stuff that he was offering, says Williams, who travelled to Mexico to buy some of the drugs he wanted. I was very much aware of the risks. But one of the huge advantages of using repurposed drugs is that you have a lot of toxicity information available already, because they have been used for such a long time.

In Williamss case, his treatment worked; against the odds, he remains cancer-free to this day. But even he admits he may have just got lucky and been one of the minority who responds well to chemotherapy: I will never know whether any of these things I took made a big difference, and neither will anyone else.

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A scanning electron micrograph image of two prostate cancer cells in the final stage of cell division. Photograph: Steve Gschmeissner/Getty Images/Science Photo Library RM

However, there are good reasons why cancer patients should talk to their doctors, rather than self-medicating even with something as seemingly innocuous as aspirin. Firstly, we dont know if it works, and secondly, even though aspirin is a very common drug, there are side effects, says Langley. There is a small risk of bleeding from your gut, or more seriously, even from your brain. We need to do proper studies and monitor safety very carefully.

The same goes for other common medicines that may or may not have anti-cancer effects. Even if they are effective, they are drugs that you probably need to take for long periods of time to see the effect otherwise their effects would have been recognised before, Langley adds.

Pantziarka, too, advises patients to work with their doctors rather than go it alone and also certainly not to see repurposed drugs as an alternative to conventional treatments. When we supply information to people, we encourage them to talk to their medical teams; we do not encourage them to go off and self-medicate.

But not all doctors are open to new approaches, as Pantziarka knows only too well. He first became interested in the idea of drug repurposing when his teenage son, George, was diagnosed with terminal cancer in his jaw bone. Like Williams, he started researching published trials for his sons condition on PubMed and then directly contacting the clinicians who had run them. The suggestions they came back with included a diabetes drug called pioglitazone, and another anti-inflammatory painkiller called celecoxib, in combination with continuous low doses of chemotherapy.

My sons doctor was not very positive, Pantziarka says. She said, We dont have any experience of these drugs, and the argument that millions of people take pioglitazone for diabetes had no sway. Eventually, she suggested a different combination of drugs, based on a protocol another doctor at her hospital had used previously. It was ineffective, and only made George feel worse. He died in April 2011, aged 17.

Doctors are understandably cautious about prescribing drugs for unlicensed uses; their peers may think them strange, and they may also find themselves in trouble if something goes wrong. But Dalgleish is one of those who is prepared to take these risks. He prescribes repurposed drugs for some of his cancer patients, and also liaises with their GPs and asks them to prescribe them, where appropriate. Ive had a lot of hassle for that, he says. Theres no room for freedom to do the best thing for your patients, just because someone hasnt put up millions of pounds to do a big drugs trial.

This is something that should at least partly be addressed with the Access to Medical Treatments Act which gained royal assent in March. It empowers the health secretary to create a database of innovative medical treatments, including off-label uses of existing drugs for cancer and other diseases. However, doctors still wont be protected against medical negligence claims should something go wrong.

Cancer Research UK explains how immune cells could tackle tumours

Read more: https://www.theguardian.com/science/2016/jun/12/anti-cancer-drugs-medicine-cabinet-repurposed-aspirin-thalidomide-beta-blockers

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