Erectile Dysfunction Drugs Repurposed for Cancer Treatment
Researchers report repurposing an unusual class of drugs to combat oesophageal cancer – PDE5 inhibitors, which are mainly used as erectile dysfunction treatments.
Tumours are surrounded by a microenvironment made up of blood vessels, immune cells, enzymes and a variety of other cells the tumour needs to survive, including cells called fibroblasts that are essential in building connective tissue.
Research suggests that this microenvironment is key to a cancer’s development, and now researchers have found that an erectile dysfunction drug that targets the tumour microenvironment that could improve treatment for certain cancers.
Finding a new target
In some cancers, the tumour microenvironment allows tumours to resist treatment, preventing chemotherapy from having a beneficial effect.
This is the case in oesophageal cancers, which, though rare, currently has poor survival outcomes.
To try to overcome this resistance, a team of researchers led by Professor Tim Underwood at the University of Southampton, wanted to identify the cells in the tumour microenvironment that protect the tumour from treatment so they could target them.
“Where targeting cancer cells with one specific treatment can be difficult because they differ between patients, targeting the microenvironment cells may be more likely to have traction because they are similar across patients,” said Prof Underwood.
“Rather than going after the cancer cells, actually, if we take away their ‘soil’ and go after the environment they live in, we might have more success.
“The plants might be different, but if you poison the soil, they’ll all die.”
New uses for old drugs
By examining cells from oesophageal cancers called adenocarcinomas, the team found that levels of an enzyme called PDE5 are higher in these cancer cells than in health oesophageal tissues.
Specifically, the high levels of PDE5 were found in cells called cancer associated fibroblasts (CAFs), which are important for tumour growth. They also found that the more PDE5 a tumour contained, the worse the prognosis was, suggesting that PDE5 would be an effective target for treatment.
Luckily, PDE5 inhibitors already exist, commonly used to treat erectile dysfunction.
The researchers discovered that in addition to its usual function of relaxing muscles to allow increased blood flow, PDE5 inhibitors were able to suppress CAF activity, and make them behave like normal fibroblasts again.
Improving treatment safely
Once Prof Underwood’s team had found that PDE5 inhibitors worked, a collaborating team took samples of tumour cells from 15 tissue biopsies from 8 patients and used them to create artificial lab-grown tumours. With these tumours, the researchers could test a combination of PDE5 inhibitions and standard chemotherapy in the lab.
Twelve of these samples were taken from people whose tumours had shown a poor response to chemotherapy in the clinic. Of these, 9 were made sensitive to chemotherapy following the addition of the PDE5 inhibitor targeting CAFs.
They also tested the treatment on mice implanted with chemotherapy resistant oesophageal tumours and found that there were no adverse side effects to the treatment, and that chemotherapy combined with PDE5 inhibitors shrunk the tumours more than chemotherapy alone.
Repurposing existing drugs like PDE5 inhibitors takes advantage of well-established safety profiles.
However giving PDE5 inhibitors to people with oesophageal cancer would be extremely unlikely to cause erections without the appropriate stimulation.
“The chemotherapy resistant properties of oesophageal tumours mean that many patients undergo intensive chemotherapy that won’t work for them,” said Prof Underwood.
“Finding a drug, which is already safely prescribed to people every day, could be a great step forward in tackling this hard-to-treat disease.”
Source: Cancer Research UK
