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Wednesday 22 June 2022

Erectile dysfunction drugs could help treat oesophageal cancer

Southampton researchers have shown medicines like Viagra (sildenafil) may be able to boost the effect of chemotherapy on oesophageal cancer.

Professor Tim Underwood has led new research, published in Cell Reports Medicine, that shows PDE5 inhibitors can reverse chemotherapy resistance. They do this by targeting cells called cancer-associated fibroblasts in the area around the tumour.

Although this is early research, PDE5 inhibitors combined with chemotherapy may be able to shrink some oesophageal tumours more than chemotherapy alone. This would tackle chemotherapy resistance – one of the major challenges in treating oesophageal cancer.

Overcoming chemotherapy resistance

Oesophageal cancer affects the food pipe that connects your mouth to your stomach. While it is a relatively rare cancer, the UK has one of the higher rates in the world, with 9,300 new oesophageal cancer cases in the UK every year.

Currently this disease has much poorer outcomes and treatment options compared to other cancers. Around one in 10 patients survive their disease for 10 years or more. Part of the reason for this is that it can be resistant to chemotherapy, with around 80% of people not responding.

Resistance to chemotherapy in oesophageal cancer is influenced by the tumour microenvironment. This is the area around the tumour. It consists of molecules, blood vessels, and cells such as cancer associated fibroblasts (CAFs). It feeds the tumour and can act as a protective cloak, preventing treatments like chemotherapy from having an effect.

Targeting cancer associated fibroblasts

The researchers wanted to identify cells in this microenvironment which protect the tumour from treatment. This would mean they could target them.

They found levels of PDE5 were higher in oesophageal tumours compared with healthy oesophageal tissue. PDE5 is an enzyme normally found in blood vessel walls. CAFs in the tumour microenvironment had high levels of PDE5.

They also found an association between high expression of PDE5 and worse survival. This suggests PDE5 would be an effective target for treatment.

The researchers then tested a PDE5 inhibitor, PDE5i, on CAFs from oesophageal tumours. They found that PDE5i was able to suppress CAF activity and make them look more like normal fibroblasts.

Testing on artificial tumours

Collaborating researchers at the University of Nottingham took tumour cells from eight patients. They used 15 samples to create lab-grown artificial tumours.

They tested a combination of PDE5i and standard chemotherapy on these. Twelve samples were from patients whose tumours developed a poor response to chemotherapy. Targeting CAFs in these with PDE5i made nine sensitive to standard chemotherapy.

The researchers also tested the treatment on mice implanted with chemotherapy-resistant oesophageal tumours.

Chemotherapy combined with PDE5i shrunk the tumours more than chemotherapy alone. They found there were no adverse side effects to the treatment.

Already proven as safe drugs

PDE5 inhibitors are already proven to be a safe and well tolerated class of drug given to patients world-wide. This includes at the high doses required for this treatment.

Prof Underwood, professor of gastrointestinal surgery at the University of Southampton, said: “The chemotherapy resistant properties of oesophageal tumours mean that many patients undergo intensive chemotherapy that won’t work for them. 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.”

With the proven safety of these drugs and the positive results from this research, the researchers’ next step is a phase I/II clinical trial. This will test a PDE5 inhibitor with chemotherapy in patients with advanced oesophageal cancer.

If successful, this treatment could help many of those diagnosed with oesophageal cancer over the next five to 10 years.

The study, funded by Cancer Research UK and the Medical Research Council, could also pave the way for the use of PDE5 inhibitors in other cancer types.