Southampton scientists find erectile dysfunction drugs could improve treatment of oesophageal cancer

SOUTHAMPTON scientists have discovered that drugs used in Viagra could make chemotherapy more effective in patients with oesophageal cancer.

Currently only 1 in 10 patients survive the disease for ten years or more but Professor Tim Underwood, lead author of the study which was funded by Cancer Research UK and the Medical Research Council, is hopeful the discovery could improve survival rates.

The research found that PDE5 inhibitors, used in Viagra, can help to break through a barrier of cells that sit around oesophageal tumours and therefore enable chemotherapy drugs to reach the cancer cells.

Prof Underwood, who is also a 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.”

The new research has been welcomed by Terry Daly, 60 from Aldershot who was diagnosed with oesophageal cancer last October.

Terry said: “I’d been having difficulty swallowing and digesting food for about six months but put it down to indigestion. After a particularly bad incident, I went to the GP who referred me to the hospital where they performed an endoscopy. I knew by the look on the doctor’s face when he was doing the procedure that it wasn’t good news.

“I didn’t tell my wife, Donna, that I thought it was cancer at that point because I worried that she wouldn’t cope. She did come with me to the appointment though when they confirmed that it was cancer.

“It was a shock but my initial reaction was, ‘It is what it is’ and I have always tried to be positive because I believe I can beat this.

“I had chemo to try to shrink the tumour but it only reduced in size by a small amount. Then in April, I had an operation to take the tumour out and to stretch my stomach up to the remaining oesophagus.

“On day eight, my doctor couldn’t believe how well I was recovering but that night I became critically ill. They put me in an induced coma and took me back to surgery because the junction hadn’t taken and they needed to repair it urgently. I was in and out of surgery for several days and spent two weeks in intensive care.

“Now I’ve recovered from the surgery and have just started chemo again followed by radiotherapy.

“I think the new research is brilliant news and perhaps if the drugs had been available alongside my first chemo, it could have shrunk my tumour more before my operation and made that whole process a lot better.

“It’s really reassuring to know that there are people trying to find out so much about this type of cancer and discover better treatments. They’re working tirelessly to make people’s lives better and to help them beat this.

“My son did the Race for Life and raised £3,500 to fund research like this and I couldn’t be prouder. Next year I want to do the Race for Life with him and that’s my goal. It will also be mine and Donna’s 40^th wedding anniversary. She is my rock and I want to make sure I am around for her and for my grandchildren.”

Oesophageal cancer affects the food pipe that connects your mouth to your stomach, and 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. Part of the reason for this is that, in many cases, 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, the area that sounds the tumour. This is made up of molecules, blood vessels, and cells such as cancer associated fibroblasts (CAFs), which are important for tumour growth. It feeds the tumour and can act as a protective cloak, preventing treatments like chemotherapy from having an effect.

The research, published today (Tuesday 21^st June) in Cell Reports Medicine, is still in its early stages but it is hoped that combining PDE5 inhibitors with chemotherapy will shrink some oesophageal tumours more than chemotherapy alone.

The team of researchers led by Professor Tim Underwood at the University of Southampton wanted to identify the cells in the tumour microenvironment which protects the tumour from treatment so they could target them.

The researchers found that levels of PDE5, an enzyme originally found in the wall of blood vessels are higher in oesophageal adenocarcinoma compared with healthy oesophageal tissue. High levels of PDE5 were found in CAFs within the tumour microenvironment. They also found that high expression of PDE5 is associated with worse overall survival, suggesting that PDE5 would be an effective target for treatment.

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

Next, collaborating researchers at the University of Nottingham took samples of tumour cells from 15 tissue biopsies from eight patients, and used them to create lab-grown artificial tumours. They tested a combination of PDE5i and standard chemotherapy on the tumours. Of the 12 samples from patients whose tumours developed a poor response to chemotherapy in the clinic, 9 were made sensitive by standard chemotherapy by targeting CAFs with PDE5i.

The researchers 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 PDE5i shrunk the tumours more than chemotherapy alone.

An added benefit of using PDE5 inhibitors is that they are already proven to be a safe and well tolerated class of drug that’s given to patients world-wide, even in the high doses that would be required for this treatment. The researchers also say that giving PDE5 inhibitors to people with oesophageal cancer would not cause erections without the appropriate stimulation.

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 testing a PDE5 inhibitor in combination with chemotherapy in patients with advanced oesophageal cancer.

If successful, this treatment could be helping a significant proportion of the around 9300 people a year diagnosed with oesophageal cancer within the next 5 to 10 years. The study could pave the way for the use of PDE5 inhibitors in other cancer types.

Michelle Mitchell, chief executive of Cancer Research UK, said: "Developing new drugs for cancer is incredibly important, but doing so from scratch is a challenging process, and many fail along the way. We’ve also been keen to explore whether existing drugs, licensed for other diseases, can be effective in treating cancer. If these turn out to be successful treatments, they will also prove to be more affordable and become available to patients quicker.

"Progress in treatment for oesophageal cancer over the last 40 years has seen only limited improvement, which is why we’ve made it a research priority. We’re looking forward to seeing how the combined treatment of PDE5 inhibitors with chemotherapy performs in clinical trials.”