Erectile dysfunction drugs may enhance effect of chemotherapy in esophageal cancer

A group of drugs commonly used to treat erectile dysfunction may be able to boost the effect of chemotherapy in oesophageal cancer, according to new research funded by Cancer Research UK and the Medical Research Council.

This research, published today (Tuesday) in Medicine Reports Unitfound that the drugs, known as PDE5 inhibitors, can reverse chemotherapy resistance by targeting cells called cancer-associated fibroblasts (CAFs) residing in the area surrounding the tumor.

Although this is early discovery research, PDE5 inhibitors combined with chemotherapy may shrink some esophageal tumors more than chemotherapy alone, addressing resistance to chemotherapy, which is one of the main challenges in the treatment of esophageal cancer.

Esophageal cancer affects the food pipe that connects your mouth to your stomach, and although it is a relatively rare cancer, the UK has one of the highest rates in the world, with 9,300 new cases of esophageal cancer in the UK each year.

Currently, this disease has much poorer outcomes and treatment options than other cancers, with approximately 1 in 10 patients surviving their disease for 10 years or more. This is partly because in many cases it can be resistant to chemotherapy, with around 80% of people not responding.

Chemotherapy resistance in esophageal cancer is influenced by the tumor microenvironment, the area that rings the tumor. This is made up of molecules, blood vessels and cells such as cancer-associated fibroblasts (CAFs), which are important for tumor growth. It feeds the tumor and can act as a protective cloak, preventing treatments like chemotherapy from having an effect.

The team of researchers led by Professor Tim Underwood of the University of Southampton wanted to identify the cells of the tumor microenvironment that protects the tumor from treatment in order to be able to target them.

The researchers found that levels of PDE5, an enzyme originally found in the wall of blood vessels, are higher in esophageal adenocarcinoma than in healthy esophageal tissue. Elevated levels of PDE5 have been found in CAFs within the tumor microenvironment. They also found that high expression of PDE5 is associated with lower overall survival, suggesting that PDE5 would be an effective target for treatment.

Following this, the researchers tested a PDE5 inhibitor, PDE5i, on CAFs from esophageal tumors. They found that PDE5i was able to suppress the activity of CAFs and make them look more like normal fibroblasts.

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

The researchers also tested the treatment in mice implanted with chemotherapy-resistant esophageal tumors and found that there were no adverse side effects to the treatment and that chemotherapy combined with PDE5i shrank tumors more than chemotherapy. only.

An added benefit of using PDE5 inhibitors is that they have already proven to be a safe and well-tolerated class of drugs that are administered to patients worldwide, even at the high doses that would be required for this treatment. The researchers also say that giving PDE5 inhibitors to people with esophageal cancer would be extremely unlikely to cause erections without the proper stimulation.

The chemotherapy-resistant properties of esophageal tumors mean that many patients undergo intensive chemotherapy that will not work for them. Finding a drug, which is already safely prescribed to people every day, could be a big step forward in the fight against this difficult-to-treat disease. »

Professor Tim Underwood, lead author of the study and professor of gastrointestinal surgery at the University of Southampton

With the proven safety of these drugs and the positive results of this research, the researchers’ next step is a Phase I/II clinical trial testing a PDE5 inhibitor in combination with chemotherapy in patients with prostate cancer. advanced esophagus.

If successful, this treatment could help a significant proportion of the approximately 9,300 people diagnosed each year with esophageal cancer over the next 5 to 10 years. The study could pave the way for the use of PDE5 inhibitors in other types of cancer.

Michelle Mitchell, Chief Executive of Cancer Research UK, said: “Developing new cancer drugs is hugely important, but doing it from scratch is a difficult process, and many fail along the way. We also wanted to find out if existing drugs, approved for other diseases, can be effective in treating cancer. If they prove to be effective treatments, they will also prove to be more affordable and more quickly available to patients.

“Advances in the treatment of esophageal cancer over the past 40 years have seen only limited improvement, which is why we have made it a research priority. We look forward to seeing how the combined treatment of PDE5 inhibitors and chemotherapy performs in clinical trials. .”

Nicola Packer, head of human resources at Basingstoke, was diagnosed with oesophageal cancer aged 53. She was being watched due to her diagnosis of a condition called Barrett’s esophagus, which may be a risk factor for esophageal cancer. “They found my tumor last February. They caught it at stage 2, which is unusual for esophageal tumors because they often go unnoticed for a long time and are mostly diagnosed at stage 3 or 4.”

“The chemo usually doesn’t work very well on my type of esophageal tumor, so I knew it couldn’t completely remove the tumor, it could only shrink it in hopes of making the surgery more The chemo was exhausting and every week they would tell me that my tumor was shrinking, but slowly The anxiety you feel after having chemotherapy and then having to wait weeks of recovery before you can have surgery, knowing that chemo couldn’t do much is overwhelming.”

“Research like this that could mean people like me may have a better response to chemotherapy is hugely important.”

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