Targeting cancer-associated fibroblasts to treat 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.

This research, published in Cell Reports Medicine, found 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 be able to shrink some oesophageal tumors more than chemotherapy could alone, tackling chemotherapy resistance, which is one of the major challenges in treating oesophageal cancer. 

Oesophageal cancer affects the food pipe that connects your mouth to your stomach, and is a relatively rare cancer. Currently this disease has much poorer outcomes and treatment options compared to other cancers, with around just 1 in 10 patients surviving their disease for 10 years or more. 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 tumor microenvironment, the area that sounds 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 wanted to identify the cells in the tumor microenvironment which protects the tumor 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 tumor 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 tumors. They found that PDE5i were able to suppress CAF activity and make them look more like normal fibroblasts. 

Next, collaborating researchers took samples of tumor cells from 15 tissue biopsies from eight patients, and used them to create lab-grown artificial tumors. They tested a combination of PDE5i and standard chemotherapy on the tumors. Of the 12 samples from patients 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 on mice implanted with chemotherapy resistant oesophageal tumors and found that there were no adverse side effects to the treatment, and that chemotherapy combined with PDE5i shrunk the tumors 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 be extremely unlikely to cause erections without the appropriate stimulation.

The lead author of the study 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 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.