A group of drugs indicated to combat erectile dysfunction – PDE5 inhibitors, among which is the famous Viagra – may be key in the treatment of esophageal cancer, since they target cells called fibroblasts associated with cancer ( CAF) that are found in the tumor microenvironment –which is the area surrounding the tumor– and reverse resistance to chemotherapy, thus improving its efficacy.
The tumor microenvironment is like an ecosystem that surrounds the tumor and is made up of blood vessels, immune cells, enzymes and other types of cells that the tumor needs to survive, such as fibroblasts that are essential for creating connective tissue. For this reason, the tumor maintains a constant interaction with its microenvironment and the study, which has been published in Cell Reports Medicine, suggests that this microenvironment is key to the development of cancer.
The research has been carried out by British scientists led by Professor Tim Underwood, from the University of Southampton and funded by Cancer Research UK (United Kingdom), and its objective was to identify the cells present in the tumor microenvironment that are responsible for protecting to the treatment tumor to counteract its action and make the therapy more effective.
As Underwood has explained: “Instead of going after cancer cells, actually, if we remove their ‘soil’ and look at the environment in which they live, we might be more successful.” And she gives a very graphic example: “The plants may be different, but if you poison the soil, they will all die.”
A new use for a well-known drug: Viagra
The researchers found that levels of an enzyme called PDE5 are higher in cancer cells than in healthy esophageal tissue. Specifically, high levels of PDE5 were found in cancer-associated fibroblasts (CAF), which play an important role in tumor growth. They also found that the more PDE5 a tumor contained, the worse the prognosis, suggesting that PDE5 would be an effective target for treatment.
Combination chemotherapy with PDE5i achieved a greater reduction in esophageal tumors than chemotherapy alone
Currently there are already drugs that inhibit the PDE5 enzyme, and one of them in particular is quite well known, since it is Viagra (sildenafil citrate), a PDE5 inhibitor used to treat erectile dysfunction. The study authors tested a PDE5 inhibitor, PDE5i, on CAFs from esophageal tumors and found that in addition to their usual function of relaxing muscles to facilitate blood flow, PDE5 inhibitors could suppress CAF activity and make them behave like normal fibroblasts again and stop favoring the tumor.
They took samples of tumor cells from 15 tissue biopsies from eight patients and created artificial tumors from them in the laboratory. They then tested a combination of PDE5i and standard chemotherapy on tumors and found that of the 12 samples from patients whose tumors did not respond well to the chemotherapy they had been given as treatment, nine became sensitive to standard chemotherapy when targeted at CAFs with PDE5i.
The researchers also tested this treatment in mice implanted with chemotherapy-resistant oesophageal tumors and found that it did not cause adverse side effects and that chemotherapy combined with PDE5i achieved greater tumor shrinkage than chemotherapy alone. .
PDE5 inhibitors are safe and well tolerated drugs
Patients all over the world take PDE5 inhibitors, so they have already been proven to be safe and well-tolerated drugs, even at the high doses that would be required for this treatment. In addition, the authors of the work have assured that the administration of PDE5 inhibitors to patients with esophageal cancer is very unlikely to cause erections without adequate stimulation.
“The chemotherapy-resistant properties of esophageal tumors cause many patients to undergo intensive chemotherapy that doesn’t work for them. Finding a drug that is already safely prescribed to people every day could be a huge step forward in tackling this very difficult-to-treat disease,” said Underwood.
Based on the good results obtained in this preliminary study and the proven safety of PDE5 inhibitors, the researchers intend to conduct a phase I/II clinical trial to test a PDE5 inhibitor in combination with chemotherapy in cancer patients. of advanced esophagus.
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