Medications for Erectile Dysfunction Can Provide Targeted Therapy in Esophageal Cancer

According to new research, a class of medications often used to treat erectile dysfunction may increase the effectiveness of chemotherapy in treating esophageal cancer.

Graphical Abstract

Graphical Abstract. Credit: Cell Reports Medicine

Esophageal adenocarcinoma (EAC) typically has a fatal outcome. Most patients have advanced disease, and the 5-year survival rate is  50% for those who can receive potentially curative therapy. Neoadjuvant chemotherapy with or without radiotherapy improves survival in randomized controlled trials (RCTs), but only for a small subset of patients. Neoadjuvant therapies are typically morbid, unsuccessful, and drag on decisive surgery.

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Activated cancer-associated fibroblasts (CAFs) have been shown to affect EAC outcomes and have biological characteristics that favor tumor growth. Phosphodiesterase type 5 (PDE5) is a hydrolase that catalyzes the breakdown of cAMP and cGMP to regulate their levels. PDE5 is present in both healthy tissue and many types of human cancers. With PDE5 inhibition, cGMP is increased, activating several downstream pathways, including protein kinase G (PKG) signaling. PDE5i drugs find application in the treatment of erectile dysfunction. High doses have more recently found application in managing pulmonary arterial hypertension and symptoms related to the urinary tract.

PDE5i may be repurposed to treat diseases like cancer and lung illness, according to recent studies.

PD5Ei shows potential in esophageal cancer treatment

PDE5i reduces the myofibroblast phenotype of prostatic fibroblasts, indicating that they may be able to target the inflammatory cells seen in many solid tumors. To limit the tumor-promoting effects of CAFs and increase the susceptibility of EAC to conventional chemotherapy, scientists anticipated that PDE5i would directly target the CAF phenotype in EAC. Up to 80% of patients with EAC do not react to standard-of-care neoadjuvant therapy; this could enhance their prognoses.

By concentrating on cancer-associated fibroblasts (CAFs), which are present in the region around the tumor, PDE5 inhibitors can overcome chemotherapy resistance. The combination of PDE5 inhibitors and chemotherapy may be able to reduce some esophageal cancers more than chemotherapy alone, overcoming chemotherapy resistance, one of the main difficulties in treating esophageal cancer, even though this is yet early discovery research.

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Only around 1 in 10 people with this cancer currently experience results and treatment options that are as good as those for other malignancies.

The tumor region, known as the tumor microenvironment, affects treatment resistance in esophageal cancer. The components of this include chemicals, blood vessels, and cells like cancer-associated fibroblasts (CAFs), which are crucial for tumor formation. It nourishes the tumor and can serve as a shield, thwarting the effectiveness of therapies like chemotherapy.

PDE5, an enzyme in the blood vessel wall, is more prevalent in esophageal cancer than in healthy esophageal tissue. In the tumor microenvironment, CAFs contained high PDE5 concentrations. Additionally, they discovered that higher PDE5 expression is linked to poorer overall survival, indicating that PDE5 would make an effective therapeutic target.

Clinical significance

The scientist used PD5i on mice with esophageal tumors resistant to chemotherapy. The results showed no unfavorable side effects. Chemotherapy plus PDE5i significantly reduced the tumors compared to chemotherapy alone.

PDE5 inhibitors are a class of drugs usually safe and well-tolerated, even at the high doses needed for this treatment, which is an advantage of employing them in clinical practice.

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With no advancement in esophageal cancer treatment over the past 40 years, PDE5 inhibitors could be beneficial in combination with chemotherapy for esophageal malignancies.


Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts



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