DOI: 10.25934/pr00009906
title: The putative role of Proton-Pump Inhibitors in patients with Basal Cell Carcinoma treated with vismodegib

description: Keratinocyte Skin Cancers (KSCs) are types of skin cancers that develop from the cells that make up the outer layer of the skin, called keratinocytes. KSCs are the most common cancers among humans. According to the Global Burden of Disease 2019 database, in the United States the total age-standardized incidence rate of KSC was 787 per 100.000 persons/years. Basal Cell Carcinoma (BCC) is the most common type of KSC.

In advanced stage BCC, the treatment scenario radically changed in the last decade with the advent of vismodegib (an anticancer drug), which improved the disease course of these patients. However, for some, vismodegib doesn't work as well as we would like it to.
Advanced BCC is typically diagnosed in elderly patients, who frequently require multiple therapies alongside vismodegib, including Proton Pump Inhibitors (PPIs), which are drugs used for gastric acid-related disorders. Recently, the potential effect of associated PPIs on the reduction of vismodegib efficacy has gained attention, with studies evaluating their interaction.

One hypothesis explaining how PPIs may reduce vismodegib efficacy, is that PPIs affect vismodegib absorption through altering stomach acidity. Absorption refers to the process by which substances are taken up by the body, and in this case, it means how much of the vismodegib is actually taken in by the body's system. Therefore, the lower the gastric acidity, the lower the absorption.

Additionally, several studies indicate that long-term use of PPIs might change the makeup and location of gut bacteria, which could reduce the body's response to vismodegib.
The tumor microenvironment (TME), which is the area around a tumor, is now recognized as a significant factor affecting the effectiveness of vismodegib. Studies have shown that Vascular Endothelial Growth Factor (VEGF), a molecule that regulates the tumor environment, is increased in cancer cells exposed to PPIs. This is concerning because VEGF is known to promote tumor growth and spread in patients with BCC. Additionally, PPIs can activate the production of Transforming Growth Factor Beta (TGF-Beta), another molecule that promotes tumor growth.

Our aim is to analyse clinical outcomes of patients with BCC treated with vismodegib, according to the PPIs exposure at baseline, by accessing and combining the ERIVANCE and NCT01201915 study datasets.
ERIVANCE, a phase 2 trial, involved patients with advanced BCC who received vismodegib, proving its effectiveness, safety over time, and lasting response. Similarly, the NCT01201915 is a phase 2 study that assess the feasibiliy and safety of vismodegib in patients with non-advanced BCC prior to surgical resection.

Our main objective will be assessing the effect of PPIs exposure on patients’ response to vismodegib.
This research will shed light on new possible mechanisms underlying resistance to cancer therapy in patients affected by BCC, with specific attention to the role of PPIs. With our findings, we hope to refine treatment approaches and improve outcomes for people battling with this form of KSC.