Guanylate cyclase C as a target for prevention, detection, and therapy in colorectal cancer

ABSTRACT

Introduction: Colorectal cancer remains the second leading cause of cancer death in the United States, and new strategies to prevent, detect, and treat the disease are needed. The receptor, guanylate cyclase C (GUCY2C), a tumor suppressor expressed by the intestinal epithelium, has emerged as a promising target.

Areas covered: This review outlines the role of GUCY2C in tumorigenesis, and steps to translate GUCY2C-targeting schemes to the clinic. Endogenous GUCY2C-activating ligands disappear early in tumorigenesis, silencing its signaling axis and enabling transformation. Pre-clinical models support GUCY2C ligand supplementation as a novel disease prevention paradigm. With the recent FDA approval of the GUCY2C ligand, linaclotide, and two more synthetic ligands in the pipeline, this strategy can be tested in human trials. In addition to primary tumor prevention, we also review immunotherapies targeting GUCY2C expressed by metastatic lesions, and platforms using GUCY2C as a biomarker for detection and patient staging.

Expert commentary: Results of the first GUCY2C targeting schemes in patients will become available in the coming years. The identification of GUCY2C ligand loss as a requirement for colorectal tumorigenesis has the potential to change the treatment paradigm from an irreversible disease of genetic mutation, to a treatable disease of ligand insufficiency.

KEYWORDS:

• Colorectal cancer
• GUCY2C
• hormone replacement
• immunotherapy
• linaclotide

Declaration of interest

SA Waldman has received funding from Targeted Diagnostics and Therapeutics, Inc, and the National Institutes of Health (R01 CA170533, R01 CA206026, P30 CA56036). SA Waldman is the Chair of the Data Safety Monitoring Board for the Chart-1 Trial sponsored by Celyad and the Chair (uncompensated) of the Scientific Advisory Board of Targeted Diagnostics and Therapeutics, Inc, which has a license to commercialize inventions arising from this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by Targeted Diagnostics and Therapeutics, Inc and National Institutes of Health (R01 CA170533, CA206026; P30 CA56036).