Guanylyl cyclase 2C (GUCY2C) in gastrointestinal cancers: recent innovations and therapeutic potential

ABSTRACT

Introduction

Gastrointestinal (GI) cancers account for the second leading cause of cancer-related deaths in the United States. Guanylyl cyclase C (GUCY2C) is an intestinal signaling system that regulates intestinal fluid and electrolyte secretion as well as intestinal homeostasis. In recent years, it has emerged as a promising target for chemoprevention and therapy for GI malignancies.

Areas Covered

The loss of GUCY2C signaling early in colorectal tumorigenesis suggests it could have a significant impact on tumor initiation. Recent studies highlight the importance of GUCY2C signaling in preventing colorectal tumorigenesis using agents such as linaclotide, plecanatide, and sildenafil. Furthermore, GUCY2C is a novel target for immunotherapy and a diagnostic marker for primary and metastatic diseases.

Expert Opinion

There is an unmet need for prevention and therapy in GI cancers. In that context, GUCY2C is a promising target for prevention, although the precise mechanisms by which GUCY2C signaling affects tumorigenesis remain to be defined. Furthermore, clinical trials are exploring its role as an immunotherapeutic target for vaccines to prevent metastatic disease. Indeed, GUCY2C is an emerging target across the disease continuum from chemoprevention, to diagnostic management, through the treatment and prevention of metastatic diseases.

KEYWORDS:

• cGMP
• gastrointestinal cancers
• guanylyl cyclase c
• immunotherapy
• ligand replacement
• phosphodiesterase inhibitors

Article Highlights

• The GUCY2C signaling axis regulates fluid and electrolyte secretion in the intestine.

• Loss of GUCY2C signaling occurs early and almost universally in colorectal cancer through aberrant APC-mediated suppression of guanylin hormone expression.

• An ongoing clinical trial explores the reactivation of the GUCY2C receptor as a method for colorectal cancer chemoprevention through the use of the FDA-approved GUCY2C agonist, linaclotide.

• Preclinical studies of cyclic GMP elevating agents, such as the FDA-approved PDE5 inhibitor sildenafil, suggest they may be promising for chemoprevention.

• The expression of GUCY2C in cancers of the colorectum, esophagus, stomach, and pancreas allows its use as a diagnostic biomarker for cancer staging.

• GUCY2C is a target for immunotherapies, such as vaccines, CAR-T cells, and immunotoxins. An ongoing phase II clinical trial is testing the efficacy of a GUCY2C-targeted vaccine to prevent secondary metastatic disease in patients with cancers arising in the GI tract.

Declaration of interest

SA Waldman is the Chair of the Scientific Advisory Board and member of the Board of Directors of, and AE Snook is a consultant for, Targeted Diagnostics & Therapeutics, Inc., which provided research funding that, in part, supported this work and has a license to commercialize inventions related to 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.

Reviewer Disclosures

Peer reviewers in this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported in part by the National Institutes of Health (R01 CA204881, R01 CA206026, and P30 CA56036), the Defense Congressionally Directed Medical Research Program W81XWH-17-PRCRP-TTSA, and Targeted Diagnostic & Therapeutics, Inc. to SA Waldman. AE Snook received a Research Starter Grant in Translational Medicine and Therapeutics from the PhRMA Foundation and was supported by the Defense Congressionally Directed Medical Research Programs (#W81XWH-17-1-0299, #W81XWH-19-1-0263, and #W81XWH-19-1-0067). SA Waldman and AE Snook were also supported by a grant from The Courtney Ann Diacont Memorial Foundation. SA Waldman is the Samuel MV Hamilton Professor of Thomas Jefferson University.