An update on guanylyl cyclase C in the diagnosis, chemoprevention, and treatment of colorectal cancer

ABSTRACT

Introduction: Colorectal cancer remains the second leading cause of cancer death in the United States, underscoring the need for novel therapies. Despite the successes of new targeted agents for other cancers, colorectal cancer suffers from a relative scarcity of actionable biomarkers. In this context, the intestinal receptor, guanylyl cyclase C (GUCY2C), has emerged as a promising target.Areas covered: GUCY2C regulates a tumor-suppressive signaling axis that is silenced through loss of its endogenous ligands at the earliest stages of tumorigenesis. A body of literature supports a cancer chemoprevention strategy involving reactivation of GUCY2C through FDA-approved cGMP-elevating agents such as linaclotide, plecanatide, and sildenafil. Its limited expression in extra-intestinal tissues, and retention on the surface of cancer cells, also positions GUCY2C as a target for immunotherapies to treat metastatic disease, including vaccines, chimeric antigen receptor T-cells, and antibody-drug conjugates. Likewise, GUCY2C mRNA identifies metastatic cells, enhancing colorectal cancer detection, and staging. Pre-clinical and clinical programs exploring these GUCY2C-targeting strategies will be reviewed.Expert opinion: Recent mechanistic insights characterizing GUCY2C ligand loss early in tumorigenesis, coupled with results from the first clinical trials testing GUCY2C-targeting strategies, continue to elevate GUCY2C as an ideal target for prevention, detection, and therapy.

KEYWORDS:

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

Article highlights

• The intestinal receptor, GUCY2C, and its downstream signaling axis regulated by cGMP, has emerged as tumor-suppressive regulator of several oncogenic circuits underlying colorectal cancer.

• Inactivation of the receptor occurs early and near-universally in colorectal cancer, through mutant APC-mediated inactivation of GUCY2C ligand expression. A clinical trial is underway examining reactivation of the receptor with the FDA-approved GUCY2C agonist, linaclotide, for colorectal cancer chemoprevention.

• GUCY2C expression is retained in cancer cells, enabling its use as a biomarker for cancer staging and for accurate prediction of disease recurrence.

GUCY2C represents a putative target for immunotherapies, including vaccines, CAR-T cells, and immunotoxins. A clinical trial testing efficacy of a GUCY2C-targeted vaccine is scheduled to begin this year.

Declaration of interest

S.A. Waldman is a member of Scientific Advisory Board, and the Board of Directors of Targeted Diagnostics and 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 on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institutes of Health (R01 CA204481, R01 CA206026, and P30 CA056036), the Department of Defense Congressionally Directed Medical Research Program W81XWH-17-PRCRP-TTSA, the Courtney Ann Diacont Memorial Foundation, and Targeted Diagnostic & Therapeutics, Inc. (S.A.W.). It was also supported by a PhRMA Predoctoral Fellowship Award in Pharmacology/Toxicology and an NIH Ruth Kirschstein Individual Predoctoral MD/PhD Fellowship (F30 CA232469) (J.A.R.).