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

Allison A Aka^1,2, Jeff A Rappaport¹, Amanda M Pattison¹

¹a Department of Pharmacology and Experimental Therapeutics , Sidney Kimmel Medical College at Thomas Jefferson University , Philadelphia , PA , USA.

Expert Review of Clinical Pharmacology

|February 7, 2017

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.

Insights

Colorectal cancer (CRC) is a leading cause of cancer death. Targeting guanylate cyclase C (GUCY2C) by supplementing its lost ligands offers a new prevention and treatment strategy for CRC.

Area of Science:

Oncology
Molecular Biology
Gastroenterology

Background:

Colorectal cancer (CRC) is a significant cause of cancer mortality in the US, necessitating novel therapeutic and preventative strategies.
Guanylate cyclase C (GUCY2C), a tumor suppressor in the intestinal epithelium, presents a promising therapeutic target for CRC.
Loss of endogenous GUCY2C-activating ligands during tumorigenesis silences its signaling, promoting cancer development.

Purpose of the Study:

To review the role of GUCY2C in colorectal cancer development.
To discuss the translation of GUCY2C-targeting strategies into clinical applications.
To explore GUCY2C-based immunotherapies and diagnostic biomarkers for CRC.

Main Methods:

Review of pre-clinical models demonstrating the efficacy of GUCY2C ligand supplementation for disease prevention.
Analysis of the clinical development pipeline for synthetic GUCY2C ligands, including FDA-approved linaclotide.
Examination of research on GUCY2C as a target for immunotherapies and as a biomarker for CRC detection and staging.

Main Results:

Pre-clinical studies indicate that supplementing GUCY2C ligands can serve as a novel paradigm for CRC prevention.
The development of synthetic GUCY2C ligands, with linaclotide already approved, facilitates human clinical trials.
GUCY2C is a viable target for immunotherapies against metastatic CRC and a potential biomarker for patient stratification.

Conclusions:

The identification of GUCY2C ligand loss as a critical step in colorectal tumorigenesis reframes CRC from a genetic disease to one of ligand insufficiency.
Targeting GUCY2C represents a potential paradigm shift in CRC treatment, moving towards prevention and management of ligand deficiency.
Upcoming clinical trials will evaluate the efficacy of GUCY2C-targeting schemes, potentially transforming CRC management.

Read full analysis

Keywords:

Colorectal cancer GUCY2C hormone replacement immunotherapy linaclotide

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