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

Abstract

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.

Figure 1

GUCY2C-targeting approaches. GUCY2C is an intestinal mucosal receptor involved in epithelial homeostasis and tumor suppression. Loss of GUCY2C ligands, silencing GUCY2C signaling, is an early step in tumorigenesis, leading to oncogenic signaling, metabolic reprogramming, loss of epithelial barrier integrity, and cell proliferation. Oral replacement of lost ligands is a strategy to prevent colorectal cancer. Furthermore, colorectal cancer cells overexpress GUCY2C, providing a target for immunotoxin therapy or T cell-mediated immunotherapies to eliminate metastases. Imaging agents also can target GUCY2C, improving disease detection and the monitoring of treatment progress.