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.

The prognostic and therapeutic role of hormones in colorectal cancer: a review

“…Guanylyl and uroguanylyl are both peptide hormones secreted by the small and large bowel. They are involved in maintaining epithelial homeostasis and fluid secretion via the guanylyl cyclase (GCC2C) [61]. GCC2C are naturally found in colonic epithelial cells but not in other tissues [61].…”

“…They are involved in maintaining epithelial homeostasis and fluid secretion via the guanylyl cyclase (GCC2C) [61]. GCC2C are naturally found in colonic epithelial cells but not in other tissues [61]. GCC2C is expressed in 95% of primary and metastatic CRCs, whilst uroguanylin and guanylin expression disappears early on in CRC tumorigenesis [61].…”

“…GCC2C are naturally found in colonic epithelial cells but not in other tissues [61]. GCC2C is expressed in 95% of primary and metastatic CRCs, whilst uroguanylin and guanylin expression disappears early on in CRC tumorigenesis [61].…”

“…The commonest reported adverse effects included nausea, decreased appetite, fatigue, diarrhea, anaemia, alopecia and neutropenia [65]. Research into GCC2C target therapy is rapidly progressing and the next few years, will provide a better insight in its use in primary and metastatic CRC [61,66].…”

Meeting report of the 8th International Conference on cGMP “cGMP: generators, effectors, and therapeutic implications” at Bamberg, Germany, from June 23 to 25, 2017

“…Synthesis of cGMP by soluble guanylyl cyclases (sGC) and particulate guanylyl cyclases (pGC) and degradation by phosphodiesterases (PDE) provide the basis for maintenance of body homeostasis. Consequently, dysregulation of cGMP signaling is likely to induce pathological states in many organs (Rainer and Kass 2016 ; Kraehling and Sessa 2017 ; Aka et al 2017 ; Ben Aissa et al 2016 ). Investigation of cGMP turnover by cyclases and phosphodiesterases as well as knowledge of cGMP effectors and their downstream targets are of key importance to understand the molecular physiology and pathophysiology of this signaling cascade.…”