Translating colorectal cancer prevention through the guanylyl cyclase C signaling axis

Abstract

Colorectal cancer (CRC) is a major public health concern, ranking among the leading causes of cancer death in both men and women. Because of this continued burden there is a clear need for improved treatment, and more importantly prevention of this disease. In recent years there is significant evidence to support the hypothesis that guanylyl cyclase C (GCY2C) is a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor is an important step in the disease process. Thus, ligand replacement therapy has been proposed as a strategy to prevent CRC. Until recently this strategy was not clinically plausible; however, the recent regulatory approval of linaclotide (LINZESS^TM, Forest Laboratories and Ironwood Pharmaceuticals, Inc.), an oral GUCY2C ligand, has raised the possibility of utilizing this strategy clinically to prevent CRC.

Keywords::

• biomarker
• colorectal cancer
• guanylin
• GUCY2C
• linaclotide
• preventative medicine

Financial & competing interests disclosure

Support was provided by grants from the National Institutes of Health (RC1 CA146033, P30 CA56036, R01 CA170533, F30 CA180500), the Pennsylvania 540 Department of Health (SAP #4100059197, SAP #4100051723), and Targeted Diagnostic and Therapeutics Inc. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. S Waldwan is the Samuel MV Hamilton Professor of Thomas Jefferson University, the Chair of the Data Safety Monitoring Board for the C-Cure Trial^™ sponsored by Cardio3 Biosciences, and the Chair (uncompensated) of the Scientific Advisory Board of 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. J Lin was supported by NIH institutional award T32 GM08562 for Postdoctoral Training in Clinical Pharmacology and was the recipient of the Young Investigator Award from the American Society for Clinical Pharmacology and Therapeutics.

No writing assistance was used in the production of this manuscript.

Disclaimer

The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions included in this manuscript.

Key issues

• • Colorectal cancer (CRC) is a major cause of morbidity and mortality in the developed world.

• • Although preventative strategies are presently in clinical use for this disease in the form of screening tests, there remains a clear need for improved methods of disease prevention.

• • Although the molecular defects in CRC are heterogeneous, one of the most common events in sporadic and genetic disease is the loss of expression of guanylin, the endogenous hormone ligand for the guanylyl cyclase C receptor. There is substantial evidence to support a role for GUCY2C as a tumor suppressor in intestine, and that loss of signaling by silencing of guanylin expression is permissive for tumorigenesis.

• • Regulatory agencies recently approved the oral GUCY2C ligand linaclotide (LINZESS^TM, Forest Laboratories and Ironwood Pharmaceuticals, Inc.) for clinical use in treating patients with chronic constipation. The drug is well-tolerated and possesses selective pharmacologic activity in intestine.

• • Given the body of literature that GUCY2C silencing promotes tumorigenesis, linaclotide possesses substantial potential for use as hormone replacement therapy to prevent cancer by replacing lost endogenous ligands.

Notes