GUCY2C ligand replacement to prevent colorectal cancer

ABSTRACT

Despite advances in screening and prevention strategies, colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Given this continued public health burden of CRC, there is a clear need for improved disease prevention. CRC initiates and progresses over decades, canonically proceeding via a series of stepwise molecular events that turn a normal epithelium into a dysfunctional epithelium, then subsequently into an adenoma, and finally an invasive adenocarcinoma. An emerging paradigm suggests that guanylyl cyclase C (GUCY2C) functions as a tumor suppressor in the intestine, and that the loss of hormone ligands for this receptor causes epithelial dysfunction and represents an important step in the disease process. In that context, GUCY2C ligand replacement therapy has been proposed as a strategy to prevent colorectal cancer, a translational opportunity that is underscored by the recent regulatory approval of the oral GUCY2C ligand linaclotide (Linzess™, Forest Laboratories and Ironwood Pharmaceuticals, Inc.).

KEYWORDS:

• Chemoprevention
• colorectal cancer
• guanylin
• guanylyl cyclase C
• linaclotide

Disclosure of potential conflicts of interest

SAW is 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.

Funding

Supported by grants from NIH [CA170533] and Targeted Diagnostic and Therapeutics, Inc. ESB received an F30 Ruth Kirschstein MD-PhD Fellowship Award [CA180500]. SAW is the Samuel MV Hamilton Professor of Thomas Jefferson University.