GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer

ABSTRACT

Introduction

Colorectal cancer (CRC) is one of the most-deadly malignancies worldwide. Current therapeutic regimens for CRC patients are relatively generic, based primarily on disease type and stage, with little variation. As the field of molecular oncology advances, so too must therapeutic management of CRC. Understanding molecular heterogeneity has led to a new-found promotion for precision therapy in CRC; underlining the diversity of molecularly targeted therapies based on individual tumor characteristics.

Areas covered

We review current approaches for the treatment of CRC and discuss the potential of precision therapy in advanced CRC. We highlight the utility of the intestinal protein guanylyl cyclase C (GUCY2C), as a multi-purpose biomarker and unique therapeutic target. Here, we summarize current GUCY2C-targeted approaches for treatment of CRC.

Expert opinion

The GUCY2C biomarker has multi-faceted utility in medicine. Developmental investment of GUCY2C as a diagnostic and therapeutic biomarker offers a variety of options taking the molecular characteristics of cancer into account. From GUCY2C-targeted therapies, namely cancer vaccines, CAR-T cells, and monoclonal antibodies, to GUCY2C agonists for chemoprevention in those who are at high risk for developing colorectal cancer, the utility of this protein provides many avenues for exploration with significance in the field of precision medicine.

KEYWORDS:

• Antibody Therapy
• biomarker
• cancer Vaccine
• colorectal Cancer
• car-T Cell Therapy
• guanylyl Cyclase C
• gucy2c

Article highlights

• The gastrointestinal receptor, guanylyl cyclase c (GUCY2C) has been explored as a reliable diagnostic biomarker and therapeutic target for colorectal cancer.

• GUCY2C-based precision therapies overcome some of the molecular heterogeneity of colorectal cancer and provide more targeted approaches to cancer treatment compared to the standard generic approach of chemotherapy.

• The unique protective compartmentalization of GUCY2C allows for a variety of GUCY2C-based therapeutic applications, which have demonstrated efficacy without causing systemic toxicity in preclinical models.

• The wide number of applications for GUCY2C-based therapy presents options that cover nearly all stages of colorectal cancer, carrying the potential to reduce the risk of recurrence and debulk large metastatic colorectal tumors.

Declaration of interest

SAW is the Chair of the Scientific Advisory Board and member of the Board of Directors of, and AES is a consultant for, 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. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported in part by the National Institutes of Health (R01 CA204881, R01 CA206026, and P30 CA56036), the Defense Congressionally Directed Medical Research Program W81XWH-17-PRCRP-TTSA, and Targeted Diagnostic & Therapeutics, Inc. to S.A.W. A.E.S received a Research Starter Grant in Translational Medicine and Therapeutics from the PhRMA Foundation and was supported by the Defense Congressionally Directed Medical Research Programs (W81XWH-17-1-0299, W81XWH-19-1-0263, and W81XWH-19-1-0067). S.A.W. and A.E.S. also were supported by a grant from The Courtney Ann Diacont Memorial Foundation. J.C.F. is supported by the Alfred W. and Mignon Dubbs Fellowship Fund and a PhRMA Foundation Pre-Doctoral Fellowship In Pharmacology/Toxicology. M.C. was supported by the NIH institutional award T32 GM008562 for Postdoctoral Training in Clinical Pharmacology. S.A.W. is the Samuel MV Hamilton Professor of Thomas Jefferson University.