Oral GUCY2C Ligand Blocks Colorectal Tumor Progression in Patients
Abstract
The overall objective of this proposal is to develop a prevention strategy for colorectal cancer by exploiting the role of GUCY2C signaling in inhibiting colorectal epithelial transformation. The translational hypothesis suggests that oral linaclotide restores GUCY2C signaling, repairs epithelial dysfunction, and blocks progression of tumors in patients. The linked mechanistic hypothesis suggests that linaclotide prevents tumor progression by blocking beta-catenin accumulation through proteosomal degradation. In the Translational Aim, we will conduct a "window of opportunity" trial in patients with either established adenomas or carcinomas that will define the impact of 7 days of oral linaclotide on epithelial dysfunction and hyperproliferation compared to placebo. In the Mechanistic Aim, we will test the ability of linaclotide to activate GUCY2C signaling and induce proteosomal degradation of beta-catenin, reversing mutant APC signaling, in organoids derived from human adenomas and carcinomas identified in Aim 1. We have received regulatory approval to initiate the trial at Jefferson and await that approval at Fox Chase Cancer Center and the VA Puget Sound. We will begin enrolling patients at Jefferson in November 2019.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2019
- Accession Number
- AD1086352
Entities
People
- Scott A. Waldman
Organizations
- Thomas Jefferson University