Oral GUCY2C Ligand Blocks Colorectal Tumor Progression in Patients
Abstract
This project addresses the Topic Area of “colorectal cancer” and the Military Relevance Focus Area involving “gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of active duty Service members, Veterans, and their beneficiaries.” Specifically, this project identifies new mechanisms that initiate nearly all colorectal cancers and applies that knowledge to develop novel treatments to prevent this disease. The prevailing view suggests that colorectal cancer begins as mutations in key genes that regulate the division of cells. Once these mutations occur, the normal cells are irreversibly committed to a path of uncontrolled growth and the formation of a tumor. Although the mutations that initiate this process are well-known, the mechanisms that translate those mutations into changes in cell behavior and drive tumor formation are not well-defined. This proposal takes advantage of new insights we have gained into those mechanisms. We discovered that a receptor on intestinal cells, called guanylyl cyclase C (GUCY2C), and its hormone partner, called guanylin, act together to regulate normal cell functions. Indeed, the hormone guanylin produced by the intestine binds to the GUCY2C receptor on intestinal cells. Binding of hormone and receptor sends signals into the cells that keep proliferation in check. Most recently, we made two discoveries that intimately tie the guanylin-GUCY2C system to the genetic mutations that cause colorectal cancer. These discoveries suggest that those mechanisms directly oppose each other. First, we figured out that when the guanylin hormone binds to GUCY2C, it sends a signal into cells that blocks the function of the mutated genes that start colorectal cancer. In the opposite direction, we discovered that the mutations that initiate colorectal cancer eliminate the production of the guanylin hormone, which, in turn, silences the GUCY2C receptor and its signals, permitting uncontrolled cell division. These new observations suggest that the key mutations that start cancer have, as their first step, the elimination of guanylin hormone production in intestine. This silences the GUCY2C receptor and its signaling, removing the “brakes” from cell division and allowing intestinal cells to undergo uncontrolled proliferation to form a tumor. The innovation of this hypothesis can be appreciated by considering that these observations expand the concept of colorectal cancer from a genetic disease of irreversible mutations to a syndrome of guanylin loss that can be reversed by re-activating the GUCY2C receptor. This new information suggests that we can think about colorectal cancer as a disease of hormone insufficiency, just like diabetes is a disease of insulin insufficiency. In fact, this hypothesis suggests that colorectal cancer can be prevented, like some other diseases of endocrine insufficiency, by oral replacement of GUCY2C hormones. This proposal focuses on two specific aims that are required to advance this hypothesis into cancer prevention for patients. The first aim will focus on a clinical trial to demonstrate that an oral version of guanylin called linaclotide blocks progression of precancerous polyps and invasive carcinomas in patients. The second linked aim will define the molecular circuits by which linaclotide and GUCY2C signaling terminate uncontrolled growth that causes cancer, using “mini-tumors” in the laboratory that we will grow from polyps and tumors from patients in the trial. These studies will provide the proof that hormone replacement prevents colorectal cancer and help to better understand the mechanisms that cause this disease. Colorectal cancer is the fourth leading cause of cancer and the second leading cause of cancer deaths in civilian and military populations, with >90% of cases initiating through disruption o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810151
Entities
People
- Scott A. Waldman
Organizations
- Thomas Jefferson University
- United States Army