Recently, we as well as other investigators have demonstrated that the expression of uroguanylin, a peptide hormone produced in the gastrointestinal tract (GI), is dramatically suppressed in colon polyps and tumor tissues. Further, we also demonstrated that the oral administration of uroguanylin inhibits formation of polyps and their progression to adenocarcinoma in Min-mouse, an animal model for colon cancer. Although the precise mechanism is still not clear, we believe uroguanylin binds to guanylate cyclase C (GC-C) and stimulates intracellular production of cyclic guanosine monophosphate (cGMP), resulting in activation of cystic fibrosis transmembrane conductance regulator (CFTR). Activation of CFTR chloride channel proteins and the subsequent enhancement of transepithelial efflux of sodium (Na+), potassium (K+), chloride and water leads to loss in cell volume, which results into inhibition of proliferation and in induction of apoptosis in enterocytes. Subsequently, we also demonstrated that uroguanylin treatment activated caspase-3, a pro-apoptotic enzyme, in human colon cancer cells (T-84). Human uroguanylin has been shown to exist in two isomers (conformational families), and only one of which is biologically active. We will develop novel agonist peptides with rigid three- dimensional structure that stabilizes only the conformational family, which is biologically functional. In Phase I of this SBIR Grant, a series of peptide analogs will be developed, based on conformational design, and evaluated in in vitro assays for inhibition of cell proliferation, induction of apoptosis and activation of pro-apoptotic nucleases (caspase-3). The overall goal of the proposed study is to develop novel analogs of UG that have longer half-lives, better stabilities, and thereby higher potencies. Accomplishment of this goal will identify a lead peptide for further evaluation in animal models for colon cancer and in human patients is part of a planned Phase II SBIR program. Given the need to find specific colon cancer drugs, the introduction of guanylate cyclase agonist as prophylactic and/or therapeutic agents for treatment of colon cancer is extremely important.
This research may lead to a drug, or drugs for prevention, treatment and delay in onset of colorectal cancer, which is one of the leading causes of cancer-related deaths in the U.S. Current chemo- and radiation therapies do not discriminate between normal and metastatic, resulting in severe side effects and dose limiting toxicities. We believe that the systemic administration of UG-like peptides will specifically induce apoptosis in cells in colon cancer tissues and also delay in progression of polyps into adenocarcinoma in gastrointestinal tract.
