Callisto’s guanylyl cyclase receptor agonist (GCRA) program is focused on a field of pharmacology with profound implications for future treatment of colon cancer, other cancers, and treatment of inflammation including Crohn’s disease, ulcerative colitis, and general organ inflammation, such as asthma. The basic focus of this work is the control of cyclic GMP (cGMP), an important second messenger involved in regulation of a variety of physiological conditions in the body. Recent advances in our understanding of cellular signaling pathways have elucidated the central role of cGMP, an intracellular signaling molecule involved in key cellular functions that are tied to inflammation, anti-tumorigenic responses and/or cellular death (apoptosis). Synthesis of cGMP in cells of the gastrointestinal tract and other specific organs of the body is promoted through the action of a guanylyl cyclase receptor (GC-C) activated by binding of the agonist uroguanylin, a hormone discovered in the early 1990’s. Uroguanylin is produced and secreted by specialized cells in the human gastrointestinal tract and binds to GC-C receptors of the intestine and colon where it activates synthesis of cGMP, leading to apoptosis, an important event in the turnover of cells lining the GI tract mucosa. Disruption and/or irregularities in the turnover of cells, as is the case with individuals displaying reduced levels of endogenous uroguanylin, can lead to precancerous polyps, colon cancer and inflammatory bowel diseases. Production of uroguanylin is dramatically suppressed in colon cancer patients, and there is increasing evidence that the deficiency of uroguanylin is one of the major reasons for development of polyps and colon cancer. Since the discovery of guanylin peptides (agonists of cGMP production) a decade ago, this area of research has grown considerably as demonstrated by the large number of publications in this new field. The discovery that uroguanylin is dramatically reduced in gastrointestinal polyps and colon cancer and that the deficiency of this hormone peptide is linked to the onset of colon carcinogenesis is the basis for the development of GCRA peptides as drugs to treat colon cancer.
Callisto has established a program to develop agonists as drugs that enhance cGMP production for treatment of this cancer condition. In addition, GCRA compounds are being developed by Callisto to treat other cancers, gastrointestinal inflammation and asthma and other general organ inflammation. Callisto expects the guanylate cyclase-signaling pathway to eventually reach similar standing to that of the cAMP/adenylase cyclase system in terms of regulation of a wide range of important cellular functions in the body.