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GCRA for Colon Cancer
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.
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