The therapeutic potential of modulators of the

Hedgehog-Gli signaling pathway

Abstract
The hedgehog-Gli signaling pathway regulates numerous events during the normal
development of many cell types and organs, including the brain, bone, skin, gonads,
lung, prostate, gastrointestinal tract and blood. Small-molecule modulators of the Hh-
signaling system have been proposed as potential therapeutic agents.
Hedgehogs (Hh) are secreted glycoproteins that act through the transmembrane
proteins Patched1 (Ptc1) and Smoothened (Smo) to activate an intricate intracellular
signal-transduction pathway. Gli proteins are transcription factors that can act as
activators or repressors of transcription depending on the particular cellular context.
Mutations in components of the HH-GLI pathway in humans lead to several
diseases, including holoprosencephaly, basal cell carcinomas and
medulloblastomas.
A synthetic non-peptidyl small molecule that faithfully activates the Hh-Gli pathway
has been identified. This agonist promotes proliferation and differentiation in a cell-
type-specific manner in vitro, and rescues developmental defects of Shh-null mouse
embryos in vivo. The fact that the molecule retains its activity after oral
administration is a great advantage, but systemic side effects are to be expected.
Treatment of human diseases resulting from ectopic HH-GLI pathway activation
requires the use of pathway antagonists, such as anti-SHH antibodies, cyclopamine,
forskolin, and Gli-repressor proteins. Cyclopamine holds great promise, while
forskolin may cause side effects.
Cyclopamine inhibits the activation of the HH-GLI pathway, which may be involved in
the initiation and maintenance of different tumors. It is possible that cyclopamine
could be used to treat diseases arising from activation of the HH-signaling pathway
at the level of SMOH or above. Frank-Kamenetsky et al.[1] report the use of
Cur61414, a new small-molecule inhibitor of Smo, which has inhibitory properties
similar to those of cyclopamine.
The carboxy-terminally truncated repressor forms of GLI3 are potent inhibitors of the
activating output of the HH-signaling pathway, and could be used as antagonists for
the treatment of tumors.
Agents that inhibit HH signaling may induce the regression of tumors, but may also
affect other normal pathway-dependent cells in the patient.