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studies, in addition to those mentioned above, indicate primarily caused by increased expression and activity
the existence of cross-talk between Hh signaling and of P-glycoprotein drug transporters rather than the
several other pathways. It is, therefore, possible that emergence of genetic mutations that prevent drug-target
combination therapies targeting both Hh and other interactions. [68] BMS-833923 is another Hh inhibitor
pathways may provide additional benefits to patients that acts by binding to Smo. Clinical trials have been
in comparison with individual treatments. conducted to evaluate the effects, safety, tolerability,
and pharmacokinetics of BMS-833923 alone or in
Hedgehog as a therapeutic target in glioma combination with other drugs. Resistance to this
In recent times, several inhibitors of Hh signaling drug and the mechanisms behind it still need to be
have been synthesized or discovered for use in studies studied, however. In addition, other synthetic Smo
of cancer treatment in vitro and in vivo. By targeting antagonists including TAK-441, LEQ506, PF-04449913,
important molecules in the Hh signaling pathway, Hh and Cur-61414 have already been tested in clinical
inhibitors down-regulate the activity of Hh signaling in trials in order to determine dosage levels and evaluate
cancer cells, resulting in the inhibition of cancer cell safety [Table 2 and Figure 2].
growth and tumor progression. GDC-0449 (vismodegib)
is a small-molecule inhibitor specifically designed Currently, most drugs targeted against the Hh pathway
to target Smo. In preclinical experiments, GDC-0449 function by inhibiting Smo and thus lead to the
has been shown to inhibit the activation of the Hh suppression of tumor proliferation. However, Hh
pathway, leading to the inhibition of tumor growth signaling could also be altered by targeting components
initiated by mutations of Ptch or by increased levels located downstream of Smo. Accordingly, several
of Hh ligands. [65] A search of the clinicaltrials.gov groups are attempting to develop agents that target Gli
database identified 38 clinical trials of GDC-0449 or other molecules in the Hh pathway. For example,
focused on the treatment of different malignancies. GANT61 is an Hh inhibitor targeting Gli1 and Gli2.
In one trial, for example, GDC-0449 was tested in GANT61 has been shown to effectively down-regulate
combination with Avastin (bevacizumab) and Gli expression, inhibit cell proliferation and migration,
traditional chemotherapy in metastatic colorectal and induce G1 arrest and apoptosis. [69] GANT61 may
cancer. Treatment with GDC-0449 resulted in a also decrease cell invasiveness by inhibiting Gli2 in
reduction of symptoms, and the data suggests that human bladder transitional cell carcinoma. [70] Another
GDC-0449 may be safely used in combination with potential therapeutic agent is arsenic trioxide (ATO).
conventional agents. Unfortunately, mutations in Smo ATO has been proposed to block the accumulation
and its downstream targets are common, and may lead of Gli2, resulting in reduced protein levels, [71] and to
to GDC-0449 resistance. However, it has been shown bind directly to Gli1, inhibiting its transcriptional
that resistant medulloblastomas are sensitive to PI3K function. [72] Furthermore, four Hh pathway
inhibition, which may indicate that combined therapy inhibitors (HPIs) have been identified that act
is necessary. [66] downstream of Sufu to modulate Gli processing,
activation, and/or trafficking, including small
LDE225, another Hh inhibitor specifically targeting molecule antagonist of ciliogenesis. HPI-1 has been
Smo, has also been shown to reduce Hh-dependent shown to inhibit activation of the Hh pathway induced
proliferation. The main side effects include nausea, by overexpression of Gli1. HPI-2, on the other hand,
vomiting, anorexia, fatigue, muscle cramps, and inhibits Hh target gene expression in cells lacking Sufu
dysgeusia. During the course of LDE225 treatments, function or overexpressing Gli2, but is less effective
resistance to the drug was observed. Possible mechanisms against exogenous Gli1. HPI-3 likely blocks activation
for this resistance include Gli2 amplification and Smo
mutations, leading to reactivation of Hh signaling. Table 2: Synthetic inhibitors of Hedgehog signaling
Similar to the GDC-0449 study, a combination pathway
treatment of LDE225 with PI3K inhibitor delayed the Synthetic inhibitors Target
development of resistance. [67] Thus, combined therapy GDC‑0449 (Erivedge, vismodegib) Smo
targeting multiple pathways needs more investigation. LDE225 Smo
IPI‑926 (Saridegib)
Smo
BMS‑833923 Smo
IPI-926 (saridegib) is a unique, selective, and potent TAK‑441 Smo
molecule that inhibits Smo. IPI-926 is orally bioavailable LEQ506 Smo
PF‑04449913
Smo
and has demonstrated biological activity in multiple Cur‑61414 Smo
preclinical animal models of cancer. IPI-926 appears Arsenic trioxide Gli
to down-regulate Hh signaling, leading to inhibition GANT61 Gli
Shh
Robotnikinin
of the potential for self-renewal. Drug resistance was HPI 1‑4 Gli
observed after extended treatment periods, but was HPI: Hedgehog pathway inhibitor; Shh: sonic Hedgehog; Smo: smoothened

Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014 55