Targeted Inhibition of Hh, Wnt, TGF-B Signalling Complex - Therapeutic Strategies in Cancer Biology and Pathology - page 35

occurs quite independently of SMO. This conclusion is justified by the finding that
GAS3 does not inhibit EMT (Roux et al., 2005).
Small Molecule Inhibitors of SMO
GDC-0449 (Vismodegib, 2-chloro- N -[4-chloro-3-pyridin-2-ylphenyl]-4-methylsul-
fonyl benzamide), an Hh pathway inhibitor is in phase II multicentre clinical trial
to assess tumour response and drug toxicity in patients with metastatic and locally
advanced BCC (basal cell carcinoma). Clinical trials are also being conducted to
evaluate GDC-0449 treatment for other forms of cancer such as pancreatic, small
cell lung cancer, oesophageal, stomach, breast and prostate cancers, among oth-
ers (Curis Inc. and Genentech in collaboration with NCI). A partial response was
reported in a patient with a refractory metastatic medulloblastoma. Investigations of
the tumour revealed that the Hh pathway was active and the activation seemed to be
due to loss of heterozygosity (LOH) at the PTCH locus and mutation of the PTCH-1.
Skulic et al. (2012) noted that objective response rate was 33% (30 patients in meta-
static BCC cohort) and the response rate was 43% (63 of the locally advanced BCC
cohort) and 13 of the 63 patients showed complete response. The duration of objec-
tive response in both cohorts was 7.6 months and progression-free survival was 9.5
months. Low response rates were recorded in patients with other types of cancer
(11.8% in pancreatic and <5% in others) (Rudin et al., 2009; LoRusso et al., 2011).
GDC-0449 has displayed a range of oral bioavailability (Wong et al., 2009). Mean
bioavailability in female subjects was 35% (Graham et al., 2010). GDC-0449 (up to
95%) binds with high affinity to plasma alpha-1-acid glycoprotein (AAG) and often
levels of GDC-0449 have corresponded with those of AAG. In vitro this binding
is reversible. This binding might be increasing single dose half-life of the drug by
approximately 200-fold (Giannetti et al., 2011). GDC-0449 (at 15 μM) did not signif-
icantly inhibit efflux transporter P-glycoprotein in MDR1-MDCK cells carrying the
MDR1 gene that codes for P-glycoprotein (ABCB1) (Wong et al., 2009). But Zhang
et al. (2009c) have reported inhibition of both P-glycoprotein (IC 50 =3 μM) and
ABCG2 (IC 50 =1.4 μM). Overall, there could be important implications for treatment
from the GDC-0449/AAG binding influencing both drug clearance and distribution.
Several new putative candidates for the inhibition of Hh signalling are
being studies in vitro and in animal models, a prominent one being LDE225
( N -(6-((2S,6R)-2,6-dimethyl morpholino) pyridin-3-yl)-2methy1-4′-(trifluoromethoxy)
biphenyl-3-carboxamide), which has been described as a potent SMO inhibitor (Pan
et al., 2010). Using the transgenic Rip1Tag2 mice, which develop islet cell neo-
plasms, Fendrich et al. (2011) were able to show that treatment with LDE225 inhibited
tumour growth substantially and there was demonstrable downregulation of SMO in
the tumours. Preliminary studies with BCC, LDE225 inhibited basaloid tumour nest
formation and induced regression of preformed tumours in organ cultures of PTCH1
heterozygous murine skin. Also in a provisional clinical study involving nevoid BCC
syndrome patients with BCCs, of 13 LDE225-treated BCCs three showed complete
and nine partial response, and in one case no response was recorded (Skvara et al.,