Targeted Inhibition of Hh, Wnt, TGF-B Signalling Complex - Therapeutic Strategies in Cancer Biology and Pathology - page 37

Strand et al. (2011) have identified another small molecule benzamide deriva-
tive inhibitor MS-0022 (2-bromo- N -(4-(8-methylimidazo[1,2- a ]pyridin-2-yl)phenyl)
benzamide) of SMO. MS-0022 at nM levels effectively inhibited SMO. Its effect at
lower μM levels extended downstream to Suppressor of Fused (see Figures 4.1 and
4.2). MS-0022 inhibited cell proliferation in vitro . In tumour xenografts, delayed
growth correlated with reduced levels of Gli1. Many other SMO inhibitors are
known. The Smoothened antagonists SANT74 and -75 and SAG (SMO agonist)
are chlorobenzothiophene derivatives with small structural differences yet function-
ing markedly antagonistically. SANTs and SAG regulate SMO by modulating its
molecular conformation, possibly involving alltosteric alteration (Yang et al., 2009a;
Rominger et al., 2009).
Combination therapy has much ground to make. In pancreatic cancers for
instance neither cyclopamine nor rapamycin on its own had any effect in vitro or
in vivo . Only when both Hh and mTOR pathways were blocked along with standard
chemotherapy, there was any discernible reduction in the stem cell pool of pancreatic
cancer (Mueller et al., 2009). The possibility that acquired resistance to the inhibitors
might be a factor needs to be taken into account. Buonamici (2010) have reported
that the SMO antagonist LDE225 produced tumour regression in animal models of
medulloblastoma but resistance to the antagonist developed. Upon detailed analy-
sis they noticed that Gli1 gene had amplified and also PI3K signalling system had
been activated. The appearance of resistance could be delayed by employing the dual
PI3K/mTOR NVP-BEZ235 at the start of the experiment.
At the risk of reiteration, the problem basically is that currently combinations are
virtually random selections. The combinations have to be designed because more
often than not more than one signalling systems might be operating in a tumour
model and so many combinations turn out ineffective. This is where one has to look
at inhibitors TGF-β and family, Wnt and miRNA as potential candidates for combi-
nation between them and with conventional chemotherapeutic agents. Deregulation
of Hh signalling has been associated with aggressive cancers coupled with enhanced
tumour vascularisation. So it is rather surprising that de novo clinical trials combin-
ing Hh and inhibitors of neovascularisation such as avastin have not received the
degree of attention they merit.
HDAC Inhibitors Combination with Hh Inhibition
Histone acetyl transferases (HATs) acetylate histones and lead to increased transcrip-
tion of genes. In contrast, histone deacetylases (HDACs) remove acetyl groups of
lysine residues of histones and lead to chromatin condensation and silenced gene
transcription. The HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) arrests
growth and induces apoptosis and so inhibits tumour growth. Combination of SAHA
and SANT-1 has led to growth suppression of Gemcitabine-resistant pancreatic
adenocarcinoma cell lines Panc-1 and BxPC-3. The additive inhibitory effects are
attributed to upregulation of human hedgehog-interacting protein (HHIP), a negative