Rationale for Inhibition of the Hedgehog

Anastasios Dimou, Kostas Syrigos, Muhammad Wasif Saif
Columbia University College of Physicians and Surgeons and Pancreas Center,
New York Presbyterian Hospital. New York, NY, USA
Summary
The role of hedgehog pathway in the biology of pancreatic adenocarcinoma is an emerging area of investigation and provides a
novel field for treatment intervention. Recent studies have shown the activation of the hedgehog pathway in pancreatic cancer.
Despite the initial assumption of an autocrine mechanism, it seems that the hedgehog pathway contributes to the molecular
conversation between tumor and its microenvironment through a paracrine loop. Furthermore, members of the hedgehog pathway
crosstalk with other pathways; they regulate tumor angiogenesis and are associated with cancer stem cells. In addition, there is
preclinical evidence about the efficiency of hedgehog inhibitors both in vitro and in vivo and the first clinical trials with those
compounds in the treatment of patients with pancreatic adenocarcinoma, are already under way.
Introduction
Pancreatic Adenocarcinoma
Ductal adenocarcinoma of the pancreas, which defines
the vast majority of pancreatic neoplastic diseases, is
the fourth most common cause of cancer related death
in USA [1]. Most of the patients are diagnosed at a
time when distant metastases are present and usually
the tumors are resistant to treatment. Gemcitabine and
erlotinib are the only compounds that have proven to
marginally improve prognosis for some of the patients.
Even the patients with localized disease that undergo
surgery have a five year survival of only 20% [1].
Pancreatic adenocarcinoma is derived from its
precursor lesions, the pancreatic cancer precursor
lesions (PanINs) which progress to pancreatic
adenocarcinoma through accumulation of a series of
genetic alterations in several genes including KRAS,
p16INK4A, Trp53 and smad4 [2]. The spectrum of
pancreatic carcinogenesis starts with the low grade
PanIN that gives rise to PanIN lesions of grade 2 and 3
(in situ adenocarcinoma of the pancreas) in a stepwise
fashion [2]. A lot of genetic alterations that are found
in invasive pancreatic adenocarcinomas are present in
PanIN lesions at lower frequencies [2].
Hedgehog Pathway
The hedgehog pathway has an important role during
embryonic development [3, 4]. Recently, aberrant
activation of the pathway has been described in human
neoplastic diseases like basal cell carcinoma [5],
medulloblastoma [6], small cell carcinoma [7] and
others. The canonical hedgehog pathway includes three
hedgehog ligands, sonic (SHH), Indian (IHH) and
desert (DHH) hedgehog that bind to patched, a 12 pass
transmembrane protein which releases smoothened
homolog (SMO). SMO subsequently allows Gli family
transcription factors to locate in the nucleus and affect
the expression of a variety of genes [8].
This is a review of the literature concerning the role of
the hedgehog pathway in pancreatic adenocarcinoma
and the rationale of inhibiting this pathway in the
context of clinical trials.
Hedgehog Pathway Activation in Pancreatic
Adenocarcinoma Cells
The initial reports about the role of the hedgehog
pathway in pancreatic adenocarcinoma suggested an
autocrine loop that leads to the pathway activation
through overexpression of the hedgehog ligands like
SHH [9]. This concept was based on the aberrant
Received August 20th, 2010 - Accepted October 7th, 2010
Key words cyclopamine; Hedgehog Proteins; HhAntag691;
Histone Deacetylase Inhibitors; Pancreatic Neoplasms; vorinostat
Abbreviations DHH: desert hedgehog; GDC-0449: HhAntag691;
HEPM: human embryonic palatal mesenchymal; IHH: Indian
hedgehog; SAHA: suberoylanilide hydroxamic acid; SHH: sonic
hedgehog; SIL: SCL/TAL1 interrupting locus; SMO: smoothened
homolog; SUFU: suppressor of fused homolog
Correspondence Muhammad Wasif Saif
Division of Hematology/Oncology; Department of Medicine;
Milstein Hospital; 177 Fort Washington Avenue, Suite 6-435;
New York, NY 10032; USA
Phone: +1-212.305.4954; Fax: +1-212.305.3035
E-mail: mws2138@columbia.edu
Document URL http://www.joplink.net/prev/201101/01.html

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expression of SHH in pancreatic cancer and its
precursor lesions PanIN 1-3 whereas it was absent in
normal pancreatic tissue [9]. In addition, inhibition of
the hedgehog pathway at the level of SMO with
cyclopamine resulted in blockage of cell proliferation
and induction of apoptosis in many pancreatic cell lines
in vitro, depending on their SMO expression level [9].
Cyclopamine was able to reduce tumor volume and
promote apoptosis in mouse xenografts demonstrating
in vivo activity [9]. Besides, activation of the hedgehog
pathway in human pancreatic epithelial cells through
Gli1 transfection lead to up regulation of a series of
genes that are over-expressing in early PanIN lesions in
comparison to normal pancreatic ducts [10]. Finally,
SHH was reported to enhance proliferation and
invasiveness by increasing matrix metalloproteinase 9
(MMP9) [11], cathepsin B [12] or loss of E-cadherin
[13] in pancreatic duct adenocarcinoma cells.
However, cyclopamine concentration needed to inhibit
proliferation in pancreatic duct adenocarcinoma cells
was high and even higher for inducing apoptosis in all
those first studies [14]. Furthermore, there was lack of
correlation between growth inhibition and hedgehog
pathway target gene activity in various tumor types
including pancreatic adenocarcinoma [14]. Recombinant
SHH failed to increase the endogenous Gli mRNA
levels in two pancreatic adenocarcinoma cell lines and
inhibition of the hedgehog pathway with specific
antagonists did not have any effect either [14]. Those
data taken together indicate that SHH presence in
pancreatic adenocarcinoma cells is not linked with Gli
activation in the same cells and make the autocrine
loop assumption less likely. It was suggested that the
effects of cyclopamine at high concentrations on
proliferation and apoptosis of the pancreatic duct
adenocarcinoma cells had been the result of altering
non-specific targets. Xu et al. [15] has provided
evidence that this is the case in apoptosis where a SMO
specific activator, purmorphamine was not able to
reduce the apoptosis caused by cyclopamine at basal
levels. Nevertheless, cell proliferation was fully
restored implying that the role of the hedgehog
pathway might be different between cell proliferation
and cell survival. An open question is how Gli gets
activated in pancreatic duct adenocarcinoma cells
supposing that this does not happen via SHH.
Nolan-Stevaux et al. [16] have sought the possibility of
Gli1 regulation independently of SMO and showed that
TGFbeta was able to induce expression of Gli1 and
Gli3 in pancreatic adenocarcinoma cell lines regardless
of the SMO status. Furthermore, KRAS inhibition with
small interfering RNA (siRNA) resulted in a marked
reduction of Gli1 expression and vice versa implying a
feedback loop. Cooperation between the hedgehog
pathway and KRAS has been shown before in
transgenic mice [17]: over expression of Gli2 only
gave rise to tumors that did not resemble pancreatic
adenocarcinoma and did not progress through PanINs.
On the other hand, when both Gli2 and KRAS were
over expressed, PanIN lesions and later on pancreatic
adenocarcinoma tumors were formed. Interestingly,
this was the case when only KRAS was over
expressed, but the addition of Gli2 over expression
accelerated the process of carcinogenesis. The same
study shows that Gli2 can activate Akt pathway but
cannot induce KRAS mutations. Negative regulation of
Gli2 from suppressor of fused homolog (SUFU) has
been shown to be a possible connection between
KRAS and Gli1 given that the cytoplasmic protein
SCL/TAL1 interrupting locus (SIL) was able to abolish
this negative regulation and that it was KRAS rather
than SHH that enhanced the interaction of SIL with
SUFU [18]. When SUFU interacts with SIL, Gli1 is
free to translocate in the nucleus and act as a
transcription factor. This interaction between KRAS
and Gli1 was shown to be SIL dependent. Activated
KRAS is believed to promote Gli1 via the RAS/RAF/
MEK/ERK pathway in cell lines [19]. However, in a
recent study [20] mutated KRAS was shown to
suppress the hedgehog pathway and specifically Gli2 in
pancreatic duct adenocarcinoma cells while increasing
SHH release at the same time. Given the high
frequency of KRAS mutations in pancreatic adeno-
carcinoma, this piece of data provides a mechanism
through which an autocrine hedgehog loop is blocked
in favor of a paracrine one. The discrepancy with
previous studies [16, 19] was attributed partially to
different experimental conditions.
Hedgehog Pathway Activation in the Stroma of
Pancreatic Adenocarcinomas
Yauch et al. [14] showed that the concentration of
cyclopamine needed to inhibit cell growth in a human
embryonic palatal mesenchymal (HEPM) cell line is
significantly lower than in the pancreatic cancer cell
lines and this inhibition correlated with the level of the
inhibitor. In addition, recombinant SHH was able to
activate the hedgehog pathway in the HEPM cell line
but not in pancreatic cancer cell lines [14]. They finally
showed that the hedgehog pathway was activated in the
stroma of xenografts and that this activation was
necessary for the growth of the xenografts. These data
favor a paracrine role of Hedgehog family ligands like
IHH and SHH which are produced in the pancreatic
cancer epithelial component and act in the tumor
stroma. The paracrine activity of hedgehog ligands was
validated in a series of mouse pancreatic adeno-
carcinoma models [21, 22].
SHH signaling pathway has been found to be activated
in fibroblasts in the stroma of pancreatic adeno-
carcinomas. Specifically, gene expression profiling
showed that SMO was upregulated in cancer associated
fibroblasts but not in normal pancreatic fibroblasts
[23]. Besides, overexpressing SHH was shown to
induce desmoplasia and to promote motility of
fibroblasts from the tumor stroma in a pancreatic
cancer cell line (Capan 2) [24]. Interestingly, it was
shown that stromal hedgehog signaling had a role in
tumor angiogenesis and lymphangiogenesis and that
hypoxia inducible factor-1 alpha (HIF1 alpha) and

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vascular endothelial growth factor (VEGF) were
expressed in tumor fibroblasts under the influence of
SHH [21].
The ability of SHH to induce angiogenesis in
pancreatic adenocarcinoma was confirmed by two
additional studies. SHH increased VEGF production in
endothelial progenitor cells [25] and regulated
migration of bone-marrow derived pro-angiogenic cells
as well as tumor vasculature formation by increasing
angiopoietin-1 (Ang-1) and insulin growth factor-1
(IGF-1) in those cells in pancreatic ductal
adenocarcinoma xenografts [26].
An alternative mechanism of SHH paracrine activity
was suggested by Yamasaki et al. [27]. In this study, it
was shown that inflammation activated monocytes
were able to produce SHH and increase cell
proliferation in pancreatic cancer cell lines. This is
different from the rest of the literature, since paracrine
activity is focused on tumor cells and not tumor
stroma. Interestingly, in contrast to Yauch et al., they
show that recombinant SHH was able to promote
relative Gli1 mRNA expression in pancreatic cancer
cell lines. This might be because they used different
cell lines and higher recombinant SHH concentration
(10 µg/mL instead of 1 µg/mL).
Targeting Hedgehog Pathway in Pancreatic Cancer
A number of compounds have been suggested to
inhibit the hedgehog pathway [28]. In an early report,
cyclopamine was shown to increase the effect of
paclitaxel or irradiation but not cisplatin or gemcitabine
on pancreatic cancer cell lines with an activated
hedgehog pathway [29]. Combination of cyclopamine
and gefitinib was able to inhibit growth and enhance
apoptosis in pancreatic cancer cell lines that express
both epidermal growth factor receptor (EGFR) and
SMO at a greater extent than any compound alone [30].
Interestingly, cyclopamine alone was able to
downregulate EGFR. However, these studies do not
take into account the possible role of hedgehog
inhibition in tumor stroma or in pancreatic cancer stem
cells.
A different approach was employed by Chun et al. [31]
who tested the effect of the combination of SANT-1
which is a SMO antagonist with a histone deacetylase
(HDAC) inhibitor, suberoylanilide hydroxamic acid
(SAHA). The combination showed supra additive
effects on growth inhibition and apoptosis. Besides,
SAHA lead to hedgehog interacting protein (HHIP, a
hedgehog antagonist) upregulation and Ptc-1 repression
providing a possible mechanism for the synergistic
effect of the two compounds.
Olive et al. [32] provided evidence that chemotherapy
does not have access to the tumor cells in KRAS and
p53 mutant pancreatic adenocarcinoma xenografts in a
gemcitabine resistant mouse model due to poor
vascularization of the tumors. When combining
gemcitabine with hedgehog inhibition (IPI-926, a
specific SMO inhibitor) however, tumor vasculature
and subsequently gemcitabine delivery in the tumors
were enhanced. Mean vessel density and CD31
positive cells increased whereas stromal myofibroblasts
were reduced. Mice treated with the combination had
their tumors reduced in size, undergoing apoptosis and
had significantly improved survival eventually. On the
other hand, IPI-926 had no effect on cell proliferation
in these KRAS driven tumors.
When xenografts derived from pancreatic ductal
adenocarcinoma cell lines are treated with gemcitabine,
cells that express stem cell markers like aldehyde
dehydrogenase (ADAC) and CD24 are enriched [33].
However, co-treatment of those xenografts with
cyclopamine results in reduction of the cells which
express stem cell markers, implying the possible role of
hedgehog inhibition in reducing the stem cell burden of
the tumor that is responsible for resistance to therapy
and recurrences. Co-administration of cyclopamine
with gemcitabine was tested in two studies in mouse
models [13, 34]. Both studies concluded that the
addition of hedgehog inhibition in chemotherapy
specifically targets aldehyde dehydrogenase positive
cells and reduces the number of metastases observed
whereas it does not have significant effect on primary
tumor volume. Interestingly, one of the two studies
[34] showed that when cyclopamine is administered at
the same time with implantation of the tumor rather
than later, primary tumor gets significantly smaller.
This is compatible with the assumption that
cyclopamine targets cancer initiating cells.
There are currently five clinical studies that are
recruiting patients with pancreatic adenocarcinoma and
include hedgehog inhibition in their arms. The first is a
phase I trial that recruits patients with metastatic
pancreatic cancer or other solid tumors that cannot
undergo surgery. Treatment consists of the SMO
inhibitor GDC-0449 (HhAntag691) plus erlotinib or
gemcitabine. The second is a placebo controlled
randomized phase II study for patients with metastatic
or recurrent pancreatic cancer who receive gemcitabine
plus GDC-0449 or placebo. The third is a one armed
Table 1. Clinical trials that include hedgehog pathway inhibition in pancreatic cancer (source: http://clinicaltrials.gov ).
Trial
Regimen
Randomization
Setting
Phase
Recruitment frame
#1
GDC-0449 plus erlotinib or gemcitabine
No
Metastatic
I
March 2009 - November 2009
#2
Gemcitabine plus GDC-0449 versus gemcitabine plus
placebo
Yes
Metastatic or
recurrent disease
II September 2009 - September 2011
#3
GDC-0449 plus nab paclitaxel plus gemcitabine
No
First line
II September 2010 - December 2012
#4
GDC-0449 plus gemcitabine
No
First line
0
June 2010 - June 2012
#5
IPI-926 plus gemcitabine versus gemcitabine plus placebo
Yes
First line
Ib/II
April 2010 - March 2012
#6
GDC-0449
No
Pre-operative
II
July 2010 - January 2012

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phase II study of the triple combination of GDC-0449,
nab-paclitaxel and gemcitabine in the first line setting
of pancreatic cancer. The fourth is a trial that focuses
on the pancreatic cancer stem cell population after
treatment with GDC-0449 plus gemcitabine in the first
line as a primary objective. Another interesting
randomized phase Ib/II study with a different SMO
inhibitor, IPI-926 in combination with gemcitabine or
placebo is under way for patients in the first line of
pancreatic cancer (Table 1).
Last but not least, there is an additional clinical trial
that will test GDC-0449 in pancreatic cancer patients
and will start recruitment soon (Table 1).
Discussion
The unraveling of the role of the hedgehog pathway in
cancer biology, and specifically in pancreatic
adenocarcinoma, has been emerging during the past
five years. In this review we go through the majority of
studies that provide preclinical data and rationale for
designing clinical trials.
The notion of a hedgehog based paracrine loop
between the tumor and its microenvironment was first
introduced for prostate cancer [35]. There is a wealth
of data that supports the notion of paracrine action of
hedgehog ligands to the adjacent stroma in pancreatic
adenocarcinoma. There is also evidence that indicates
the activation of the hedgehog pathway in tumor cells,
by ligands like TGFbeta or the KRAS pathway rather
than the hedgehog ligands themselves. However, there
are a lot of questions to be answered from future
research: the exact mechanism that tumor cells interact
with their microenvironment through the hedgehog
pathway and especially how the stroma influences
tumor cell proliferation and survival is unknown to a
large extent. Furthermore, the role of a possible
autocrine loop where hedgehog ligands might activate
Gli2 in tumor cells, especially in cancer initiating cells
is still an open question. Last but not least, the cross
talking of the hedgehog pathway with other pathways
in pancreatic cancer remains to be further illuminated.
Figure 1 illustrates the current knowledge about the
hedgehog pathway in pancreatic adenocarcinoma.
Summary
The present studies provide the rationale for the first
clinical trials with hedgehog inhibitors in the various
settings of pancreatic adenocarcinoma. Possible
synergistic role of hedgehog inhibitors with
chemotherapy like gemcitabine, as well as biologics
like tyrosine kinase inhibitors might introduce novel
combinations as treatment options. The involvement of
the hedgehog pathway in pancreatic cancer stem cell
biology and the preclinical data that show prevention
of metastases and inhibition of occult tumors, imply
that such inhibitors can be tested in the adjuvant setting
of pancreatic cancer. Poor chemotherapy delivery
might be the reason for the discrepancy in the
efficiency of the various regimens between clinical
trials and in vitro or mouse models. The effect of
hedgehog inhibitors in tumor vasculature and
chemotherapy delivery is suggestive of a possible role
of those compounds in locally advanced and metastatic
disease.
Careful design of clinical trials that takes into account
the preclinical data is mandatory. The translational
analysis of the clinical trials can unravel exciting
aspects of the role of the hedgehog pathway in the
biology of pancreatic adenocarcinomas and is equally
important.
Figure 1. Sonic hedgehog (SHH) ligand is produced from pancreatic ductal adenocarcinoma cells and acts mainly in a paracrine way to release SMO
from PTCH control, in the tumor microenvironment. Subsequently, smoothened homolog (SMO) causes Gli to locate to the nucleus and activate a
number of genes that promote survival and proliferation of the tumor cells. The tumor cells themselves, can activate the hedgehog pathway through
SMO independent signals like TGFbeta. Mutated KRAS blocks the autocrine loop of hedgehog action in favour of the paracrine loop.
mtKRAS: mutated KRAS; PDAC: pancreatic ductal adenocarcinoma; SHH: sonic hedgehog; PTCH: patched; SMO: smoothened

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Conflict of interest The authors have no potential
conflict of interest
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