2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

MB models have served as an invaluable preclinical tool for
the testing of HH pathway inhibitors for the treatment of
SHH-driven MB.
It has long been known that a constellation of midline
developmental anomalies that are observed in embryos with
primary congenital defects in SHH activation has similarly
been observed in developing embryos exposed to naturally
occurring teratogenic alkaloids such as cyclopamine, found
in extracts from Veratrum Album, commonly known as
White Hellebore, a plant within the lily family. 3 It has been
demonstrated that these teratogens function as specific
inhibitors of HH signaling by binding to SMO. As all HH
signaling through the canonical pathway requires SMO,
small molecules such as cyclopamine, which inhibit SMO
function, completely block all HH pathway signaling regardless
of the ligand. 3 HH pathway antagonists also provide
valuable tools for dissecting the biochemistry and biology of
HH signaling and have enabled the current development of
unique molecularly targeted therapies for HH-driven cancer.
For example, treatment with SMO inhibitors have been
shown to completely eradicate HH-driven murine MB as
well as markedly inhibit SHH in human BCC, and transiently
induce full remission in adult human metastatic MB,
indicating great promise for the clinical use of these agents
for HH-driven disease. 15-17
Although the HH pathway is activated by autocrine signaling
by HH ligands, it can also initiate paracrine signaling
with cells in the microenvironment. This creates a network
of HH pathway signaling that determines the malignant
behavior of the tumor cells. As a result of paracrine signal
transmission, the effects of HH signaling most profoundly
influence the stromal cells that constitute the tumor microenvironment.
The stromal cells in turn produce factors
that nurture the tumor. Thus, such cellular cross-talk can
KEY POINTS
● Hedgehog (HH) signaling has been investigated for
its role in tumorigenesis because of its known function
in embryonic stem cell maintenance, cell differentiation,
tissue polarity, and cell proliferation.
● Key constituents of the HH pathway include Sonic
hedgehog (SHH) ligand and its receptor Patched1
(PTCH1), which in the absence of SHH represses
Smoothened (SMO) and prevents GLI transcription
factor activation.
● PTCH1 germ-line mutation results in nevoid basal
cell carcinoma (BCC) syndrome, while somatic HH
pathway mutations are found in sporadic BCC and
medulloblastoma (MB), thereby establishing a linkage
between HH activation and cancer development.
● Encouraging results have been observed using SMO
inhibitors to treat adult BCC and MB; however, the
potential risks of SMO inhibitors in developing children
remain a concern.
● HH pathway activity, but not mutations, has recently
been shown in other pediatric cancers, yet it remains
to be seen whether SMO inhibition will be effective
for this group of cancers.
606
greatly amplify HH signaling, resulting in the promotion of
tumor progression and metastasis. Ultimately, the linkage
of aberrant HH signaling to tumorigenesis is thought to
be mediated through cell-cycle dysregulation, protection of
cancer cells against apoptosis, and modulation of angiogenesis.
2,3 Several lines of evidence support three mechanistic
roles for HH signaling in cancer: (1) a cancer cellautonomous
role, in which tumor growth is driven by
activating mutations in the pathway; (2) a paracrine signaling
role involving tumor and stromal interactions that
promote tumor growth and invasion; and (3) an autocrine
signaling role via cancer stem cells that promotes selfrenewal
and proliferation. 2,3 The downstream effectors of
the HH signaling pathway are the GLI transcription factors,
which promote cell proliferation, differentiation, and survival
through induction of relevant target genes. 2,3 To date,
different molecular lesions in PTCH1, SMO, and SUFU of
the HH pathway have been described in tumors. In each
case, these alterations have resulted in increased transcriptional
activity of the GLI1 and GLI2 transcription factors.
Indeed, the first indication that genes in the HH pathway
were associated with human cancer was the observation
that GLI1 was amplified in glioblastoma, although it is now
believed that this is not a common primary mechanism
underlying glioblastoma formation. 3 Together with GLI and
PTCH1, these effector targets are representative of the gene
signature indicating SHH active tumors. Therefore, GLI1
mRNA levels either in tumor tissue or relevant surrogate
tissue is considered a reliable indicator of HH pathway
activity. 2,3 Most recently, a number of common pediatric
cancers have been shown to have expression and activation
of the HH pathway through the measurement of these target
effectors.
HH Pathway in Pediatric Cancer
The HH signaling pathway is believed to be active in
early-onset pediatric tumors, both of CNS and non-CNS
origin, because of the important role that HH plays in
embryonic development. Indeed, GLI1 amplification has also
been described in childhood sarcoma. In a more comprehensive
study of a series of pediatric surgical tumor specimens,
Oue and colleagues used expression of GLI1 as a marker of
HH pathway activation to demonstrate that almost 70% of
the pediatric tumors examined, including neuroblastoma,
hepatoblastoma, high-grade glioma, and osteosarcoma, were
positive for HH activity. 18 However, to date no HH mutations
have been identified in these other pediatric cancers.
Only descriptive studies have been performed, and thus it
remains to be determined whether a valid functional relationship
exists between HH activity and tumor progression
in these cancers. The findings of these pediatric studies
and others similarly reporting HH pathway expression and
activation in both CNS and non-CNS pediatric cancers are
further detailed below.
CNS tumors
TOBEY J. MACDONALD
The role of HH pathway in pediatric MB is well established.
However, more recent reports now suggest that the
HH pathway may be implicated in other non-MB pediatric
CNS tumors.