2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

that the HH pathway may contribute to the more unfavorable
biologic behaviors of these renal tumors. 18
Hepatic Tumors
Eichenmuller and colleagues reported that HH signaling
is active in pediatric hepatoblastoma and showed that blocking
HH signaling with cyclopamine in hepatoblastoma
cells leads to a significant decrease in cell viability and
increased apoptosis. 29 In another study, IHC of 11 hepatoblastoma
cases demonstrated that 100% of tumors stained
positive for SHH and PTCH1, while eight (73%) were positive
for GLI1. 18 One case of embryonal carcinoma and two
hepatic tumor cell lines (Heh6 and Heh7) showed strong
expression of all three HH pathway markers. No relationship
was observed between GLI1 expression and histologic
subtype, clinical stage, or prognosis.
Osteosarcoma
Recently published data also suggest HH signaling may
play a role in the pathogenesis of osteosarcoma. A study of
osteosarcoma cell lines and biopsy specimens showed overexpression
of HH target genes via real-time PCR. 30 Inhibition
of the HH pathway with cyclopamine in vitro promoted
G1 arrest and reduced the expression of positive cell-cycle
regulators, including cyclins D1 and E1. In addition, SMO
knockdown with SMO shRNA prevented the growth of
osteosarcoma, both in vitro and in vivo. 30
HH Pathway Inhibitors in Pediatric Clinical Trials
Inhibitors of HH signaling have recently been the focus of
intense research. It is noteworthy that many tumors that
appear to lack specific HH pathway mutations have been
reported to be sensitive to SMO inhibitors in vitro and in
vivo. 3 This has led to estimates that as many as 25% of
human tumors may depend on HH pathway activity for
growth. As a consequence, a wide range of tumors have been
included in the early-adult clinical trials investigating SMO
inhibitors. 3 Xenograft tumor models have shown that hu-
Author’s Disclosure of Potential Conflicts of Interest
Employment or
Leadership Consultant or
Author
Positions Advisory Role
Tobey J. MacDonald Novartis
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608
man tumors without HH pathway mutations that express
HH ligands actually induce upregulation of HH pathway
target genes in the stromal cells of mouse origin, rather than
in the tumor cells. 3 Under these conditions, treatment with
SMO inhibitors inhibited tumor growth to some degree, but
did not eliminate the tumors. Some leukemias have also
been reported to depend on SMO signaling for growth, but
more recent studies indicate that survival was not dependent
on HH ligands or SMO activity. 3 The proof of concept
for the clinical utility of SMO inhibitors has been established
in patients with metastatic or locally advanced BCC
or MB. 15-17 The more recent data suggest that this class of
agents may have broader utility in other adult and pediatric
cancers. The dilemma is to identify tumors that would
benefit most from HH inhibitor treatment, as the mere
presence of HH ligands or a pathway signature does not
guarantee a response. Because of the importance of the HH
signaling pathway in the normal growth and development,
the use of SMO inhibitors in children is a specific concern
that will need to be carefully assessed in order to manage
the potential adverse effects on bone growth plates, developing
teeth, and the immature reproductive system. 3 At
present, early phase I and II clinical trials with the SMO
inhibitors LDE225 (Novartis) and GDC-0449 (Genentech)
are being evaluated in pediatric medulloblastoma and other
pediatric tumors that are potentially dependent on HH
pathway signaling (Table 1).
Stock
Ownership Honoraria
REFERENCES
Table 1. Hedgehog Pathway Inhibitors in Current Clinical Trials
Agent Target
Research
Funding
Expert
Testimony
TOBEY J. MACDONALD
Mechanism
of Action Manufacturer
GDC-0449* SMO Antagonist GDC-0449 (Genentech)
LDE225* SMO Antagonist LDE225 (Novartis)
LEQ506 SMO Antagonist LEQ506 (Novartis)
PF-04449913 SMO Antagonist PF-04449913 (Pfizer)
IPI-926 SMO Antagonist IPI-926 (Ifinity)
BMS-833923 SMO Antagonist BMS-833923 (Bristol-Myers Squibb)
* Currently being investigated in pediatric cancer. As of February 8, 2012
(Clinicaltrials.gov).
Other
Remuneration
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Oncol. 2006;24:1924-1931.
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medulloblastoma. Nature Genet. 2002;31:306-310.
11. Pastorino, L. Ghiorzo P, Nasti S, et al. Identification of a SUFU
germline mutation in a family with Gorlin syndrome. Am J Med Genet A.
2009;149A:1539-1443.
12. Wetmore C, Eberhart DE, Curran T. Loss of p53 but not ARF accelerates
medulloblastoma in mice heterozygous for patched. Cancer Res. 2001;61:
513-516.
13. Yang ZJ, Ellis T, Markant SL, et al. Medulloblastoma can be initiated
by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer
Cell. 2008;14:135-145.
14. Hatton BA, Knoepfler PS, Kenney AM, et al. N-myc is an essential
downstream effector of Shh signaling during both normal and neoplastic
cerebellar growth. Cancer Res. 2006;66:8655-8661.
15. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog