Basal cell carcinoma (BCC) of the skin, which is the most common
malignancy in individuals of mixed European descent, is increasing
in incidence owing to the aging population and sun exposure habits.
Yearly, BCC accounts for 25% of all diagnosed cancers in the United
States.1 The pathogenesis usually involves damage to DNA
caused by ultraviolet light, and currently available treatment
options have high success rates when chosen appropriately and
applied skillfully. For example, the range of treatments for
superficial BCCs includes chemical destruction (curettage,
electrodessication, or cryosurgery), topical treatment (imiquimod,
5-fluorouracil, or photodynamic therapy with aminolevulinic acid),
and surgical excision. Nodular or infiltrative BCCs have a higher
risk of progression and can be treated with either surgical
excision or Mohs micrographic surgery, with or without adjunctive
modalities.2
In less than 1% of the American population, BCCs metastasize or
advance locally to a depth, size, or extent that makes them
completely unresectable. Moreover, those with the rare genetic
disorder basal cell nevus syndrome (also known as Gorlin syndrome)
have a high propensity for the development of multiple, even
hundreds, of BCCs in addition to ondontogenic cysts and
medulloblastomas.3 Currently, there is no standard
therapy for locally advanced or metastatic BCC.4 The
reported survival time for metastatic BCC varies widely, but the
median is 8 months.5,6
Sonic Hedgehog Signaling Pathway
First discovered in the 1970s in the Drosophila
melanogaster fruit fly, hedgehogs are secreted signaling
proteins that have sparked widespread investigations into how
embryonic cells are "directed" to differentiate into specific
structures at specific locations. This research has led not only to
the understanding of normal pathways of development but also to the
recognition of how mutations affect these
pathways.2
The hedgehog signaling pathway was first implicated as being
abnormal in those with Gorlin syndrome when an excessive or
inappropriate expression of a hedgehog ligand homolog, known as
sonic hedgehog (Shh), was linked to BCC development. Additionally,
Shh expression has been implicated in the pathogenesis of a number
of sporadic cancers, such as colon, pancreas, prostate, and B-cell
malignancies.7-9 Therefore, disruption of Shh signaling
may be beneficial for a broad array of tumor types.
Shh is known to play an important embryologic role in the
development and maintenance of structures, including the nervous
system, axial skeleton, lungs, skin, hair, and stem
cells.10 In the adult, the role of this signaling
pathway is much reduced and may be limited to sites of hair growth,
spermatogenesis, and areas of tissue damage, where it mediates
tissue repair.11,12
Cellular biology studies have revealed that extracellular Shh
protein binds to patched-1 (PTCH1), a 12-transmembrane receptor,
and prevents PTCH1-mediated inhibition of signaling through
smoothened (SMO), a seven-transmembrane protein (Figure 1). Once
the inhibition of SMO is relieved, SMO then activates GLI
transcription factors in the nucleus to induce target genes that
are responsible for cell growth.10

Figure 1. Schematic of the Shh signaling pathway.
Vismodegib (GDC-0449) inhibits the activity of
SMO.
Ordinarily, in the absence of Shh, PTCH1 acts as a braking
mechanism on the entire pathway; however, the vast majority of all
BCCs contain mutations that activate PTCH1. Less frequently,
constitutive activation of SMO stimulates the Shh pathway. Similar
activating mutations have been noted in medulloblastoma, a
malignancy also found in those with Gorlin syndrome.2
All of these mutations cause constitutive Shh signaling, which
mediates the unrestrained proliferation of basal cells in the
skin.4
Vismodegib
The first evidence that SMO could be antagonized came with the
isolation of compounds called cyclopamine and jervine from corn
lilies, which both cause teratogenic effects and cyclopia in
lambs.13,14 The novel SMO inhibitor vismodegib
(GDC-0449) was discovered by high-throughput screening of a library
of small-molecule compounds and subsequent optimization through
medicinal chemistry.7,15
Early clinical trials have confirmed the effectiveness of the
oral formulation of this selective hedgehog pathway inhibitor in
treating metastatic or locally advanced BCC. Von Hoff et
al. reported successful results in those patients who were no
longer amenable to conventional treatment secondary to either
locally advanced or metastatic BCC.4 Of the 33 subjects
enrolled, 18 had an objective response to GDC-0449: two with a
complete response and 16 with a partial response. The other 15
patients had either stable disease (11 subjects) or progressive
disease (4 subjects).4 A Phase II study involving 40
subjects with Gorlin syndrome who were randomized in a 2:1 ratio to
receive either GDC-0449 at 150 mg/day or placebo was prematurely
ended by the Data and Safety Monitoring Board because of the
significant differences that were seen between the active treatment
and placebo groups in an interim analysis of data. The analysis
showed that the 24 subjects treated with vismodegib developed 0.07
new BCCs/month compared with 1.74 BCCs/month in the placebo group
(p<0.001). In the treatment arm, the aggregate size of existing
BCCs decreased by 24 cm; the decrease in aggregate size of BCCs in
the placebo arm was 3 cm (p=0.006). Near-complete remission was
seen in several patients in the treatment arm. The most common
adverse events included fatigue, weight loss, muscle spasms,
hyponatremia, and dysgeusia.16
In November of 2011, the New Drug Application for vismodegib was
granted priority review by the Food and Drug Administration (FDA).
This filing was based on the positive results from a pivotal Phase
II clinical trial that was presented in June 2011 at the European
Association of Dermato-Oncology. This study enrolled 104 subjects,
comprising those with locally advanced BCC (71/104) and metastatic
BCC (33/104), all of whom received 150 mg/day of the study drug.
The primary endpoint of the trial showed an overall response rate
of 43% in the locally advanced cohort and 30% in the metastatic
cohort, as assessed by independent review. The median duration of
progression-free survival for both metastatic and locally advanced
BCC patients was 9.5 months. In addition, the clinical benefit rate
(defined as patients who experienced response, as well as those who
experienced prolonged stable disease for more than 24 weeks) showed
that vismodegib shrank tumors, healed visible lesions, or prevented
them from growing any further in 75% of patients.
Four serious adverse events were considered to be related to
GDC-0448 and included syncope, cardiac failure, pulmonary embolism,
and cholestasis. There were seven fatalities, but all were thought
to be caused by pre-existing risk factors and comorbid
conditions.17 Phase III studies utilizing vismodegib
have already begun, and GDC-0449 is being tested in combination
with chemotherapeutic agents and/or regimens.18 Early
indications suggest that some tumors may develop resistance over
time.15 Despite this uncertainty, vismodegib shows
significant inhibitory activity in the treatment of advanced
BCC.
Conclusions
The FDA-approved vismodegib for the treatment of advanced BCC on
January 30th 2012.19 The indication is for BCC that has
metastasized or relapsed after treatment with surgery, or for those
who are not candidates for surgery or radiation. A boxed warning
associated with this drug will state that use of this drug can
result in embryo-fetal death or severe birth defects. Women need to
be advised to use contraception and men need to be aware of the
risk of vismodegib exposure through semen. In conclusion,
vismodegib represents the first FDA-approved drug for use in
advance forms of the most common skin cancer. Further clinical
research will hopefully expand on the indications for this Shh
inhibitor and future studies result in the addition of vismodegib
to the treatment armamentarium for those with operable BCC.
Author disclosure
Dr Goldenberg is a consultant for Genetench. Dr Patel has no
conflicts of interest to report.
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