INTRODUCTION
An evolving theme in the field of cutaneous oncology
is the use of personalized or targeted therapy for the
treatment of advanced disease. Targeted therapy is the
identification of the biomolecular pathways that lead to malignancy
and the subsequent targeting and manipulation of these
pathways to halt cancer progression. Non-melanoma skin cancers
have been at the forefront of this exciting field of cancer
genetics and molecular biology. The advent of molecular targeted
therapies in oncology offers patients hope and viable alternatives
to the traditional chemotherapeutic options that are
cytotoxic. Research has elucidated the molecular pathways that
cause basal cell carcinoma (BCC) and squamous cell carcinoma
(SCC). This incredible insight has led to the development of a
new armamentarium that can target cancer genomics and halt
the progression of disease. Blockade of the hedgehog (Hh) signaling
pathway has been a breakthrough in the management
of patients with advanced basal cell carcinoma (BCC) as has
the use of cetuximab, an epidermal growth factor receptor
(EGFR) inhibitor, in advanced squamous cell carcinoma (SCC).
Although promising results have been reported, recurrence and
evolution of new tumors via circumvention of traditional pathways
has occurred. In this review, we discuss the molecular
pathways critical to the development of BCC and SCC and the
novel pharmacologic agents that have been and are in development
to target them. We herein present a two-part review of
targeted therapy for non-melanoma skin cancers. Specifically,
in part I we will review the use of the hedgehog inhibitors in
advanced BCC and continue the theme in part II for epidermal
growth factor receptor (EGFR) inhibitors in advanced SCC.
METHODS
We conducted a systematic literature review using the Pubmed
data base employing the search terms including: vismodegib,basal cell carcinoma, hedgehog inhibitor, smoothened inhibitor,
locally advanced basal cell carcinoma, metastatic basal cell
carcinoma, cetuximab, squamous cell carcinoma of the skin,
locally advanced squamous cell carcinoma, metastatic squamous
cell carcinoma, and epidermal growth factor inhibitors
for squamous cell carcinoma of the skin. We then scrutinized citation
lists from retrieved articles. We also searched the clinical
trials data base at www.clinicaltrials.org using similar search
terms. We focused our literature review on clinical trials for advanced
skin cancers.
Targeted Therapy for Basal Cell Carcinoma- The Hedgehog Inhibitors
Basal cell carcinoma (BCC) is the most common skin cancer
with a lifetime risk of developing BCC in Caucasian populations
estimated to be around 25%.1-2 Traditionally, BCC has been considered
a carcinoma of the elderly; however, accelerated rates
of incidences have been noted, especially in young women
aged 20-40 years of age.1 Generally, BCC is considered to be
an indolent carcinoma that will continue to grow and cause
local tissue destruction. Thus, surgical excision or Mohs micrographic
surgery are the standard of care for treatment with high
cure rates.3-4 Based on histologic subtype, location, and patient
co-factors, other appropriate treatments of localized disease
include electrodessication and curettage, cryosurgery, and
topical immunotherapy.2-4 Rarely, patients present with locally
advanced or metastatic BCCs or, in patients with hereditary
basal cell syndromes who accrue hundreds of BCCs over their
lifetime, present as treatment dilemmas as standard excision is
difficult or unrealistic.5-10 The study of the hereditary basal cell
syndromes, especially the basal cell nevus syndrome (BCNS)
has contributed greatly to our understanding of the pathogenesis
of BCC.11 A molecular understanding of the pathogenesis
