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 Advanced Squamous Cell Carcinoma of the Skin; the Epidermal Growth Factor Receptors and Beyond Introduction
Squamous Cell Carcinoma of the skin (SCCS) is the second most
common type of skin cancer, and similar to other non-melanoma
and melanoma skin cancers, the incidence continues to
rise. SCCS is typically found in elderly individuals in ultravioletexposed
regions of the body. It tends to be more common in
individuals with fair complexions and those with a compromised
immune system, especially solid organ transplant recipients.1-5
While both BCC and SCCS commonly occur from chronic UV
radiation, the genomics of cancer development differ. SCCS follows
a methodical process from precancerous actinic keratosis
(AK) to pre-invasive carcinoma in situ to invasive SCCS.6 In addition,
SCCS tends to behave more aggressively, with higher
rates of recurrence, metastasis, and mortality compared to BCC.7
Advanced SCCS is rare and can be defined as: 1) locally unresectable,
deeply invasive (involving muscle, nerve, or bone),
2) unresectable regional nodal disease, and/or 3) occurrence
of multiple distant metastases. Advanced SCCS have a rate of
recurrence or metastasis of 20-25% during the first 2 years of
diagnosis.3,8 When localized to the skin, topical treatment with
