Targeting the Hedgehog Pathway to Treat Basal Cell Carcinoma

May 2013 | Volume 12 | Issue 5 | Original Article | 519 | Copyright © May 2013

Pieter Geeraert MD,a,b Jonathan S. Williams BS,c and Isaac Brownell MD PhDc

aDepartment of Radiology, University Hospital, Brussels, Belgium
bNational Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
cDermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD

The discovery of mutations that activate hedgehog (Hh) signaling in basal cell carcinoma (BCC) and other cancers has spurred the development of small molecule inhibitors that target the Hh pathway. High-throughput screens have identified a number of drug candidates that antagonize smoothened (SMO), an essential protein in the Hh signaling pathway. Clinical studies of the oral SMO inhibitor vismodegib (GDC-0449) in patients with inoperable or metastatic BCC have led to its recent approval by the US Food and Drug Administration. This review aims to give the clinician an overview of vismodegib and other Hh pathway inhibitors in the treatment of patients with advanced BCC and basal cell nevus syndrome. Issues of drug mechanism, efficacy, safety, tolerability, and tumor resistance are addressed.

J Drugs Dermatol. 2013;12(5):519-523.


Basal cell carcinoma (BCC) is the most common malignancy in people of European descent.1,2 BCCs comprise approximately 80% of nonmelanoma skin cancers. In the United States, more than 2 million procedures were performed for nonmelanoma skin cancer in 2006. This constituted a 76.9% rise compared with the number of procedures in 1992. Although the cost of care of an individual case of nonmelanoma skin cancer is low compared with other cancers, they are the fifth most expensive cancer based on Medicare expenditure between 1992 and 1995.3
BCCs are slow-growing tumors that rarely metastasize. Despite their low mortality rate, BCCs can cause serious morbidity due to local invasiveness and the resulting tissue destruction and disfigurement. Surgical excision is the first-line treatment for BCC and is effective in most cases. However, surgical treatment is not an option for certain patients with extensive local disease, persistent recurrences, an unfavorable tumor location, or for the rare patient who presents with metastatic disease. These patients had few treatment options before the recent availability of small molecule inhibitors that target the hedgehog (Hh) signaling pathway.4,5
The Hh signaling pathway is an evolutionarily conserved signaling cascade that was originally discovered in Drosophila (fruit fly) by developmental biologists studying segmentation. The name of the pathway was inspired by the spiky appearance of mutant larvae that resemble a hedgehog.6 In brief, Hh proteins (ligands) are autocrine or paracrine signaling molecules that play an important role in embryogenesis and stem cell response during tissue regeneration in adults. After its secretion, the Hh ligand binds to the Patched (PTCH1) protein, a membrane receptor on the surface of target cells. This binding initiates the signaling cascade as it alleviates the Ptch1-dependent inhibition of smoothened (SMO), another membrane protein (Figure1).7 The details of the pathway downstream from SMO are not fully elucidated, but the current model postulates that SMO enters the primary cilium and promotes activation of zinc finger transcription factors in the glioma-associated oncogene (GLI) family. Certain members of the GLI family of transcription factors then translocate to the nucleus to activate Hh target genes.8-10 Numerous different transcriptional programs can be initiated depending on ligand concentration, cell type, and context. In the skin, proper Hh signaling is necessary for normal hair follicle development and function.11-13
The importance of the Hh signaling pathway in BCC was first recognized when it was discovered that patients with basal cell nevus syndrome (BCNS, also known as Gorlin syndrome) inherit one defective copy of the PTCH1 gene.14-17 This syndrome is characterized by multiple BCCs and an increased risk of developing medulloblastoma and rhabdomyosarcoma.18 After this seminal discovery, further research demonstrated that constitutive Hh signaling activity is present in almost all sporadic BCCs.16 Approximately 90% of sporadic BCC have mutations in PTCH1. Ten percent of sporadic BCCs have activating mutations of the SMO oncogene. Germline mutations in SUFU, an inhibitor of Gli protein activity, have also been described in patients with Gorlin syndrome.19,20 All these mutations found in BCCs result in ligand-independent activation of the Hh pathway.
The establishment of the importance of the Hh pathway in BCCs and other cancers such as medulloblastoma spurred the search for targeted pathway inhibitors. The first known inhibitor was cyclopamine, an alkaloid derived from the corn lily plant, known to induce holoprosencephaly and cyclopia as congenital malformations in lambs.21 Cyclopamine inhibits the Hh pathway by antagonizing SMO. As an inhibitor of Hh signaling, cyclopamine