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. 2013 Jul 31:5:197-203.
doi: 10.2147/CMAR.S45976. Print 2013.

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma

Muzafar A Macha  1 , Surinder K Batra, Apar Kishor Ganti
Affiliations

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma

Muzafar A Macha et al. Cancer Manag Res. .

Abstract

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC.

Keywords: basal cell carcinoma; hedgehog pathway; vismodegib.

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Figures

Figure 1
Figure 1
A schematic diagram showing inhibition of Hedgehog (Hh) signaling by vismodegib. Notes: The extracellular Hh ligands (Sonic, Indian, or Desert Hh) bind to Patched 1 (Ptch1), relieving the inhibition of Smoothened (SMO) by Ptch1. SMO disrupts the cytoplasmic complex containing the Suppressor of Fused (SUFU)-glioma-associated oncogene homologue (Gli) complex resulting in degradation of Gli3 and translocation of Gli1 and Gli2 to the nucleus to upregulate target genes like Ptch1, Gli1, c-Myc, Bcl2, vascular endothelial growth factor, and cyclin D1. Vismodegib binds to the extracellular domain of SMO, markedly inhibiting the release and translocation of Gli1 and Gli2 to the nucleus. Abbreviations: Gli, glioma-associated oncogene homologue; Ptch1, patched 1; SHh, sonic hedgehog; SMO, smoothened; SUFU, Suppressor of Fused; VEGF, vascular endothelial growth factor.
Figure 2
Figure 2
Chemical structure of vismodegib. Note: Structure of vismodegib is courtesy of Genentech.
See this image and copyright information in PMC

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