Hedgehog signaling pathway: a novel target for cancer therapy: vismodegib, a promising therapeutic option in treatment of basal cell carcinomas

Abstract

The Hedgehog signaling pathway is one of the major regulators of cell growth and differentiation during embryogenesis and early development. It is mostly quiescent in adults but inappropriate mutation or deregulation of the pathway is involved in the development of cancers. Therefore; recently it has been recognized as a novel therapeutic target in cancers. Basal cell carcinomas (BCC) and medulloblastomas are the two most common cancers identified with mutations in components of the hedgehog pathway. The discovery of targeted Hedgehog pathway inhibitors has shown promising results in clinical trials, several of which are still undergoing clinical evaluation. Vismodegib (GDC-0449), an oral hedgehog signaling pathway inhibitor has reached the farthest in clinical development. Initial clinical trials in basal cell carcinoma and medulloblastoma have shown good efficacy and safety and hence were approved by U.S. FDA for use in advanced basal cell carcinomas. This review highlights the molecular basis and the current knowledge of hedgehog pathway activation in different types of human cancers as well as the present and future prospects of the novel drug vismodegib.

Keywords: Basal cell carcinoma; hedgehog signaling pathway; vismodegib.

Figure 1a

Hedgehog signaling pathways in vertebrates-without hedgehog ligand

Figure 1b

Hedgehog signaling pathway in vertebrates — with hedgehog ligand

Figure 2a

Hedgehog signaling pathway in cancers-Type I-Ligand-independent cancers

Figure 2b

Hedgehog signaling pathway in cancers -Type II- Autocrine Ligand-dependent cancers

Figure 2c

Hedgehog signaling pathway in cancers -Type III- Paracrine Ligand-dependent cancers

Figure 2d

Hedgehog signaling pathway in cancers -Type IIIb-Reverse Paracrine Ligand-dependent cancers