Review
Mechanisms of Hedgehog pathway activation in cancer and implications for therapy

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The Hedgehog (Hh) signaling pathway regulates body patterning and organ development during embryogenesis. In adults the Hh pathway is mainly quiescent, with the exception of roles in tissue maintenance and repair, and its inappropriate reactivation has been linked to several disparate human cancers. In addition to cancers with mutations in components of the Hh pathway, Hh ligand-dependent cancers have been proposed to respond to Hh in an autocrine manner. More recent findings that Hh might instead signal in a paracrine manner from the tumor to the surrounding stroma or in cancer stem cells alter our understanding of Hh mechanisms in cancer, with important implications for choice of preclinical tumor models, drug screening, patient selection and therapeutic intervention. We review here the roles of the Hh pathway in cancer, Hh pathway inhibitors (HPIs) and early clinical trial results using a novel small molecule HPI, GDC-0449.

Section snippets

Key components of the Hh signaling pathway in mammals

While a comprehensive list of all the players in the mammalian Hedgehog (Hh; see Glossary) signaling pathway is outside the scope of this review (for recent reviews, see Refs 1, 2, 3), the basic components (Figure 1) start with the Hh ligand itself (used here to refer to any of the three family members Sonic [Shh], Indian [Ihh] and Desert [Dhh] Hedgehogs). Hhs are secreted from different tissues at various stages of development and all initiate signaling in receiving cells by binding and

Models of Hh pathway activity in cancer and implications for therapy

Three basic models have been proposed for Hh pathway activity in cancer [16] (Figure 2). The first discovered were type I cancers, which harbor pathway-activating mutations and are, thus, Hh ligand independent, such as basal cell carcinomas. Type II cancers are ligand dependent and autocrine (or juxtracrine), meaning that Hh is both produced and responded to by the same (or neighboring) tumor cells. Type III cancers are also ligand dependent but paracrine, in that Hh produced by the tumor

Implications of the Hh signaling models for HPI therapy

It is important to understand which model of Hh signaling applies to each tumor type because this has several implications for drug development and therapy. First, for drug selection and development, it is crucial to choose the right tumor model for testing. Aside from the obvious fact that type I ligand-independent cancers will not respond to direct Hh ligand blockers or drugs acting upstream of (or in some cases at the level of) their pathway-activating mutation, the ligand-dependent cancers

Hh pathway inhibitors in the clinic

So far, only SMO inhibitors have been tested in humans, the first being cyclopamine in a cream formulation topically applied to BCCs (with all four patients’ tumors regressing), but this required an inconvenient application schedule (every 3–4 hours) [92]. Another topical but synthetic SMO inhibitor (Cur-61414) performed well at eradicating BCCs in an ex-vivo mouse model [80], but not in humans, perhaps because the molecule as formulated did not adequately penetrate human skin (//www.curis.com/news.php

Conclusions

Hh signaling is strongly implicated in a variety of ligand-dependent and mutationally driven cancers. Although all models of Hh signaling have their strengths and weaknesses, they might not necessarily be mutually exclusive. Initial clinical trial results with GDC-0449 show good efficacy and safety in BCC, but it remains to be determined how long this will perdure and whether ligand-dependent cancers will also benefit. Better understanding of which signaling models apply to which cancers and

Disclosure statement

Both authors are employees of Genentech.

Acknowledgements

We thank the Genentech Hedgehog team for stimulating discussions, Jennifer Low for input on the GDC-0449 clinical results and Bob Yauch, Fernando Bazan and our colleagues at Curis for critical reading of the manuscript.

Glossary

Autocrine signaling
a mode of signaling in which the same cell that produces the signaling molecule (such as Hh ligand) binds and responds to it; thus, the sending cell is also the receiving cell.
B-cell lymphoma 2 (Bcl2)
an anti-apoptotic outer mitochondrial protein that is upregulated (or overexpressed by chromosomal translocation) in a variety of cancers, promoting tumor survival. Its constitutive expression by reciprocal chromosomal translocation in B-cell lymphocytes is thought to be the

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