Trends in Pharmacological Sciences
ReviewMechanisms of Hedgehog pathway activation in cancer and implications for therapy
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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