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Targeting the Hedgehog pathway in cancer

Nature Reviews Drug Discovery volume 5, pages 1026–1033 (2006)Cite this article

Key Points

  • The hedgehog (Hh) signalling pathway is a key regulator of embryonic development, and its deregulation is associated with various birth defects.

  • Although mostly quiescent in adult tissues, Hh signalling has recently been recognized to participate in tissue repair and tumour growth.

  • Basal cell carcinoma and medulloblastoma, two cancers that involve mutation-driven upregulation of Hh signalling, were the first cancers shown to involve the Hh pathway.

  • Numerous other solid tumours, including pancreatic and prostate cancers, are now thought to have hyper-activated Hh signalling. In these cases, the signalling is stimulated by excessive production of Hh ligands by tumour cells.

  • Several families of small-molecule Hh inhibitors have been identified and are in varying stages of clinical development.

  • The pleiotropic nature of the Hh pathway, seen to be involved in tumour-cell and tumour stem-cell proliferation, as well as in angiogenesis, suggests that Hh antagonists might constitute, under some circumstances, an exciting new type of cancer treatment.

Abstract

Several key signalling pathways, such as Hedgehog, Notch, Wnt and BMP–TGFβ–Activin (bone morphogenetic protein–transforming growth factor-β–Activin), are involved in most processes essential to the proper development of an embryo. It is also becoming increasingly clear that these pathways can have a crucial role in tumorigenesis when reactivated in adult tissues through sporadic mutations or other mechanisms. We will focus here on the Hedgehog pathway, which is abnormally activated in most basal cell carcinomas, and discuss potential therapeutic opportunities offered by the progress made in understanding this signalling pathway.

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Figure 1: A schematic of the vertebrate Hh signalling pathway in the absence or presence of Hh ligands.
Figure 2: Models of Hh pathway activation in cancer.
Figure 3: Types of cancer with possible Hedgehog deregulation.

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Acknowledgements

The authors would like to thank their many colleagues at Curis and Genentech who have participated so actively in the Hedgehog antagonist program. We would like to thank K. Kotkow for helpful suggestions, J. LaLonde for editorial assistance, D. Wood and M. Dina for help with artwork and figures.

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Authors and Affiliations

  1. Harvard Stem Cell Institute, Biolabs, Room 150, 16 Divinity Avenue, Cambridge, 02138, Massachusetts, USA

    Lee L. Rubin

  2. Department of Molecular Biology, Genentech, Inc, South San Francisco, 94080, California, USA

    Frederic J. de Sauvage

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Correspondence to Lee L. Rubin.

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L.L.R. is a consultant for and shareholder in Curis, Inc. F.S. is an employee of and shareholder in Genetech.

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DATABASES

OMIM

Gorlin syndrome

Glossary

Holoprosencephaly

A birth defect that can result as a consequence of insufficient Hh signalling. It relates to a failure of the brain to properly separate into two halves and in its extreme form can be associated with cyclopia, the presence of a single centrally located eye.

Mitogen

Any molecule that stimulates the division of a cell.

Allograft

As used here, a mouse cancer model in which a tumour is removed from one mouse — in which it has occurred spontaneously, for example — and implanted into another mouse or into several mice in order to test the efficacy of an antitumour drug.

Xenograft

A graft of tissue or cells transplanted between animals of different species.

Autocrine, juxtacrine and paracrine signalling

Three modes of signalling in which a molecule produced by one cell can activate signalling in the same cell (autocrine), a neighbouring cell (juxtacrine) or a cell at a distance (paracrine).

Gleason grade

A scoring system for prostate cancers that reflects the degree of disease progression. A score of 1 indicates mild cancer and a score of 5 indicates advanced cancer.

Epithelial—mesenchymal transition

A morphological change in cells such that they lose their epithelial or adhesive organized phenotype and become more motile, sometimes as the beginning of the metastatic process.

Cancer stem cell

A slowly proliferating stem-like cell thought to be present in small numbers in solid tumours, to be resistant to standard chemotherapy and to have an enhanced capacity to give rise to new tumours.

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Rubin, L., de Sauvage, F. Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5, 1026–1033 (2006). https://doi.org/10.1038/nrd2086

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