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Review
. 2011 May 26;11(7):493-501.
doi: 10.1038/nrc3079.

The Hedgehog's tale: developing strategies for targeting cancer

Jessica M Y Ng  1 , Tom Curran
Affiliations
Review

The Hedgehog's tale: developing strategies for targeting cancer

Jessica M Y Ng et al. Nat Rev Cancer. .

Abstract

Research into basic developmental biology has frequently yielded insights into cancer biology. This is particularly true for the Hedgehog (HH) pathway. Activating mutations in the HH pathway cause a subset of sporadic and familial, skin (basal cell carcinoma) and brain (medulloblastoma) tumours. Furthermore, the growth of many human tumours is supported by HH pathway activity in stromal cells. Naturally occurring and synthetic inhibitors of HH signalling show great promise in animal models and in early clinical studies. However, it remains unclear how many cancers will ultimately benefit from these new, molecularly targeted therapies.

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Figures

Figure 1
Figure 1. Summary of HH Signaling Pathway
Hedgehog (HH) ligands bind to Patched (PTCH1), causing internalization and degradation, and release the suppression of Smoothened (SMO) by PTCH1. SMO enters the primary cilia where it is activated. SMO then interacts with Suppressor-of-fused (SUFU), which, in turn, promotes activation and nuclear translocation of glioma associated oncogene homolog1 (GLI1) and GLI2 and degradation of GLI3.
See this image and copyright information in PMC

References

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    1. Yauch RL, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009;326:572–4. This study shows that an activating mutation in SMO confers resistance to GDC-0449 in advanced medulloblastoma validating SMO as a clinical target. - PMC - PubMed
    1. Von Hoff DD, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New Engl J Med. 2009;361:1164–72. The first report of clinical results showing responses in advanced basal cell carcinoma patients to a SMO inhibitor. - PubMed
    1. Rudin CM, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. New Engl J Med. 2009;361:1173–8. Describes the drammatic but transient response of a metastatic medulloblastoma to SMO inhibition. - PMC - PubMed
    1. Low JA, de Sauvage FJ. Clinical experience with Hedgehog pathway inhibitors. J Clin Oncol. 2010;28:5321–6. - PubMed

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