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The Hedgehog's tale: developing strategies for targeting cancer

Nature Reviews Cancer volume 11, pages 493–501 (2011)Cite this article

Subjects

Key Points

  • The Hedgehog (HH) pathway is an important regulator of embryogenesis that has also been implicated in tumour development. As all HH signalling through the canonical pathway requires Smoothened (SMO), small molecules such as GDC-0449, which inhibit SMO function, completely block all HH pathway signalling regardless of the ligand.

  • Drugs based on cyclopamine and other compounds that target SMO have been developed and are currently in Phase I and Phase II clinical trials. Drugs that target other aspects of the HH signalling pathway are also in development.

  • Initial results suggest that SMO inhibitors will prove useful in the treatment of basal cell carcinoma and in the subtype of medulloblastoma that is dependent on HH signalling.

  • It is important to understand how HH inhibitors could be used to treat other cancers, perhaps in combination with other therapies, which do not carry genetic lesions in the HH pathway, but that rely on HH signalling for disease progression. Improved understanding of cancer biology, particularly the interplay among cancer cells and stromal tissues, will help broaden the usefulness of such agents.

  • The identification of reliable biomarkers that indicate patients who are most likely to benefit from HH inhibitors, including non-invasive imaging approaches, is essential.

  • Understanding resistance mechanisms and developing methods to overcome resistance to SMO inhibitors will also be important in the future.

  • The importance of HH pathways during development and studies in mice indicate that SMO inhibitors in children with medulloblastoma will need to be used with care, so that potential effects on skeletal and brain development are avoided.

  • Given the dramatic responses reported in basal cell carcinoma and medulloblastoma in early trials, it is highly likely that SMO inhibitors will ultimately be approved as new therapeutic agents for treating cancer. This should be viewed as a success for basic, broad-based research in developmental biology, as well as cancer research, which laid a strong foundation for this translational opportunity.

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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Figure 1: Summary of the HH signalling pathway.

References

  1. Strizzi, L. et al. Development and cancer: at the crossroads of Nodal and Notch signaling. Cancer Res. 69, 7131–7134 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yauch, R. L. et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326, 572–574 (2009). This study shows that an activating mutation in SMO confers resistance to GDC-0449 in advanced medulloblastoma, thus validating SMO as a clinical target.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Von Hoff, D. D. et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New Engl. J. Med. 361, 1164–1172 (2009). The first report of clinical results showing responses in patients with advanced BCC to a SMO inhibitor.

    Article  CAS  PubMed  Google Scholar 

  4. Rudin, C. M. et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. New Engl. J. Med. 361, 1173–1178 (2009). Describes the dramatic but transient response of a metastatic medulloblastoma to SMO inhibition.

    Article  CAS  PubMed  Google Scholar 

  5. Low, J. A. & de Sauvage, F. J. Clinical experience with Hedgehog pathway inhibitors. J. Clin. Oncol. 28, 5321–5326 (2010).

    Article  CAS  Google Scholar 

  6. Lorusso, P. M. et al. Phase I trial of hedgehog pathway inhibitor GDC-0449 in patients with refractory, locally-advanced or metastatic solid tumors. Clin. Cancer Res. 17, 2502–2511 (2011). Conclusions of the Phase I analysis of GDC-0449 showing it has an acceptable safety profile and antitumour activity in BCC and medulloblastoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Skvara, H. et al. Topical treatment of basal cell carcinomas in nevoid basal cell carcinoma syndrome with a Smoothened inhibitor. J. Invest. Dermatol. 24 Mar 2011 [epub ahead of print].

  8. Yauch, R. L. et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406–410 (2008). In contrast to previous reports, this study demonstrates that tumorigenesis is mediated by a paracrine effect of HH secreted by certain tumour cells on the stromal environment.

    Article  CAS  PubMed  Google Scholar 

  9. Curran, T. & Ng, J. M. Cancer: Hedgehog's other great trick. Nature 455, 293–294 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Bastida, M. F., Sheth, R. & Ros, M. A. A BMP-Shh negative-feedback loop restricts Shh expression during limb development. Development 136, 3779–3789 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Deschaseaux, F., Sensebe, L. & Heymann, D. Mechanisms of bone repair and regeneration. Trends Mol. Med. 15, 417–429 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Bertrand, N. & Dahmane, N. Sonic hedgehog signaling in forebrain development and its interactions with pathways that modify its effects. Trends Cell Biol. 16, 597–605 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Ingham, P. W., Nakano, Y. & Seger, C. Mechanisms and functions of Hedgehog signalling across the metazoa. Nature Rev. Genet. 19 Apr 2011 (epub ahead of print).

  14. Teglund, S. & Toftgard, R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim. Biophys. Acta 1805, 181–208 (2010).

    CAS  PubMed  Google Scholar 

  15. Chidambaram, A. et al. Mutations in the human homologue of the Drosophila patched gene in Caucasian and African-American nevoid basal cell carcinoma syndrome patients. Cancer Res. 56, 4599–4601 (1996).

    CAS  PubMed  Google Scholar 

  16. Hahn, H. et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Lench, N. J. et al. Characterisation of human patched germ line mutations in naevoid basal cell carcinoma syndrome. Hum. Genet. 100, 497–502 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Unden, A. B. et al. Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation. Cancer Res. 56, 4562–4565 (1996).

    CAS  PubMed  Google Scholar 

  19. Vorechovsky, I. et al. Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Oncogene 15, 361–366 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Wicking, C. et al. Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident. Am. J. Hum. Genet. 60, 21–26 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Raffel, C. et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 57, 842–845 (1997).

    CAS  PubMed  Google Scholar 

  23. Wolter, M., Reifenberger, J., Sommer, C., Ruzicka, T. & Reifenberger, G. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 57, 2581–2585 (1997).

    CAS  PubMed  Google Scholar 

  24. Xie, J. et al. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 57, 2369–2372 (1997).

    CAS  PubMed  Google Scholar 

  25. Cowan, R. et al. The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma. Br. J. Cancer 76, 141–145 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Taylor, M. D. et al. Mutations in SUFU predispose to medulloblastoma. Nature Genet. 31, 306–310 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Pastorino, L. et al. Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am. J. Med. Genet. A 149A, 1539–1543 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Visvader, J. E. & Lindeman, G. J. Stem cells and cancer - the promise and puzzles. Mol. Oncol. 4, 369–372 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Epstein, E. H. Basal cell carcinomas: attack of the hedgehog. Nature Rev. Cancer 8, 743–754 (2008).

    Article  CAS  Google Scholar 

  30. Cotsarelis, G., Sun, T. T. & Lavker, R. M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329–1337 (1990).

    Article  CAS  PubMed  Google Scholar 

  31. Youssef, K. K. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nature Cell Biol. 12, 299–305.

  32. Wang, G. Y., Wang, J., Mancianti, M. L. & Epstein, E. H. Jr. Basal cell carcinomas arise from hair follicle stem cells in Ptch1+/− mice. Cancer Cell 19, 114–124 (2011). This study shows, by cell fate mapping, that keratin 15-expressing bulge stem cells are the cell of origin of BCC and demonstrates that loss of p53 can affect tumorigenesis by enhancing SMO expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Barnes, E. A., Kong, M., Ollendorff, V. & Donoghue, D. J. Patched1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J. 20, 2214–2223 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wetmore, C., Eberhart, D. E. & Curran, T. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res. 61, 513–516 (2001).

    CAS  PubMed  Google Scholar 

  35. Grachtchouk, M. et al. Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations. J. Clin. Invest. 121, 1768–1781 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Thompson, M. C. et al. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J. Clin. Oncol. 24, 1924–1931 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Kool, M. et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PloS ONE 3, e3088 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Northcott, P. A. et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nature Genet. 41, 465–472 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Sausville, E. A. & Burger, A. M. Contributions of human tumor xenografts to anticancer drug development. Cancer Res. 66, 3351–3354 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Huse, J. T. & Holland, E. C. Genetically engineered mouse models of brain cancer and the promise of preclinical testing. Brain Pathol. 19, 132–143 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Hahn, H. et al. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nature Med. 4, 619–622 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Wetmore, C., Eberhart, D. E. & Curran, T. The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. Cancer Res. 60, 2239–2246 (2000).

    CAS  PubMed  Google Scholar 

  44. Pazzaglia, S. et al. High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice. Oncogene 21, 7580–7584 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Uziel, T. et al. The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation. Genes Dev. 19, 2656–2667 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Frappart, P. O. et al. Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. Proc. Natl Acad. Sci. USA 106, 1880–1885 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Reifenberger, J. et al. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 58, 1798–1803 (1998).

    CAS  PubMed  Google Scholar 

  49. Xie, J. et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90–92 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Hatton, B. A. et al. The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res. 68, 1768–1776 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Hallahan, A. R. et al. The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res. 64, 7794–7800 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Sasai, K. et al. Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies. Cancer Res. 66, 4215–4222 (2006). Describes the rapid downregulation of HH pathway activity in tumour cell culture and the acquisition of resistance to SMO inhibitors, although not in direct allograft tumours, raising questions about the use of tumour cell lines to test SMO inhibitors.

    Article  CAS  PubMed  Google Scholar 

  53. Stecca, B. & Ruiz i Altaba, A. A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J. 28, 663–676 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Grachtchouk, M. et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nature Genet. 24, 216–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Weiner, H. L. et al. Induction of medulloblastomas in mice by sonic hedgehog, independent of Gli1. Cancer Res. 62, 6385–6389 (2002).

    CAS  PubMed  Google Scholar 

  56. Gibson, P. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lee, Y. et al. A molecular fingerprint for medulloblastoma. Cancer Res. 63, 5428–5437 (2003).

    CAS  PubMed  Google Scholar 

  58. Yang, Z. J. et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14, 135–145 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schuller, U. et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14, 123–134 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Parsons, D. W. et al. The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435–439 (2011). Analysis of the medulloblastoma genome by exome sequencing shows fewer gene alterations in paediatric solid tumours compared with adult tumours and identifies a novel molecular class of tumours harboring mutations in histone methylases.

    Article  CAS  PubMed  Google Scholar 

  61. Hahn, H. et al. Genetic mapping of a Ptch1-associated rhabdomyosarcoma susceptibility locus on mouse chromosome 2. Genomics 84, 853–858 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Gorlin, R. J. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet. Med. 6, 530–539 (2004).

    Article  PubMed  Google Scholar 

  63. Barr, F. G. & Womer, R. in Oncology of Infancy and Childhood (eds Orkin, S. H et al.) 743–782 (Saunders, Philadelphia, 2009).

    Book  Google Scholar 

  64. Calzada-Wack, J. et al. Analysis of the PTCH coding region in human rhabdomyosarcoma. Hum. Mutat. 20, 233–234 (2002).

    Article  PubMed  CAS  Google Scholar 

  65. Tostar, U. et al. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J. Pathol. 208, 17–25 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Paulson, V. et al. High-resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis. Gene Chromosom. Cancer 50, 397–408 (2011).

    Article  CAS  Google Scholar 

  67. Rubin, B. P. et al. Evidence for an unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma. Cancer Cell 19, 177–191 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ecke, I. et al. Cyclopamine treatment of full-blown Hh/Ptch-associated RMS partially inhibits Hh/Ptch signaling, but not tumor growth. Mol. Carcinog. 47, 361–372 (2008). Describes the lack of effect of cyclopamine on rhabdomyosarcoma growth in mice showing that increased HH pathway activity promotes tumour formation but is not required for tumour maintenance.

    Article  CAS  PubMed  Google Scholar 

  69. Kinzler, K. W. et al. Identification of an amplified, highly expressed gene in a human glioma. Science 236, 70–73 (1987).

    Article  CAS  PubMed  Google Scholar 

  70. Roberts, W. M., Douglass, E. C., Peiper, S. C., Houghton, P. J. & Look, A. T. Amplification of the gli gene in childhood sarcomas. Cancer Res. 49, 5407–5413 (1989).

    CAS  PubMed  Google Scholar 

  71. Khatib, Z. A. et al. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res. 53, 5535–5541 (1993).

    CAS  PubMed  Google Scholar 

  72. Dahlen, A. et al. Activation of the GLI oncogene through fusion with the beta-actin gene (ACTB) in a group of distinctive pericytic neoplasms: pericytoma with t(7;12). Am. J. Pathol. 164, 1645–1653 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and routers. Science 304, 1755–1759 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Berman, D. M. et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425, 846–851 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Thayer, S. P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Watkins, D. N. et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422, 313–317 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Qualtrough, D., Buda, A., Gaffield, W., Williams, A. C. & Paraskeva, C. Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment. Int. J. Cancer 110, 831–837 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dierks, C. et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14, 238–249 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Hegde, G. V. et al. Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: a potential new therapeutic target. Mol. Cancer Res. 6, 1928–1936 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Desch, P. et al. Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells. Oncogene 29, 4885–4895 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Lauth, M., Bergstrom, A., Shimokawa, T. & Toftgard, R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc. Natl Acad. Sci. USA 104, 8455–8460 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim, J., Lee, J. J., Gardner, D. & Beachy, P. A. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc. Natl Acad. Sci. USA 107, 13432–13437 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Beauchamp, E. M. et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J. Clin. Invest. 121, 148–160 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Lipinski, R. J. et al. Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse. Toxicol. Sci. 104, 189–197 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Dahmane, N., Lee, J., Robins, P., Heller, P. & Ruiz i Altaba, A. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389, 876–881 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Kimura, H., Stephen, D., Joyner, A. & Curran, T. Gli1 is important for medulloblastoma formation in Ptc1+/− mice. Oncogene 24, 4026–4036 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Sheng, H. et al. Dissecting the oncogenic potential of Gli2: deletion of an NH(2)-terminal fragment alters skin tumor phenotype. Cancer Res. 62, 5308–5316 (2002).

    CAS  PubMed  Google Scholar 

  89. Chen, J. K., Taipale, J., Young, K. E., Maiti, T. & Beachy, P. A. Small molecule modulation of Smoothened activity. Proc. Natl Acad. Sci. USA 99, 14071–14076 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Frank-Kamenetsky, M. et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1, 10 (2002). Description of the small-molecule screen that identified SMO agonists and antagonists.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Mas, C. & Ruiz i Altaba, A. Small molecule modulation of HH-GLI signaling: current leads, trials and tribulations. Biochem. Pharmacol. 80, 712–723 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Robarge, K. D. et al. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg Med. Chem. lett 19, 5576–5581 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Tremblay, M. R. et al. Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J. Med. Chem. 52, 4400–4418 (2009).

    Article  CAS  Google Scholar 

  94. Zuber, J. et al. Mouse models of human AML accurately predict chemotherapy response. Genes Dev. 23, 877–889 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Berman, D. M. et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297, 1559–1561 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Karhadkar, S. S. et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–712 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Zhang, J., Lipinski, R., Shaw, A., Gipp, J. & Bushman, W. Lack of demonstrable autocrine hedgehog signaling in human prostate cancer cell lines. J. Urol. 177, 1179–1185 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Sanchez, P. et al. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc. Natl Acad. Sci. USA 101, 12561–12566 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. McCarthy, F. R. & Brown, A. J. Autonomous Hedgehog signalling is undetectable in PC-3 prostate cancer cells. Biochem. Bioph Res. Co 373, 109–112 (2008).

    Article  CAS  Google Scholar 

  100. Slusarz, A. et al. Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer. Cancer Res. 70, 3382–3390 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Romer, J. T. et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/−p53−/− mice. Cancer Cell 6, 229–240 (2004). Preclinical demonstration of the efficacy of SMO inhibitors in a GEM model of medulloblastoma.

    Article  CAS  PubMed  Google Scholar 

  102. Kim, J. et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17, 388–399 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Curran, T. Mouse models and mouse supermodels. EMBO Mol. Med. 2, 385–386; author reply 386–7 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Clement, V., Sanchez, P., de Tribolet, N., Radovanovic, I. & Ruiz i Altaba, A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 17, 165–172 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Varnat, F. et al. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol. Med. 1, 338–351 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Williams, J. A. et al. Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc. Natl Acad. Sci. USA 100, 4616–4621 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gajjar, A. J. et al. A phase I pharmacokinetic trial of sonic hedgehog (SHH) antagonist GDC-0449 in pediatric patients with recurrent or refractory medulloblastoma: A Pediatric Brain Tumor Consortium study (PBTC 25). J. Clin. Oncol. ASCO Annual Meeting Proceedings Vol 28, No 18 (2010).

  108. Druker, B. J. Translation of the Philadelphia chromosome into therapy for CML. Blood 112, 4808–4817 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Buonamici, S. et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med. 2, 51ra70 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Dijkgraaf, G. J. et al. Small molecule inhibition of GDC-0449 refractory Smoothened mutants and downstream nechanisms of drug resistance. Cancer Res. 71, 435–444 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Dancey, J. & Sausville, E. A. Issues and progress with protein kinase inhibitors for cancer treatment. Nature Rev. Drug Discov. 2, 296–313 (2003).

    Article  CAS  Google Scholar 

  112. Graham, R. A. et al. Pharmacokinetics of hedgehog pathway inhibitor GDC-0449 in patients with locally-advanced or metastatic solid tumors: the role of α-1-acid glycoprotein binding. Clin. Cancer Res. 17, 2512–2511 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Goetz, S. C. & Anderson, K. V. The primary cilium: a signalling centre during vertebrate development. Nature Rev. Genet. 11, 331–344 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Wilson, C. W., Chen, M. H. & Chuang, P. T. Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PloS ONE 4, e5182 (2009).

  115. Wang, Y., Zhou, Z., Walsh, C. T. & McMahon, A. P. Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc. Natl Acad. Sci. USA 106, 2623–2628 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kimura, H., Ng, J. M. & Curran, T. Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 13, 249–260 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Ehlen, H. W., Buelens, L. A. & Vortkamp, A. Hedgehog signaling in skeletal development. Birth Defects Res. C. Embryo Today 78, 267–279 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. St-Jacques, B., Hammerschmidt, M. & McMahon, A. P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13, 2072–2086 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Maeda, Y. et al. Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone. Proc. Natl Acad. Sci. USA 104, 6382–6387 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hellemans, J. et al. Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Am. J. Hum. Genet. 72, 1040–1046 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Nusslein-Volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795–801 (1980).

    Article  CAS  PubMed  Google Scholar 

  122. McMahon, A. P., Ingham, P. W. & Tabin, C. J. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53, 1–114 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 (1996).

    Article  CAS  PubMed  Google Scholar 

  124. Roessler, E. et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nature Genet. 14, 357–360 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Belloni, E. et al. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nature Genet. 14, 353–356 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Binns, W., James, L. F., Shupe, J. L. & Thacker, E. J. Cyclopian-type malformation in lambs. Arch. Environ. Health 5, 106–108 (1962).

    Article  CAS  PubMed  Google Scholar 

  127. Leroi, A. M. Mutants: On Genetic Variety and the Human Body (Viking, New York, 2003).

    Google Scholar 

  128. Cooper, M. K., Porter, J. A., Young, K. E. & Beachy, P. A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280, 1603–1607 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Incardona, J. P., Gaffield, W., Kapur, R. P. & Roelink, H. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125, 3553–3562 (1998).

    CAS  PubMed  Google Scholar 

  130. Chen, J. K., Taipale, J., Cooper, M. K. & Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16, 2743–2748 (2002). Demonstration that cyclopmanine inhibits HH pathway activity by direct binding to SMO.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ellison, D. W. et al. Medulloblastoma: clinicopathological correlates of, S. H. H., WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 121, 381–396 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Northcott, P. A. et al. Medulloblastoma comprises four distinct molecular variants. J. Clin. Oncol. 29, 8199–8210 (2010).

    Google Scholar 

  133. Seidel, K. et al. Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor. Development 137, 3753–3761 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grant CA096832 from the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, 4060 Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, 19104, PA, USA

    Jessica M. Y. Ng & Tom Curran

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  1. Jessica M. Y. Ng
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Correspondence to Jessica M. Y. Ng or Tom Curran.

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Glossary

Cancer stem cells

Tumours are thought to harbour a subset of cells, sharing the characteristics of normal stem cells that have a high capacity for self-renewal and an ability to differentiate into the many cell types that make up the bulk of the tumour mass.

Acrocapitofemoral dysplasia

An autosomal recessive disorder caused by hypomorphic mutations in Indian Hedgehog (IHH) that is associated with cone-shaped epiphyses in hands and hips.

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Ng, J., Curran, T. The Hedgehog's tale: developing strategies for targeting cancer. Nat Rev Cancer 11, 493–501 (2011). https://doi.org/10.1038/nrc3079

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