Mechanisms of Hedgehog pathway activation in cancer and implications for therapy

Trends in Pharmacological Sciences

Volumn 30, Issue 6, 2009, Pages 303-312

  Scales, Suzie J ^a   de Sauvage, Frederic J ^a  

^a GENENTECH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBODY 5E1; ANTINEOPLASTIC AGENT; BMS 833923; CYCLOPAMINE; GANT 5861; GDC 0449; HH ANTAG; IPI 269609; IPI 926; JERVINE; KAAD CYCLOPAMINE; N (3 METHOXYBENZYL) 3,3 DIMETHYL N [1 (3,4 METHYLENEDIOXYBENZYL) 2 (1 PIPERAZINYLCARBONYL) 4 PYRROLIDINYL]BUTYRAMIDE; PROTEIN ANTIBODY; PROTEIN INHIBITOR; PROTEIN PATCHED 1 INHIBITOR; ROBOTNIKININ; SANT1 SANT4; SONIC HEDGEHOG PROTEIN; SONIC HEDGEHOG PROTEIN INHIBITOR; UNCLASSIFIED DRUG; XL 139;

AUTOCRINE EFFECT; CANCER STEM CELL; CANCER THERAPY; CLINICAL TRIAL; DECREASED APPETITE; DRUG SCREENING; DYSPEPSIA; ELECTROLYTE DISTURBANCE; EMBRYO DEVELOPMENT; FATIGUE; HAIR LOSS; HUMAN; MORPHOGENESIS; MUTATION; NAUSEA; NEOPLASM; NONHUMAN; ORGANOGENESIS; PARACRINE SIGNALING; PATIENT SELECTION; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; SOLID TUMOR; STROMA; TASTE DISORDER; TISSUE REPAIR; TUMOR MODEL; VOMITING; WEIGHT REDUCTION;

ANILIDES; ANIMALS; ANTINEOPLASTIC AGENTS; DRUG EVALUATION, PRECLINICAL; HEDGEHOG PROTEINS; HUMANS; LIGANDS; NEOPLASMS; PYRIDINES; SIGNAL TRANSDUCTION;

EID: 67650289584     PISSN: 01656147     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tips.2009.03.007     Document Type: Review

References (101)

1. Riobo N.A., and Manning D.R. Pathways of signal transduction employed by vertebrate Hedgehogs. Biochem. J. 403 (2007) 369-379
2. Varjosalo M., and Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 22 (2008) 2454-2472
3. Jiang J., and Hui C.C. Hedgehog signaling in development and cancer. Dev. Cell 15 (2008) 801-812
4. Eggenschwiler J.T., and Anderson K.V. Cilia and developmental signaling. Annu. Rev. Cell Dev. Biol. 23 (2007) 345-373
5. Cheng S.Y., and Bishop J.M. Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 5442-5447
6. Cheng S.Y., and Yue S. Role and regulation of human tumor suppressor SUFU in Hedgehog signaling. Adv. Cancer Res. 101 (2008) 29-43
7. McMahon A.P., et al. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53 (2003) 1-114
8. Duman-Scheel M., et al. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature 417 (2002) 299-304
9. Yoon J.W., et al. Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J. Biol. Chem. 277 (2002) 5548-5555
10. Bigelow R.L., et al. Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J. Biol. Chem. 279 (2004) 1197-1205
11. Regl G., et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 64 (2004) 7724-7731
12. Bar E.E., et al. Hedgehog signaling promotes medulloblastoma survival via Bc/II. Am. J. Pathol. 170 (2007) 347-355
13. Dierks C., et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat. Med. 13 (2007) 944-951
14. Pola R., et al. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat. Med. 7 (2001) 706-711
15. Feldmann G., et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 67 (2007) 2187-2196
16. Rubin L.L., and de Sauvage F.J. Targeting the Hedgehog pathway in cancer. Nat. Rev. Drug Discov. 5 (2006) 1026-1033
17. Hahn H., et al. A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J. Biol. Chem. 271 (1996) 12125-12128
18. Johnson R.L., et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272 (1996) 1668-1671
19. Epstein E.H. Basal cell carcinomas: attack of the hedgehog. Nat. Rev. Cancer 8 (2008) 743-754
20. 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 (1996) 4562-4565
21. Gailani M.R., et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat. Genet. 14 (1996) 78-81
22. 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 (1998) 1798-1803
23. Xie J., et al. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 57 (1997) 2369-2372
24. Reifenberger J., et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br. J. Dermatol. 152 (2005) 43-51
25. Evans D.G., et al. The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br. J. Cancer 64 (1991) 959-961
26. Raffel C., et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 57 (1997) 842-845
27. Pietsch T., et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 57 (1997) 2085-2088
28. Vorechovsky I., et al. Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Oncogene 15 (1997) 361-366
29. Taylor M.D., et al. Mutations in SUFU predispose to medulloblastoma. Nat. Genet. 31 (2002) 306-310
30. -/- mice. Cancer Cell 6 (2004) 229-240
31. Sanchez P., and Ruiz i Altaba A. In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech. Dev. 122 (2005) 223-230
32. 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 (2006) 17-25
33. Kimura H., et al. Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 13 (2008) 249-260
34. Watkins D.N., et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422 (2003) 313-317
35. Yuan Z., et al. Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene 26 (2007) 1046-1055
36. Thayer S.P., et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425 (2003) 851-856
37. Berman D.M., et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425 (2003) 846-851
38. Ma X., et al. Hedgehog signaling is activated in subsets of esophageal cancers. Int. J. Cancer 118 (2006) 139-148
39. Qualtrough D., et al. Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment. Int. J. Cancer 110 (2004) 831-837
40. Karhadkar S.S., et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431 (2004) 707-712
41. Sanchez P., et al. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 12561-12566
42. Mukherjee S., et al. Hedgehog signaling and response to cyclopamine differ in epithelial and stromal cells in benign breast and breast cancer. Cancer Biol. Ther. 5 (2006) 674-683
43. Stecca B., et al. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 5895-5900
44. Zhang J., et al. Lack of demonstrable autocrine hedgehog signaling in human prostate cancer cell lines. J. Urol. 177 (2007) 1179-1185
45. Chatel G., et al. Hedgehog signaling pathway is inactive in colorectal cancer cell lines. Int. J. Cancer 121 (2007) 2622-2627
46. Zhang, X. et al. (2008) Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo). Breast Cancer Res. Treat. www.springerlink.com 10.1007/s10549-008-0093-3
47. Yauch R.L., et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455 (2008) 406-410
48. Sasai K., et al. Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies. Cancer Res. 66 (2006) 4215-4222
49. Becher O.J., et al. Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas. Cancer Res. 68 (2008) 2241-2249
50. 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 (2008) 189-197
51. Fan L., et al. Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145 (2004) 3961-3970
52. Bailey J.M., et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin. Cancer Res. 14 (2008) 5995-6004
53. Tian H., et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 4254-4259
54. Feldmann G., et al. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 57 (2008) 1420-1430
55. Seeley E.S., et al. Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia. Cancer Res. 69 (2009) 422-430
56. Nolan-Stevaux O., et al. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 23 (2009) 24-36
57. Hahn H., et al. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J. Biol. Chem. 275 (2000) 28341-28344
58. Chao W., and D'Amore P.A. IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev. 19 (2008) 111-120
59. Geng L., et al. Hedgehog signaling in the murine melanoma microenvironment. Angiogenesis 10 (2007) 259-267
60. Yamazaki M., et al. Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells. Cancer Sci. 99 (2008) 1131-1138
61. 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 (2008) 1928-1936
62. Clement V., et al. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 17 (2007) 165-172
63. Visvader J.E., and Lindeman G.J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat. Rev. Cancer 8 (2008) 755-768
64. Stupp R., et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352 (2005) 987-996
65. Beier D., et al. Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res. 68 (2008) 5706-5715
66. Bar E.E., et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25 (2007) 2524-2533
67. Li C., et al. Identification of pancreatic cancer stem cells. Cancer Res. 67 (2007) 1030-1037
68. Feldmann G., et al. An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol. Cancer Ther. 7 (2008) 2725-2735
69. Liu S., et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66 (2006) 6063-6071
70. Peacock C.D., et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 4048-4053
71. Dierks C., et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14 (2008) 238-249
72. Zhao C., et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458 (2009) 776-779
73. Bryden M.M., et al. Cyclopia in sheep caused by plant teratogens. J. Anat. 110 (1971) 507
74. Cooper M.K., et al. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280 (1998) 1603-1607
75. Chen J.K., et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16 (2002) 2743-2748
76. Kiselyov A.S. Targeting the hedgehog signaling pathway with small molecules. Anticancer. Agents Med. Chem. 6 (2006) 445-449
77. Chen J.K., et al. Small molecule modulation of Smoothened activity. Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 14071-14076
78. Tremblay M.R., et al. Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists. J. Med. Chem. 51 (2008) 6646-6649
79. Frank-Kamenetsky M., et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1 (2002) 10
80. 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. U. S. A. 100 (2003) 4616-4621
81. Gould S., et al. Inhibition of tumor-stromal signaling by specific small molecule hedgehog antagonists delays growth of primary human pancreatic cancer xenografts [abstract]. AACR Meeting Abstracts 2007 (2007) 2802
82. Mahindroo N., et al. Hedgehog-Gli signaling pathway inhibitors as anticancer agents. J. Med. Chem. (2009). http://pubs.acs.org 10.1021/jm801420y
83. Ericson J., et al. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87 (1996) 661-673
84. Stanton B.Z., et al. A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat. Chem. Biol. 5 (2009) 154-156
85. Nakamura M., et al. Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation. Anticancer Res. 27 (2007) 3743-3747
86. Kinzler K.W., et al. Identification of an amplified, highly expressed gene in a human glioma. Science 236 (1987) 70-73
87. Taipale J., et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406 (2000) 1005-1009
88. Lauth M., et al. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 8455-8460
89. Lauth M., and Toftgard R. Non-canonical activation of GLI transcription factors: implications for targeted anti-cancer therapy. Cell Cycle 6 (2007) 2458-2463
90. Fernandez-Zapico M.E. Primers on molecular pathways GLI: more than just Hedgehog?. Pancreatology 8 (2008) 227-229
91. de Fougerolles A., et al. Interfering with disease: a progress report on siRNA-based therapeutics. Nat. Rev. Drug Discov. 6 (2007) 443-453
92. Tabs S., and Avci O. Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur. J. Dermatol. 14 (2004) 96-102
93. LoRusso P.M., et al. A first-in-human, first-in-class, phase 1 study of systemic Hedgehog pathway antagonist, GDC-0449, in patients with advanced solid tumors. J. Clin. Oncol. 26 Suppl. (2008) 3516
94. Rudin C.M., et al. Updated safety and efficacy data from a first-in-human, first-in-class phase I study of Hedgehog pathway antagonist GDC-0449. European Journal of Cancer Supplements 6 (2008) 112-113
95. Mistretta C.M., et al. Cyclopamine and jervine in embryonic rat tongue cultures demonstrate a role for Shh signaling in taste papilla development and patterning: fungiform papillae double in number and form in novel locations in dorsal lingual epithelium. Dev. Biol. 254 (2003) 1-18
96. Hall J.M., et al. Disruption of sonic hedgehog signaling alters growth and patterning of lingual taste papillae. Dev. Biol. 255 (2003) 263-277
97. St-Jacques B., et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8 (1998) 1058-1068
98. Chiang C., et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205 (1999) 1-9
99. Von Hoff, D.D. et al. (2008) Efficacy data of GDC-0449, a systemic Hedgehog pathway antagonist, in a first-in-human, first-in-class Phase I study with locally advanced, multifocal or metastatic basal cell carcinoma patients [abstract]. 99th AACR Annual Meeting, LB-138
100. Omnell M.L., et al. Expression of Veratrum alkaloid teratogenicity in the mouse. Teratology 42 (1990) 105-119
101. Pink M., et al. Activity of IPI-926, a potent Hedgehog pathway inhibitor, in a novel model of medulloblastoma derived from Ptch/HIC +/- mice [abstract]. 99th AACR Annual Meeting (2008) 1588