Targeting GLI factors to inhibit the Hedgehog pathway

Trends in Pharmacological Sciences

Volumn 36, Issue 8, 2015, Pages 547-558

  Infante, Paola ^a   Alfonsi, Romina ^b   Botta, Bruno ^b   Mori, Mattia ^a   Di Marcotullio, Lucia ^a,b,c  

^a ISTITUTO ITALIANO DI TECNOLOGIA   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

^c Pasteur Institute   (Italy)

Author keywords

cancer; drug discovery; GLI antagonists; Hedgehog pathway

Indexed keywords

4 (4 CHLOROPHENYL) 2,3,9 TRIMETHYL 6H THIENO[3,2 F][1,2,4]TRIAZOLO[4,3 A][1,4]DIAZEPINE 6 ACETIC ACID TERT BUTYL ESTER; 7 (3,5 DIMETHYL 4 ISOXAZOLYL) 1,3 DIHYDRO 8 METHOXY 1 [1 (2 PYRIDINYL)ETHYL] 2H IMIDAZO[4,5 C]QUINOLIN 2 ONE; ARSENIC TRIOXIDE; BELINOSTAT; CYCLOHEXYL METHYL AMINOPYRIMIDINE DERIVATIVE; CYCLOPAMINE; EGGMANONE; GLABRESCIONE B; GLI ANTAGONIST; GLI ANTAGONIST 61; HEDGEHOG PATHWAY INHIBITOR 1; HEDGEHOG PATHWAY INHIBITOR 2; HEDGEHOG PATHWAY INHIBITOR 3; HEDGEHOG PATHWAY INHIBITOR 4; HISTONE DEACETYLASE INHIBITOR; IMIQUIMOD; ITRACONAZOLE; PATIDEGIB; PROTEIN INHIBITOR; PYRIMIDINE DERIVATIVE; PYRVINIUM EMBONATE; RICOLINOSTAT; ROMIDEPSIN; SMOOTHENED PROTEIN ANTAGONIST; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR GLI; UNCLASSIFIED DRUG; UNINDEXED DRUG; VISMODEGIB; VORINOSTAT; ANTINEOPLASTIC AGENT; G PROTEIN COUPLED RECEPTOR; GLI1 PROTEIN, HUMAN; SMO PROTEIN, HUMAN;

ADVANCED CANCER; ALOPECIA; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; BASAL CELL CARCINOMA; CANCER RESEARCH; CANCER RESISTANCE; CANCER THERAPY; CARCINOGENESIS; CLINICAL TRIAL (TOPIC); COLON CANCER; CUTANEOUS T CELL LYMPHOMA; DECREASED APPETITE; DIARRHEA; DRUG APPROVAL; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG EFFICACY; DRUG ELIMINATION; DRUG MECHANISM; DRUG RESEARCH; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; DYSGEUSIA; EPIGENETICS; ESOPHAGEAL ADENOCARCINOMA; FATIGUE; GENE MUTATION; HEMATOLOGIC MALIGNANCY; HIGH THROUGHPUT SCREENING; HUMAN; HYPONATREMIA; LIVER CELL CARCINOMA; LUNG CANCER; MEDULLOBLASTOMA; MELANOMA; METASTASIS; MUSCLE CRAMP; NAUSEA; NONHUMAN; OSTEOSARCOMA; OVARY CANCER; PANCREAS CANCER; PERIPHERAL T CELL LYMPHOMA; PHASE 1 CLINICAL TRIAL (TOPIC); PLEURA MESOTHELIOMA; PRIORITY JOURNAL; PROMYELOCYTIC LEUKEMIA; PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN INTERACTION; PROTEIN PROCESSING; RHABDOID TUMOR; RISK BENEFIT ANALYSIS; SIDE EFFECT; SIGNAL TRANSDUCTION; SOLID TUMOR; UNSPECIFIED SIDE EFFECT; WEIGHT REDUCTION; X RAY CRYSTALLOGRAPHY; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; METABOLISM;

ANIMALS; ANTINEOPLASTIC AGENTS; HEDGEHOG PROTEINS; HUMANS; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

EID: 84938953364     PISSN: 01656147     EISSN: 18733735     Source Type: Journal    
DOI: 10.1016/j.tips.2015.05.006     Document Type: Review

References (109)

1. M. Varjosalo, and J. Taipale Hedgehog: functions and mechanisms Genes Dev. 22 2008 2454 2472
2. K.E. Ryan, and C. Chiang Hedgehog secretion and signal transduction in vertebrates J. Biol. Chem. 287 2012 17905 17913
3. J.D. Benazet, and R. Zeller Vertebrate limb development: moving from classical morphogen gradients to an integrated 4-dimensional patterning system Cold Spring Harb. Perspect. Biol. 1 2009 a001339
4. P.S. Gill, and N.D. Rosenblum Control of murine kidney development by sonic hedgehog and its GLI effectors Cell Cycle 5 2006 1426 1430
5. M.C. Kugler, and et al. Sonic hedgehog signaling in the lung. From development to disease Am. J. Respir. Cell Mol. Biol. 52 2015 1 13
6. A.M. Hynes, and et al. Murine Joubert syndrome reveals Hedgehog signaling defects as a potential therapeutic target for nephronophthisis Proc. Natl. Acad. Sci. U.S.A. 111 2014 9893 9898
7. R.J. Lipinski, and et al. Characterization of subtle brain abnormalities in a mouse model of Hedgehog pathway antagonist-induced cleft lip and palate PLoS ONE 9 2014 e102603
8. Y.H. Bian, and et al. Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas World J. Gastroenterol. 13 2007 1659 1665
9. A.N. Gerber, and et al. The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation Oncogene 26 2007 1122 1136
10. A. Ruiz i Altaba, and et al. Gli and hedgehog in cancer: tumours, embryos and stem cells Nat. Rev. Cancer 2 2002 361 372
11. P. Sanchez, and 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
12. M.R. Gailani, and et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas Nat. Genet. 14 1996 78 81
13. M.D. Taylor, and et al. Mutations in SUFU predispose to medulloblastoma Nat. Genet. 31 2002 306 310
14. J. Xie, and et al. Activating Smoothened mutations in sporadic basal-cell carcinoma Nature 391 1998 90 92
15. K.W. Kinzler, and et al. Identification of an amplified, highly expressed gene in a human glioma Science 236 1987 70 73
16. F. Aberger, and I.A.A. Ruiz Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy Semin. Cell Dev. Biol. 33 2014 93 104
17. S. Coni, and et al. Control of stem cells and cancer stem cells by Hedgehog signaling: pharmacologic clues from pathway dissection Biochem. Pharmacol. 85 2013 623 628
18. L. Di Marcotullio, and et al. Protected from the inside: endogenous histone deacetylase inhibitors and the road to cancer Biochim. Biophys. Acta 1815 2011 241 252
19. A. Po, and et al. Hedgehog controls neural stem cells through p53-independent regulation of Nanog EMBO J. 29 2010 2646 2658
20. F. Varnat, and 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 2009 338 351
21. J.K. Chen, and et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened Genes Dev. 16 2002 2743 2748
22. R.J. Lipinski, and 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
23. M.K. Hadden Hedgehog pathway inhibitors: a patent review (2009 - present) Expert Opin. Ther. Pat. 23 2013 345 361
24. F. Manetti, and et al. Structure-activity relationships and mechanism of action of small molecule smoothened modulators discovered by high-throughput screening and rational design Top. Med. Chem. 2014 10.1007/7355-2014-61 Published online October 25, 2014
25. M. Ruat, and et al. Targeting of Smoothened for therapeutic gain Trends Pharmacol. Sci. 35 2014 237 246
26. D. Amakye, and et al. Unraveling the therapeutic potential of the Hedgehog pathway in cancer Nat. Med. 19 2013 1410 1422
27. J.M. Ng, and T. Curran The Hedgehog's tale: developing strategies for targeting cancer Nat. Rev. Cancer 11 2011 493 501
28. A. Dlugosz, and et al. Vismodegib Nat. Rev. Drug Discov. 11 2012 437 438
29. R.L. Yauch, and et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma Science 326 2009 572 574
30. A. Jimeno, and et al. Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors Clin. Cancer Res. 19 2013 2766 2774
31. S.X. Atwood, and et al. Smoothened variants explain the majority of drug resistance in basal cell carcinoma Cancer Cell 27 2015 342 353
32. H.J. Sharpe, and et al. Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma Cancer Cell 27 2015 327 341
33. S. Buonamici, and et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma Sci. Transl. Med. 2 2010 51ra70
34. M.J. Lee, and et al. Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model Proc. Natl. Acad. Sci. U.S.A. 109 2012 7859 7864
35. C. Metcalfe, and F.J. de Sauvage Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists Cancer Res. 71 2011 5057 5061
36. C.M. Rudin, and et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449 N. Engl. J. Med. 361 2009 1173 1178
37. J.Y. Tang, and et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome N. Engl. J. Med. 366 2012 2180 2188
38. R. Teperino, and et al. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat Cell 151 2012 414 426
39. E.G. Huntzicker, and et al. Dual degradation signals control Gli protein stability and tumor formation Genes Dev. 20 2006 276 281
40. L. Di Marcotullio, and et al. Multiple ubiquitin-dependent processing pathways regulate hedgehog/gli signaling: implications for cell development and tumorigenesis Cell Cycle 6 2007 390 393
41. A. Gulino, and et al. Hedgehog/Gli control by ubiquitination/acetylation interplay Vitam. Horm. 88 2012 211 227
42. Y. Katoh, and M. Katoh Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation Curr. Mol. Med. 9 2009 873 886
43. L. Di Marcotullio, and et al. Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination Nat. Cell Biol. 8 2006 1415 1423
44. L. Di Marcotullio, and et al. Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal Oncogene 30 2011 65 76
45. G. Canettieri, and et al. Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation Nat. Cell Biol. 12 2010 132 142
46. E. De Smaele, and et al. Identification and characterization of KCASH2 and KCASH3, 2 novel Cullin3 adaptors suppressing histone deacetylase and Hedgehog activity in medulloblastoma Neoplasia 13 2011 374 385
47. B. Stecca, and I.A.A. Ruiz Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals J. Mol. Cell Biol. 2 2010 84 95
48. V. Clement, and et al. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity Curr. Biol. 17 2007 165 172
49. N. Hatta, and et al. Molecular diagnosis of basal cell carcinoma and other basaloid cell neoplasms of the skin by the quantification of Gli1 transcript levels J. Cutan. Pathol. 32 2005 131 136
50. A.M. Snijders, and et al. Stromal control of oncogenic traits expressed in response to the overexpression of GLI2, a pleiotropic oncogene Oncogene 28 2009 625 637
51. V.I. Alexaki, and et al. GLI2-mediated melanoma invasion and metastasis J. Natl. Cancer Inst. 102 2010 1148 1159
52. S. Thiyagarajan, and et al. Role of GLI2 transcription factor in growth and tumorigenicity of prostate cells Cancer Res. 67 2007 10642 10646
53. H. Sheng, and et al. Dissecting the oncogenic potential of Gli2: deletion of an NH(2)-terminal fragment alters skin tumor phenotype Cancer Res. 62 2002 5308 5316
54. Y. Kim, and et al. Selective down-regulation of glioma-associated oncogene 2 inhibits the proliferation of hepatocellular carcinoma cells Cancer Res. 67 2007 3583 3593
55. S. Pandolfi, and B. Stecca Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: implications for cancer therapy Expert Rev. Mol. Med. 17 2015 e5
56. M. Mimeault, and S.K. Batra Frequent deregulations in the hedgehog signaling network and cross-talks with the epidermal growth factor receptor pathway involved in cancer progression and targeted therapies Pharmacol. Rev. 62 2010 497 524
57. O. Nolan-Stevaux, and 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
58. H. Schnidar, and et al. Epidermal growth factor receptor signaling synergizes with Hedgehog/GLI in oncogenic transformation via activation of the MEK/ERK/JUN pathway Cancer Res. 69 2009 1284 1292
59. J. Xie, and et al. A role of PDGFRalpha in basal cell carcinoma proliferation Proc. Natl. Acad. Sci. U.S.A. 98 2001 9255 9259
60. E. Beauchamp, and et al. GLI1 is a direct transcriptional target of EWS-FLI1 oncoprotein J. Biol. Chem. 284 2009 9074 9082
61. N.A. Riobo, and et al. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling Proc. Natl. Acad. Sci. U.S.A. 103 2006 4505 4510
62. S.X. Atwood, and et al. GLI activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas Nature 494 2013 484 488
63. F. Bassilana, and et al. Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39 Nat. Chem. Biol. 10 2014 343 349
64. P. Filippakopoulos, and et al. Selective inhibition of BET bromodomains Nature 468 2010 1067 1073
65. Z. Yang, and et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4 Mol. Cell 19 2005 535 545
66. J. Long, and et al. The BET bromodomain inhibitor I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers J. Biol. Chem. 289 2014 35494 35502
67. Y.H. Wang, and et al. BRD4 promotes pancreatic ductal adenocarcinoma cell proliferation and enhances gemcitabine resistance Oncol. Rep. 33 2015 1699 1706
68. S. Coni, and et al. Gli2 acetylation at lysine 757 regulates hedgehog-dependent transcriptional output by preventing its promoter occupancy PLoS ONE 8 2013 e65718
69. T. Milde, and et al. HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth Clin. Cancer Res. 16 2010 3240 3252
70. P.K. Dhanyamraju, and et al. Histone deacetylase 6 represents a novel drug target in the oncogenic Hedgehog signaling pathway Mol. Cancer Ther. 14 2014 727 739
71. M. Mottamal, and et al. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents Molecules 20 2015 3898 3941
72. M. Slingerland, and et al. Histone deacetylase inhibitors: an overview of the clinical studies in solid tumors Anticancer. Drugs 25 2014 140 149
73. S.E. Spiller, and et al. Suberoylanilide hydroxamic acid is effective in preclinical studies of medulloblastoma J. Neurooncol. 79 2006 259 270
74. B. Li, and et al. Pyrvinium attenuates Hedgehog signaling downstream of smoothened Cancer Res. 74 2014 4811 4821
75. B. Li, and et al. Repurposing the FDA-approved pinworm drug pyrvinium as a novel chemotherapeutic agent for intestinal polyposis PLoS ONE 9 2014 e101969
76. A. Ruiz i Altaba, and et al. The Gli code: an information nexus regulating cell fate, stemness and cancer Trends Cell Biol. 17 2007 438 447
77. Y. Wang, and et al. The crosstalk of mTOR/S6K1 and Hedgehog pathways Cancer Cell 21 2012 374 387
78. C.H. Williams, and et al. An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition Cell Rep. 11 2015 43 50
79. F. Wolff, and et al. Imiquimod directly inhibits Hedgehog signalling by stimulating adenosine receptor/protein kinase A-mediated GLI phosphorylation Oncogene 32 2013 5574 5581
80. G. Bosco-Clement, and et al. Targeting Gli transcription activation by small molecule suppresses tumor growth Oncogene 33 2014 2087 2097
81. M. Lauth, and 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
82. M. Lauth, and et al. Antipsychotic drugs regulate hedgehog signaling by modulation of 7-dehydrocholesterol reductase levels Mol. Pharmacol. 78 2010 486 496
83. J. Fu, and et al. GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft Cancer Lett. 330 2013 22 32
84. L. Huang, and et al. Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung cancer Clin. Cancer Res. 20 2014 1566 1575
85. T. Mazumdar, and et al. Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells Cancer Res. 71 2011 5904 5914
86. Y. Wang, and et al. Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells Hepatology 58 2013 995 1010
87. Q. Chen, and et al. Down-regulation of Gli transcription factor leads to the inhibition of migration and invasion of ovarian cancer cells via integrin beta4-mediated FAK signaling PLoS ONE 9 2014 e88386
88. M. Kebenko, and et al. ErbB2 signaling activates the Hedgehog pathway via PI3K-Akt in human esophageal adenocarcinoma: identification of novel targets for concerted therapy concepts Cell. Signal. 27 2015 373 381
89. R. Santini, and et al. Hedgehog-GLI signaling drives self-renewal and tumorigenicity of human melanoma-initiating cells Stem Cells 30 2012 1808 1818
90. J. Wang, and et al. Inhibition of autophagy potentiates the efficacy of Gli inhibitor GANT-61 in MYCN-amplified neuroblastoma cells BMC Cancer 14 2014 768
91. Y. Xu, and et al. Inhibition of the Hedgehog pathway induces autophagy in pancreatic ductal adenocarcinoma cells Oncol. Rep. 31 2014 707 712
92. J. Kim, and et al. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector Proc. Natl. Acad. Sci. U.S.A. 107 2010 13432 13437
93. E.M. Beauchamp, and et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway J. Clin. Invest. 121 2011 148 160
94. J. Kim, and et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists Cancer Cell 23 2013 23 34
95. L. Di Magno, and et al. Druggable glycolytic requirement for Hedgehog-dependent neuronal and medulloblastoma growth Cell Cycle 13 2014 3404 3413
96. M. You, and et al. Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro J. Thorac. Cardiovasc. Surg. 147 2014 508 516
97. K. Kerl, and et al. Arsenic trioxide inhibits tumor cell growth in malignant rhabdoid tumors in vitro and in vivo by targeting overexpressed Gli1 Int. J. Cancer 135 2014 989 995
98. S. Nakamura, and et al. Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation PLoS ONE 8 2013 e69466
99. D. Ding, and et al. Arsenic trioxide inhibits Hedgehog, Notch and stem cell properties in glioblastoma neurospheres Acta Neuropathol. Commun. 2 2014 31
100. J.M. Hyman, and et al. Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade Proc. Natl. Acad. Sci. U.S.A. 106 2009 14132 14137
101. Y. Xu, and et al. Polymeric nanoparticle-encapsulated hedgehog pathway inhibitor HPI-1 (NanoHHI) inhibits systemic metastases in an orthotopic model of human hepatocellular carcinoma Clin. Cancer Res. 18 2012 1291 1302
102. W. Xiang, and et al. Hedgehog pathway inhibitor-4 suppresses malignant properties of chondrosarcoma cells by disturbing tumor ciliogenesis Oncol. Rep. 32 2014 1622 1630
103. A. Slusarz, and et al. Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer Cancer Res. 70 2010 3382 3390
104. L. Zhang, and et al. Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway Cancer Lett. 323 2012 48 57
105. N.P. Pavletich, and C.O. Pabo Crystal structure of a five-finger GLI-DNA complex: new perspectives on zinc fingers Science 261 1993 1701 1707
106. P. Infante, and et al. Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors EMBO J. 34 2015 200 217
107. M. Snuderl, and et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma Cell 152 2013 1065 1076
108. K. Roemer Notch and the p53 clan of transcription factors Adv. Exp. Med. Biol. 727 2012 223 240
109. Y. Tang, and et al. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition Nat. Med. 20 2014 732 740