Hedgehog signaling in prostate cancer and its therapeutic implication

International Journal of Molecular Sciences

Volumn 14, Issue 7, 2013, Pages 13979-14007

  Gonnissen, Annelies ^a   Isebaert, Sofie ^a   Haustermans, Karin ^a  

^a UNIVERSITY HOSPITALS LEUVEN   (Belgium)

Author keywords

Chemotherapy; Combination treatment; Hedgehog pathway; Molecular targeted agents; Prostate cancer; Radiotherapy

Indexed keywords

CYCLOPAMINE; ENZALUTAMIDE; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; ERLOTINIB; GEMCITABINE; LEUPRORELIN; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN INHIBITOR; PROTEIN PATCHED; PROTEIN PATCHED 1; SARIDEGIB; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; SONIC HEDGEHOG PROTEIN INHIBITOR; TRANSCRIPTION FACTOR GLI1; TRANSCRIPTION FACTOR GLI2; UNCLASSIFIED DRUG; VISMODEGIB;

ADVANCED CANCER; ALOPECIA; ANDROGEN DEPRIVATION THERAPY; ANTINEOPLASTIC ACTIVITY; BASAL CELL CARCINOMA; CANCER COMBINATION CHEMOTHERAPY; CANCER PROGNOSIS; CANCER RADIOTHERAPY; CANCER RESISTANCE; CASTRATION RESISTANT PROSTATE CANCER; CELLULAR DISTRIBUTION; CHEMORADIOTHERAPY; DISEASE ASSOCIATION; DNA REPAIR; DRUG MECHANISM; DYSGEUSIA; FATIGUE; GAIN OF FUNCTION MUTATION; GENE ACTIVATION; GENE EXPRESSION; GENETIC ASSOCIATION; GLI1 GENE; HUMAN; LOSS OF FUNCTION MUTATION; MEDULLOBLASTOMA; METASTASIS; MOLECULARLY TARGETED THERAPY; MULTIMODALITY CANCER THERAPY; MUSCLE SPASM; NAUSEA; NONHUMAN; PANCREAS CANCER; PROSTATE CANCER; PROTEIN INTERACTION; PROTEIN LOCALIZATION; PTCH1 GENE; REOXYGENATION; REVIEW; SHH GENE; SIGNAL TRANSDUCTION; SUFU GENE; TUMOR SUPPRESSOR GENE;

ANILIDES; ANIMALS; CARCINOMA, BASAL CELL; COMBINED MODALITY THERAPY; HEDGEHOG PROTEINS; HUMANS; MALE; PROSTATIC NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; PYRIDINES; PYRIMIDINES; SIGNAL TRANSDUCTION;

EID: 84880150812     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms140713979     Document Type: Review

References (152)

1. Karhadkar, S.S.; Bova, G.S.; Abdallah, N.; Dhara, S.; Gardner, D.; Maitra, A.; Isaacs, J.T.; Berman, D.M.; Beachy, P.A. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004, 431, 707-712.
2. Teglund, S.; Toftgard, R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim. Biophys. Acta 2010, 1805, 181-208.
3. Beachy, P.A.; Karhadkar, S.S.; Berman, D.M. Tissue repair and stem cell renewal in carcinogenesis. Nature 2004, 432, 324-331.
4. Lai, K.; Kaspar, B.K.; Gage, F.H.; Schaffer, D.V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat. Neurosci. 2003, 6, 21-27.
5. Pasca di, M.M.; Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer 2003, 3, 903-911.
6. Jiang, J.; Hui, C.C. Hedgehog signaling in development and cancer. Dev. Cell 2008, 15, 801-812.
7. Yang, L.; Xie, G.; Fan, Q.; Xie, J. Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 2010, 29, 469-481.
8. Chuang, P.T.; McMahon, A.P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999, 397, 617-621.
9. Zhang, W.; Kang, J.S.; Cole, F.; Yi, M.J.; Krauss, R.S. Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev. Cell 2006, 10, 657-665.
10. Tenzen, T.; Allen, B.L.; Cole, F.; Kang, J.S.; Krauss, R.S.; McMahon, A.P. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev. Cell 2006, 10, 647-656.
11. Carpenter, D.; Stone, D.M.; Brush, J.; Ryan, A.; Armanini, M.; Frantz, G.; Rosenthal, A.; de Sauvage, F.J. Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc. Natl. Acad. Sci. USA 1998, 95, 13630-13634.
12. Stone, D.M.; Hynes, M.; Armanini, M.; Swanson, T.A.; Gu, Q.; Johnson, R.L.; Scott, M.P.; Pennica, D.; Goddard, A.; Phillips, H., et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 1996, 384, 129-134.
13. Corbit, K.C.; Aanstad, P.; Singla, V.; Norman, A.R.; Stainier, D.Y.; Reiter, J.F. Vertebrate Smoothened functions at the primary cilium. Nature 2005, 437, 1018-1021.
14. Singla, V.; Reiter, J.F. The primary cilium as the cell's antenna: Signaling at a sensory organelle. Science 2006, 313, 629-633.
15. Haycraft, C.J.; Banizs, B.; Aydin-Son, Y.; Zhang, Q.; Michaud, E.J.; Yoder, B.K. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 2005, 1, e53.
16. Rohatgi, R.; Milenkovic, L.; Scott, M.P. Patched1 regulates hedgehog signaling at the primary cilium. Science 2007, 317, 372-376.
17. Riobo, N.A.; Manning, D.R. Pathways of signal transduction employed by vertebrate Hedgehogs. Biochem. J. 2007, 403, 369-379.
18. Rohatgi, R.; Milenkovic, L.; Corcoran, R.B.; Scott, M.P. Hedgehog signal transduction by Smoothened: Pharmacologic evidence for a 2-step activation process. Proc. Natl. Acad. Sci. USA 2009, 106, 3196-3201.
19. Sasaki, H.; Nishizaki, Y.; Hui, C.; Nakafuku, M.; Kondoh, H. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: Implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 1999, 126, 3915-3924.
20. Dai, P.; Akimaru, H.; Tanaka, Y.; Maekawa, T.; Nakafuku, M.; Ishii, S. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem. 1999, 274, 8143-8152.
21. Ingham, P.W.; McMahon, A.P. Hedgehog signaling in animal development: Paradigms and principles. Genes Dev. 2001, 15, 3059-3087.
22. Kogerman, P.; Grimm, T.; Kogerman, L.; Krause, D.; Unden, A.B.; Sandstedt, B.; Toftgard, R.; Zaphiropoulos, P.G. Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat. Cell Biol. 1999, 1, 312-319.
23. Yue, S.; Chen, Y.; Cheng, S.Y. Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin-proteasome pathway. Oncogene 2009, 28, 492-499.
24. Stecca, B.; Ruiz, I.A. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. J. Mol. Cell Biol. 2010, 2, 84-95.
25. Lauth, M.; Toftgard, R. Non-canonical activation of GLI transcription factors: Implications for targeted anti-cancer therapy. Cell Cycle 2007, 6, 2458-2463.
26. Onishi, H.; Katano, M. Hedgehog signaling pathway as a therapeutic target in various types of cancer. Cancer Sci. 2011, 102, 1756-1760.
27. Hahn, H.; Wicking, C.; Zaphiropoulous, P.G.; Gailani, M.R.; Shanley, S.; Chidambaram, A.; Vorechovsky, I.; Holmberg, E.; Unden, A.B.; Gillies, S., et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996, 85, 841-851.
28. Johnson, R.L.; Rothman, A.L.; Xie, J.; Goodrich, L.V.; Bare, J.W.; Bonifas, J.M., et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996, 272, 1668-1671.
29. Szkandera, J.; Kiesslich, T.; Haybaeck, J.; Gerger, A.; Pichler, M. Hedgehog signaling pathway in ovarian cancer. Int. J. Mol. Sci. 2013, 14, 1179-1196.
30. Rubin, L.L.; de Sauvage, F.J. Targeting the Hedgehog pathway in cancer. Nat. Rev. Drug Discov. 2006, 5, 1026-1033.
31. Scales, S.J.; de Sauvage, F.J. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol. Sci. 2009, 30, 303-312.
32. Yauch, R.L.; Gould, S.E.; Scales, S.J.; Tang, T.; Tian, H.; Ahn, C.P.; Marshall, D.; Fu, L.; Januario, T.; Kallop, D., et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008, 455, 406-410.
33. Tian, H.; Callahan, C.A.; DuPree, K.J.; Darbonne, W.C.; Ahn, C.P.; Scales, S.J.; de Sauvage, F.J. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc. Natl. Acad. Sci. USA 2009, 106, 4254-4259.
34. Fan, L.; Pepicelli, C.V.; Dibble, C.C.; Catbagan, W.; Zarycki, J.L.; Laciak, R.; Laciak, R.; Gipp, J.; Shaw, A.; Lamm, M.L.G., et al. Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 2004, 145, 3961-3970.
35. Dierks, C.; Grbic, J.; Zirlik, K.; Beigi, R.; Englund, N.P.; Guo, G.R.; Veelken, H.; Engelhardt, M.; Mertelsmann, R.; Kelleher, J.F., et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat. Med. 2007, 13, 944-951.
36. Hegde, G.V.; Peterson, K.J.; Emanuel, K.; Mittal, A.K.; Joshi, A.D.; Dickinson, J.D.; Kollessery, G.J.; Bociek, R.G.; Bierman, P.; Vose, J.M., 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. 2008, 6, 1928-1936.
37. Huangfu, D.; Anderson, K.V. Cilia and Hedgehog responsiveness in the mouse. Proc. Natl. Acad. Sci. USA 2005, 102, 11325-11330.
38. Han, Y.G.; Kim, H.J.; Dlugosz, A.A.; Ellison, D.W.; Gilbertson, R.J.; Alvarez-Buylla, A. Dual and opposing roles of primary cilia in medulloblastoma development. Nat. Med. 2009, 15, 1062-1065.
39. Wong, S.Y.; Seol, A.D.; So, P.L.; Ermilov, A.N.; Bichakjian, C.K.; Epstein, E.H., Jr.; Dlugosz, A.A.; Reiter, J.F. Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat. Med. 2009, 15, 1055-1061.
40. Hassounah, N.B.; Bunch, T.A.; McDermott, K.M. Molecular pathways: The role of primary cilia in cancer progression and therapeutics with a focus on Hedgehog signaling. Clin. Cancer Res. 2012, 18, 2429-2435.
41. Podlasek, C.A.; Barnett, D.H.; Clemens, J.Q.; Bak, P.M.; Bushman, W. Prostate development requires Sonic hedgehog expressed by the urogenital sinus epithelium. Dev. Biol. 1999, 209, 28-39.
42. Lamm, M.L.; Catbagan, W.S.; Laciak, R.J.; Barnett, D.H.; Hebner, C.M.; Gaffield, W.; Walterhouse, D.; Iannaccone, P.; Bushman, W. Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev. Biol. 2002, 249, 349-366.
43. Freestone, S.H.; Marker, P.; Grace, O.C.; Tomlinson, D.C.; Cunha, G.R.; Harnden, P.; Thomson, A.A. Sonic hedgehog regulates prostatic growth and epithelial differentiation. Dev. Biol. 2003, 264, 352-362.
44. Berman, D.M.; Desai, N.; Wang, X.; Karhadkar, S.S.; Reynon, M.; Abate-Shen, C.; Beachy, P.A.; Shen, M.M. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev. Biol. 2004, 267, 387-398.
45. Sheng, T.; Li, C.; Zhang, X.; Chi, S.; He, N.; Chen, K.; McCormick, F.; Gatalica, Z.; Xie, J. Activation of the hedgehog pathway in advanced prostate cancer. Mol. Cancer 2004, 3, 29.
46. Datta, S.; Datta, M.W. Sonic Hedgehog signaling in advanced prostate cancer. Cell Mol. Life Sci. 2006, 63, 435-448.
47. Sanchez, P.; Hernandez, A.M.; Stecca, B.; Kahler, A.J.; DeGueme, A.M.; Barrett, A.; Beyna, M.; Datta, M.W.; Datta, S.; Altaba, A. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc. Natl. Acad. Sci. USA 2004, 101, 12561-12566.
48. Tzelepi, V.; Karlou, M.; Wen, S.; Hoang, A.; Logothetis, C.; Troncoso, P.; Efstathiou, E. Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling. Histopathology 2011, 58, 1037-1047.
49. Azoulay, S.; Terry, S.; Chimingqi, M.; Sirab, N.; Faucon, H.; Gil Diez de, M.S.; Moutereau, S.; Maille, P.; Soyeux, P.; Abbou, C., et al. Comparative expression of Hedgehog ligands at different stages of prostate carcinoma progression. J. Pathol. 2008, 216, 460-470.
50. Kim, T.J.; Lee, J.Y.; Hwang, T.K.; Kang, C.S.; Choi, Y.J. Hedgehog signaling protein expression and its association with prognostic parameters in prostate cancer: A retrospective study from the view point of new 2010 anatomic stage/prognostic groups. J. Surg. Oncol. 2011, 104, 472-479.
51. Chen, M.; Carkner, R.; Buttyan, R. The hedgehog/Gli signaling paradigm in prostate cancer. Expert. Rev. Endocrinol. Metab 2011, 6, 453-467.
52. Gipp, J.; Gu, G.; Crylen, C.; Kasper, S.; Bushman, W. Hedgehog pathway activity in the LADY prostate tumor model. Mol. Cancer 2007, 6, 19.
53. Bragina, O.; Njunkova, N.; Sergejeva, S.; Jarvekulg, L.; Kogerman, P. Sonic Hedgehog pathway activity in prostate cancer. Oncol. Lett. 2010, 1, 319-325.
54. Efstathiou, E.; Karlou, M.; Wen, S.; Hoang, A.; Pettaway, C.A.; Pisters, L.L.; Maity, S.; Troncoso, P.; Logothetis, C.J. Integrated Hedgehog signaling is induced following castration in human and murine prostate cancers. Prostate 2013, 73, 153-161.
55. Ibuki, N.; Ghaffari, M.; Pandey, M.; Iu, I.; Fazli, L.; Kashiwagi, M.; Tojo, H.; Nakanishi, O.; Gleave, M.E.; Cox, M.E. TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling. Int. J. Cancer 2013, doi:10.1002/ijc.28193.
56. Shaw, G.; Price, A.M.; Ktori, E.; Bisson, I.; Purkis, P.E.; McFaul, S.; Oliver, R.T.; Prowse, D.M. Hedgehog signalling in androgen independent prostate cancer. Eur. Urol. 2008, 54, 1333-1343.
57. Chen, M.; Tanner, M.; Levine, A.C.; Levina, E.; Ohouo, P.; Buttyan, R. Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells. Cell Cycle 2009, 8, 149-157.
58. Chen, M.; Feuerstein, M.A.; Levina, E.; Baghel, P.S.; Carkner, R.D.; Tanner, M.J.; Shtutman, M.; Vacherot, F.; Terry, S.; de la Taille, A., et al. Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells. Mol. Cancer 2010, 9, 89.
59. Chen, G.; Goto, Y.; Sakamoto, R.; Tanaka, K.; Matsubara, E.; Nakamura, M.; Zheng, H.; Lu, J.; Takayanagi, R.; Nomura, M. GLI1, a crucial mediator of sonic hedgehog signaling in prostate cancer, functions as a negative modulator for androgen receptor. Biochem. Biophys. Res. Commun. 2011, 404, 809-815.
60. Shaw, G.; Prowse, D.M. Inhibition of androgen-independent prostate cancer cell growth is enhanced by combination therapy targeting Hedgehog and ErbB signalling. Cancer Cell Int. 2008, 8, 3.
61. Thiyagarajan, S.; Bhatia, N.; Reagan-Shaw, S.; Cozma, D.; Thomas-Tikhonenko, A.; Ahmad, N.; Spiegelman, V.S. Role of GLI2 transcription factor in growth and tumorigenicity of prostate cells. Cancer Res. 2007, 67, 10642-10646.
62. Chung, M.K.; Kim, H.J.; Lee, Y.S.; Han, M.E.; Yoon, S.; Baek, S.Y.; Kim, B.S.; Kim, J.B.; Oh, S.O. Hedgehog signaling regulates proliferation of prostate cancer cells via stathmin1. Clin. Exp. Med. 2010, 10, 51-57.
63. Bar, E.E.; Chaudhry, A.; Farah, M.H.; Eberhart, C.G. Hedgehog signaling promotes medulloblastoma survival via Bc/II. Am. J. Pathol. 2007, 170, 347-355.
64. Narita, S.; So, A.; Ettinger, S.; Hayashi, N.; Muramaki, M.; Fazli, L.; Kim, Y.; Gleave, M.E. GLI2 knockdown using an antisense oligonucleotide induces apoptosis and chemosensitizes cells to paclitaxel in androgen-independent prostate cancer. Clin. Cancer Res. 2008, 14, 5769-5777.
65. Nanta, R.; Kumar, D.; Meeker, D.; Rodova, M.; Van Veldhuizen, P.J.; Shankar, S.; Srivastava, R.K. NVP-LDE-225 (Erismodegib) inhibits epithelial-mesenchymal transition and human prostate cancer stem cell growth in NOD/SCID IL2Rgamma null mice by regulating Bmi-1 and microRNA-128. Oncogenesis. 2013, 2, e42.
66. McKee, C.M.; Xu, D.; Cao, Y.; Kabraji, S.; Allen, D.; Kersemans, V.; Beech, J.; Smart, S.; Hamdy, F.; Ishkanian, A., et al. Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma. J. Clin. Invest 2012, 122, 4025-4036.
67. Ferlay, J.; Parkin, D.M.; Steliarova-Foucher, E. Estimates of cancer incidence and mortality in Europe in 2008. Eur. J. Cancer 2010, 46, 765-781.
68. Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin. 2011, 61, 69-90.
69. Spahn, M.; Joniau, S.; Gontero, P.; Fieuws, S.; Marchioro, G.; Tombal, B.; Kneitz, B.; Hsu, C.Y.; van der Eeckt, K.; Bader, P., et al. Outcome predictors of radical prostatectomy in patients with prostate-specific antigen greater than 20 ng/mL: A European multi-institutional study of 712 patients. Eur. Urol. 2010, 58, 1-7.
70. Cooperberg, M.R.; Lubeck, D.P.; Mehta, S.S.; Carroll, P.R. Time trends in clinical risk stratification for prostate cancer: Implications for outcomes (data from CaPSURE). J. Urol. 2003, 170, S21-S25.
71. Mas, C.; Altaba, A. Small molecule modulation of HH-GLI signaling: Current leads, trials and tribulations. Biochem. Pharmacol. 2010, 80, 712-723.
72. Stanton, B.Z.; Peng, L.F. Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol. Biosyst. 2010, 6, 44-54.
73. Karlou, M.; Lu, J.F.; Wu, G.; Maity, S.; Tzelepi, V.; Navone, N.M.; Hoang, A.; Logothetis, C.J.; Efstathiou, E. Hedgehog signaling inhibition by the small molecule smoothened inhibitor GDC-0449 in the bone forming prostate cancer xenograft MDA PCa 118b. Prostate 2012, 72, 1638-1647.
74. LoRusso, P.M.; Rudin, C.M.; Reddy, J.C.; Tibes, R.; Weiss, G.J.; Borad, M.J.; Hann, C.L.; Brahmer, J.R.; Chang, I.; Darbonne, W.C., et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin. Cancer Res. 2011, 17, 2502-2511.
75. Tang, J.Y.; Mackay-Wiggan, J.M.; Aszterbaum, M.; Yauch, R.L.; Lindgren, J.; Chang, K.; Coppola, C.; Chanana, A.M.; Marji, J.; Bickers, D.R., et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N. Engl. J. Med. 2012, 366, 2180-2188.
76. Sekulic, A.; Migden, M.R.; Oro, A.E.; Dirix, L.; Lewis, K.D.; Hainsworth, J.D.; Solomon, J.A.; Yoo, S.; Arron, S.T.; Friedlander, P.A. et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med. 2012, 366, 2171-2179.
77. NCI Clinical Trail Database. Available online: http://www.clinicaltrials.gov (accessed on 13 March 2013).
78. Rudin, C.M. Vismodegib. Clin. Cancer Res. 2012, 18, 3218-3222.
79. Kimura, H.; Ng, J.M.; Curran, T. Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 2008, 13, 249-260.
80. Rudin, C.M.; Hann, C.L.; Laterra, J.; Yauch, R.L.; Callahan, C.A.; Fu, L.; Holcomb, T.; Stinson, J.; Gould, S.E.; Coleman, B., et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N. Engl. J. Med. 2009, 361, 1173-1178.
81. Atwood, S.X.; Chang, A.L.; Oro, A.E. Hedgehog pathway inhibition and the race against tumor evolution. J. Cell Biol. 2012, 199, 193-197.
82. Buonamici, S.; Williams, J.; Morrissey, M.; Wang, A.; Guo, R.; Vattay, A.; Hsiao, K.; Yuan, J.; Green, J.; Ospina, B., et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med. 2010, 2, 51ra70.
83. Yauch, R.L.; Dijkgraaf, G.J.; Alicke, B.; Januario, T.; Ahn, C.P.; Holcomb, T.; Pujara, K.; Stinson, J.; Callahan, C.A.; Tang, T., et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009, 326, 572-574.
84. Coni, S.; Infante, P.; Gulino, A. Control of stem cells and cancer stem cells by Hedgehog signaling: Pharmacologic clues from pathway dissection. Biochem. Pharmacol. 2013, 85, 623-628.
85. Kim, J.; Aftab, B.T.; Tang, J.Y.; Kim, D.; Lee, A.H.; Rezaee, M.; Kim, J.; Chen, B.; King, E.M.; Borodovsky, A., et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell 2013, 23, 23-34.
86. Chen, Y.J.; Lin, C.P.; Hsu, M.L.; Shieh, H.R.; Chao, N.K.; Chao, K.S. Sonic hedgehog signaling protects human hepatocellular carcinoma cells against ionizing radiation in an autocrine manner. Int. J. Radiat. Oncol. Biol. Phys. 2011, 80, 851-859.
87. Sims-Mourtada, J.; Izzo, J.G.; Apisarnthanarax, S.; Wu, T.T.; Malhotra, U.; Luthra, R.; Liao, Z.; Komaki, R.; van der Kogel, A.; Ajani, J., et al. Hedgehog: An attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin. Cancer Res. 2006, 12, 6565-6572.
88. Shafaee, Z.; Schmidt, H.; Du, W.; Posner, M.; Weichselbaum, R. Cyclopamine increases the cytotoxic effects of paclitaxel and radiation but not cisplatin and gemcitabine in Hedgehog expressing pancreatic cancer cells. Cancer Chemother. Pharmacol. 2006, 58, 765-770.
89. Zeng, J.; Aziz, K.; Chettiar, S.T.; Aftab, B.T.; Armour, M.; Gajula, R.; Gandhi, N.; Salih, T.; Herman, J.M.; Wong, J., et al. Hedgehog pathway inhibition radiosensitizes non-small cell lung cancers. Int. J. Radiat. Oncol. Biol. Phys. 2012, 86, 143-149.
90. Yoshikawa, R.; Nakano, Y.; Tao, L.; Koishi, K.; Matsumoto, T.; Sasako, M.; Tsujimura, T.; Hashimoto-Tamaoki, T.; Fujiwara, Y. Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Br. J. Cancer 2008, 98, 1670-1674.
91. Zhu, W.; You, Z.; Li, T.; Yu, C.; Tao, G.; Hu, M.; Chen, X. Correlation of hedgehog signal activation with chemoradiotherapy sensitivity and survival in esophageal squamous cell carcinomas. Jpn. J. Clin. Oncol. 2011, 41, 386-393.
92. Chaudary, N.; Pintilie, M.; Hedley, D.; Fyles, A.W.; Milosevic, M.; Clarke, B.; Hill, R.P.; Mackay, H. Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation. Cancer 2012, 118, 3105-3115.
93. Leonard, J.M.; Ye, H.; Wetmore, C.; Karnitz, L.M. Sonic Hedgehog signaling impairs ionizing radiation-induced checkpoint activation and induces genomic instability. J. Cell Biol. 2008, 183, 385-391.
94. Frappart, P.O.; Lee, Y.; Russell, H.R.; Chalhoub, N.; Wang, Y.D.; Orii, K.E.; Zhao, J.; Kondo, N.; Baker, S.J.; McKinnon, P.J. Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. Proc. Natl. Acad. Sci. USA 2009, 106, 1880-1885.
95. Mazumdar, T.; Devecchio, J.; Agyeman, A.; Shi, T.; Houghton, J.A. 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. 2011, 71, 5904-5914.
96. Pawlik, T.M.; Keyomarsi, K. Role of cell cycle in mediating sensitivity to radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2004, 59, 928-942.
97. Onishi, H.; Kai, M.; Odate, S.; Iwasaki, H.; Morifuji, Y.; Ogino, T.; Morisaki, T.; Nakashima, Y.; Katano, M. Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer. Cancer Sci. 2011, 102, 1144-1150.
98. Wang, G.; Zhang, Z.; Xu, Z.; Yin, H.; Bai, L.; Ma, Z.; Decoster, M.A.; Qian, G.; Wu, G. Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia. Biochim. Biophys. Acta 2010, 1803, 1359-1367.
99. Bijlsma, M.F.; Groot, A.P.; Oduro, J.P.; Franken, R.J.; Schoenmakers, S.H.; Peppelenbosch, M.P.; Spek, C.A. Hypoxia induces a hedgehog response mediated by HIF-1alpha. J. Cell Mol. Med. 2009, 13, 2053-2060.
100. Nakamura, K.; Sasajima, J.; Mizukami, Y.; Sugiyama, Y.; Yamazaki, M.; Fujii, R.; Kawamoto, T.; Koizumi, K.; Sato, K.; Fujiya, M., et al. Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells. PLoS One 2010, 5, e8824.
101. Pola, R.; Ling, L.E.; Silver, M.; Corbley, M.J.; Kearney, M.; Blake, P.R.; Shapiro, R.; Taylor, F.R.; Baker, D.P.; Asahara, T., et al. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat. Med. 2001, 7, 706-711.
102. Olive, K.P.; Jacobetz, M.A.; Davidson, C.J.; Gopinathan, A.; McIntyre, D.; Honess, D.; Madhu, B.; Goldgraben, M.A.; Caldwell, M.E.; Allard, D., et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009, 324, 1457-1461.
103. Bahra, M.; Kamphues, C.; Boas-Knoop, S.; Lippert, S.; Esendik, U.; Schuller, U.; Hartmann, W.; Waha, A.; Neuhaus, P.; Heppner, F., et al. Combination of hedgehog signaling blockage and chemotherapy leads to tumor reduction in pancreatic adenocarcinomas. Pancreas 2012, 41, 222-229.
104. McKee, C.M.; Xu, D.; Muschel, R.J. Protease nexin 1: A novel regulator of prostate cancer cell growth and neo-angiogenesis. Oncotarget. 2013, 4, 1-2.
105. McKenna, W.G.; Muschel, R.J.; Gupta, A.K.; Hahn, S.M.; Bernhard, E.J. The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene 2003, 22, 5866-5875.
106. Bussink, J.; van der Kogel, A.J.; Kaanders, J.H. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol. 2008, 9, 288-296.
107. Meyn, R.E.; Munshi, A.; Haymach, J.V.; Milas, L.; Ang, K.K. Receptor signaling as a regulatory mechanism of DNA repair. Radiother. Oncol. 2009, 92, 316-322.
108. Debucquoy, A.; Machiels, J.P.; McBride, W.H.; Haustermans, K. Integration of epidermal growth factor receptor inhibitors with preoperative chemoradiation. Clin. Cancer Res. 2010, 16, 2709-2714.
109. Stecca, B.; Mas, C.; Clement, V.; Zbinden, M.; Correa, R.; Piguet, V.; Beermann, F.; Ruizi Altaba, A. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc. Natl. Acad. Sci. USA 2007, 104, 5895-5900.
110. Riobo, N.A.; Lu, K.; Ai, X.; Haines, G.M.; Emerson, C.P., Jr. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc. Natl. Acad. Sci. USA 2006, 103, 4505-4510.
111. Riobo, N.A.; Haines, G.M.; Emerson, C.P., Jr. Protein kinase C-delta and mitogen-activated protein/extracellular signal-regulated kinase-1 control GLI activation in hedgehog signaling. Cancer Res. 2006, 66, 839-845.
112. Ji, Z.; Mei, F.C.; Xie, J.; Cheng, X. Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. J. Biol. Chem. 2007, 282, 14048-14055.
113. Sigal, A.; Rotter, V. Oncogenic mutations of the p53 tumor suppressor: The demons of the guardian of the genome. Cancer Res. 2000, 60, 6788-6793.
114. Navone, N.M.; Troncoso, P.; Pisters, L.L.; Goodrow, T.L.; Palmer, J.L.; Nichols, W.W.; von Eschenbach, A.C.; Conti, C.J. p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. J. Natl. Cancer Inst. 1993, 85, 1657-1669.
115. Osman, I.; Drobnjak, M.; Fazzari, M.; Ferrara, J.; Scher, H.I.; Cordon-Cardo, C. Inactivation of the p53 pathway in prostate cancer: Impact on tumor progression. Clin. Cancer Res. 1999, 5, 2082-2088.
116. Lu, C.; El-Deiry, W.S. Targeting p53 for enhanced radio-and chemo-sensitivity. Apoptosis 2009, 14, 597-606.
117. Lehmann, B.D.; McCubrey, J.A.; Terrian, D.M. Radiosensitization of prostate cancer by priming the wild-type p53-dependent cellular senescence pathway. Cancer Biol. Ther. 2007, 6, 1165-1170.
118. Abe, Y.; Oda-Sato, E.; Tobiume, K.; Kawauchi, K.; Taya, Y.; Okamoto, K.; Oren, M.; Tanaka, N. Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2. Proc. Natl. Acad. Sci. USA 2008, 105, 4838-4843.
119. Mahon, K.L.; Henshall, S.M.; Sutherland, R.L.; Horvath, L.G. Pathways of chemotherapy resistance in castration-resistant prostate cancer. Endocr. Relat Cancer 2011, 18, R103-R123.
120. Balk, S.P. Androgen receptor as a target in androgen-independent prostate cancer. Urology 2002, 60, 132-138.
121. Holzbeierlein, J.; Lal, P.; LaTulippe, E.; Smith, A.; Satagopan, J.; Zhang, L.; Ryan, C.; Smith, S.; Scher, H.; Scardino, P., et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am. J. Pathol. 2004, 164, 217-227.
122. Mohler, J.L. Castration-recurrent prostate cancer is not androgen-independent. Adv. Exp. Med. Biol. 2008, 617, 223-234.
123. Schweizer, M.T.; Antonarakis, E.S. Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: A new era of hormonal therapies is born. Ther. Adv. Urol. 2012, 4, 167-178.
124. Scher, H.I.; Fizazi, K.; Saad, F.; Taplin, M.E.; Sternberg, C.N.; Miller, K.; de Wit, R.; Mulders, P.; Chi, K.N.; Shore, N.D., et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 2012, 367, 1187-1197.
125. Tredan, O.; Galmarini, C.M.; Patel, K.; Tannock, I.F. Drug resistance and the solid tumor microenvironment. J. Natl. Cancer Inst. 2007, 99, 1441-1454.
126. Minchinton, A.I.; Tannock, I.F. Drug penetration in solid tumours. Nat. Rev. Cancer 2006, 6, 583-592.
127. Jain, R.K. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 2005, 307, 58-62.
128. Croker, A.K.; Allan, A.L. Cancer stem cells: Implications for the progression and treatment of metastatic disease. J. Cell Mol. Med. 2008, 12, 374-390.
129. Chen, J.; Li, Y.; Yu, T.S.; McKay, R.M.; Burns, D.K.; Kernie, S.G.; Parada, L.F. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 2012, 488, 522-526.
130. Gilbertson, R.J.; Graham, T.A. Cancer: Resolving the stem-cell debate. Nature 2012, 488, 462-463.
131. Janikova, M.; Skarda, J. Differentiation pathways in carcinogenesis and in chemo-and radioresistance. Neoplasma 2012, 59, 6-17.
132. Fu, J.; Rodova, M.; Roy, S.K.; Sharma, J.; Singh, K.P.; Srivastava, R.K.; Shankar, S. GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft. Cancer Lett. 2013, 330, 22-32.
133. Sims-Mourtada, J.; Izzo, J.G.; Ajani, J.; Chao, K.S. Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 2007, 26, 5674-5679.
134. Chen, Y.; Bieber, M.M.; Teng, N.N. Hedgehog signaling regulates drug sensitivity by targeting ABC transporters ABCB1 and ABCG2 in epithelial ovarian cancer. Mol. Carcinog. 2013, doi:10.1002/mc.22015.
135. Zhang, Y.; Laterra, J.; Pomper, M.G. Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp. Neoplasia 2009, 11, 96-101.
136. Singh, S.; Chitkara, D.; Mehrazin, R.; Behrman, S.W.; Wake, R.W.; Mahato, R.I. Chemoresistance in prostate cancer cells is regulated by miRNAs and Hedgehog pathway. PLoS One 2012, 7, e40021.
137. Mimeault, M.; Johansson, S.L.; Henichart, J.P.; Depreux, P.; Batra, S.K. Cytotoxic effects induced by docetaxel, gefitinib, and cyclopamine on side population and nonside population cell fractions from human invasive prostate cancer cells. Mol. Cancer Ther. 2010, 9, 617-630.
138. Domingo-Domenech, J.; Vidal, S.J.; Rodriguez-Bravo, V.; Castillo-Martin, M.; Quinn, S.A.; Rodriguez-Barrueco, R.; Bonal, D.M.; Charytonowicz, E.; Gladoun, N.; de la Lglesia-Vicente J., et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch-and hedgehog-dependent tumor-initiating cells. Cancer Cell 2012, 22, 373-388.
139. Infinity Pharmaceuticals, Infinity Reports Update from Phase 2 Study of Saridegib Plus Gemcitabine in Patients with Metastatic Pancreatic Cancer. Available online: http://phx.corporate-ir.net/phoenix.zhtml?c=121941&p=irol-newsArticle&ID=1653550&highlight= (accessed on 13 June 2013).
140. Kwak, E.L.; Clark, J.W.; Chabner, B. Targeted agents: The rules of combination. Clin. Cancer Res. 2007, 13, 5232-5237.
141. Dancey, J.E.; Chen, H.X. Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat. Rev. Drug Discov. 2006, 5, 649-659.
142. Bitting, R.L.; Armstrong, A.J. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr. Relat Cancer 2013, 20, R83-R89.
143. Taylor, B.S.; Schultz, N.; Hieronymus, H.; Gopalan, A.; Xiao, Y.; Carver, B.S.; Arora, V.K.; Kaushik, P.; Cerami, E.; Reva, B., et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010, 18, 11-22.
144. Mulholland, D.J.; Kobayashi, N.; Ruscetti, M.; Zhi, A.; Tran, L.M.; Huang, J.; Gleave, M.; Wu, H. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 2012, 72, 1878-1889.
145. Gioeli, D.; Mandell, J.W.; Petroni, G.R.; Frierson, H.F., Jr.; Weber, M.J. Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res. 1999, 59, 279-284.
146. Wang, Y.; Ding, Q.; Yen, C.J.; Xia, W.; Izzo, J.G.; Lang, J.Y.; Li, C.W.; Hsu, J.L.; Miller, S.A.; Wang, X., et al. The crosstalk of mTOR/S6K1 and Hedgehog pathways. Cancer Cell 2012, 21, 374-387.
147. Mimeault, M.; Batra, S.K. Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies. Carcinogenesis 2006, 27, 1-22.
148. Shi, Y.; Brands, F.H.; Chatterjee, S.; Feng, A.C.; Groshen, S.; Schewe, J.; Lieskovsky, G.; Cote, R.J. Her-2/neu expression in prostate cancer: High level of expression associated with exposure to hormone therapy and androgen independent disease. J. Urol. 2001, 166, 1514-1519.
149. Shah, R.B.; Ghosh, D.; Elder, J.T. Epidermal growth factor receptor (ErbB1) expression in prostate cancer progression: Correlation with androgen independence. Prostate 2006, 66, 1437-1444.
150. Canil, C.M.; Moore, M.J.; Winquist, E.; Baetz, T.; Pollak, M.; Chi, K.N.; Berry, C.S.; Ernst, D.S.; Douglas, L.; Brundage, M., et al. Randomized phase II study of two doses of gefitinib in hormone-refractory prostate cancer: A trial of the National Cancer Institute of Canada-Clinical Trials Group. J. Clin. Oncol. 2005, 23, 455-460.
151. Mimeault, M.; Johansson, S.L.; Vankatraman, G.; Moore, E.; Henichart, J.P.; Depreux, P.; Lin, M.F.; Batra, S.K. Combined targeting of epidermal growth factor receptor and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells. Mol. Cancer Ther. 2007, 6, 967-978.
152. Leuprolide Acetate or Goserelin With or Without GDC-0449 Followed by Surgery in Treating Patients With Locally Advanced Prostate Cancer. NCI Clinical Trial Database NCT01163084. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01163084?term=Hedgehog&rank=13 (accessed on 13 March 2013).