Targeted Oncology

, Volume 12, Issue 5, pp 623–641 | Cite as

Targeting the Wnt Pathway in Cancer: A Review of Novel Therapeutics

  • Roya Tabatabai
  • Yuliya Linhares
  • David Bolos
  • Monica Mita
  • Alain Mita
Review Article

Abstract

Wnt signaling is an evolutionarily conserved pathway that controls cell-to-cell interactions during embryogenesis. In adults, Wnt signaling plays a role in tissue homeostasis in almost every organ system. Aberrations within this pathway are implicated in a spectrum of human diseases. A variety of perturbations have been described in both solid and hematologic malignancies, lending way to Wnt signaling as a target for anti-cancer therapy. Of particular interest is the role of Wnt signaling in the development and maintenance of cancer stem cells, a rare population of cells that are able to maintain a tumor via self-renewal and thought to be more resistant to chemotherapy than bulk tumor cells. The ability to eradicate cancer stem cells may decrease the risk of cancer relapse and metastasis. A number of therapeutic agents specifically targeting the Wnt pathway have entered clinical trials, either as monotherapy or in combination with chemotherapy. We will provide an overview of agents that have been developed to target the Wnt pathways and a summary of pre-clinical and clinical trials.

Notes

Compliance with Ethical Standards

Funding

None.

Conflict of Interest

The authors declare no conflict of interest.

References

  1. 1.
    Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982;31(1):99–109.PubMedCrossRefGoogle Scholar
  2. 2.
    Baker NE. Molecular cloning of sequences from wingless, a segment polarity gene in Drosophila: the spatial distribution of a transcript in embryos. EMBO J. 1987;6(6):1765–73.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Loh KM, van Amerongen R, Nusse R. Generating cellular diversity and spatial form: Wnt signaling and the evolution of multicellular animals. Dev Cell. 2016;38(6):643–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.Google Scholar
  5. 5.
    Katoh M. WNT/PCP signaling pathway and human cancer (review). Oncol Rep. 2005;14(6):1583–8.PubMedGoogle Scholar
  6. 6.
    Clevers H, Nusse R. Wnt/ β-catenin signaling and disease. Cell. 2012;149(6):1192–205.PubMedCrossRefGoogle Scholar
  7. 7.
    Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13(12):767–79.PubMedCrossRefGoogle Scholar
  8. 8.
    Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434(7035):843–50.PubMedCrossRefGoogle Scholar
  9. 9.
    Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14(15):1837–51.PubMedGoogle Scholar
  10. 10.
    Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13(7):513–32.Google Scholar
  11. 11.
    Janda CY, et al. Structural basis of Wnt recognition by frizzled. Science. 2012;337(6090):59–64.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Takada R, et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell. 2006;11(6):791–801.PubMedCrossRefGoogle Scholar
  13. 13.
    Proffitt KD, Virshup DM. Precise regulation of porcupine activity is required for physiological Wnt signaling. J Biol Chem. 2012;287(41):34167–78.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Nile AH, Hannoush RN. Fatty acylation of Wnt proteins. Nat Chem Biol. 2016;12(2):60–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Langton PF, Kakugawa S, Vincent J-P. Making, exporting, and modulating Wnts. Trends Cell Biol. 2016;26(10):756–65.PubMedCrossRefGoogle Scholar
  16. 16.
    Coombs GS, et al. WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification. J Cell Sci. 2010;123(19):3357–67.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Liu J, et al. Targeting Wnt-driven cancer through the inhibition of porcupine by LGK974. Proc Natl Acad Sci U S A. 2013;110(50):20224–9.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Janku F, et al. Abstract C45: phase I study of WNT974, a first-in-class Porcupine inhibitor, in advanced solid tumors. Mol Cancer Ther. 2015;14(12 Supplement 2):C45.Google Scholar
  19. 19.
    Madan B, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016;35(17):2197–207.PubMedCrossRefGoogle Scholar
  20. 20.
    Bilic J, et al. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science. 2007;316(5831):1619–22.PubMedCrossRefGoogle Scholar
  21. 21.
    Kikuchi A, et al. New insights into the mechanism of Wnt signaling pathway activation. Int Rev Cell Mol Biol. 2011;291:21–71.Google Scholar
  22. 22.
    Cruciat C-M, Niehrs C. Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb Perspect Biol. 2013;5(3):a015081.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Mao B, Niehrs C. Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene. 2003;302(1):179–83.PubMedCrossRefGoogle Scholar
  24. 24.
    Leyns L, et al. Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann organizer. Cell. 1997;88(6):747–56.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Lin K, et al. The cysteine-rich frizzled domain of Frzb-1 is required and sufficient for modulation of Wnt signaling. Proc Natl Acad Sci U S A. 1997;94(21):11196–200.Google Scholar
  26. 26.
    Li Y, et al. Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling. Genes Dev. 2008;22(21):3050–63.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Surmann-Schmitt C, et al. Wif-1 is expressed at cartilage-mesenchyme interfaces and impedes Wnt3a-mediated inhibition of chondrogenesis. J Cell Sci. 2009;122(20):3627–37.PubMedCrossRefGoogle Scholar
  28. 28.
    Binnerts ME, et al. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proc Natl Acad Sci U S A. 2007;104(37):14700–5.Google Scholar
  29. 29.
    Ohkawara B, Glinka A, Niehrs C. Rspo3 binds syndecan 4 and induces Wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis. Dev Cell. 2011;20(3):303–14.PubMedCrossRefGoogle Scholar
  30. 30.
    Esteve P, et al. SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis. Nat Neurosci. 2011;14(5):562–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee HX, et al. Embryonic dorsal-ventral signaling: secreted frizzled-related proteins as inhibitors of tolloid proteinases. Cell. 2006;124(1):147–59.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Aberle H, et al. β-catenin is a target for the ubiquitin–proteasome pathway. EMBO J. 1997;16(13):3797–804.Google Scholar
  33. 33.
    Ikeda S, et al. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3β and β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J. 1998;17(5):1371–84.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kishida S, et al. Axin, a negative regulator of the Wnt signaling pathway, directly interacts with adenomatous polyposis coli and regulates the stabilization of β-catenin. J Biol Chem. 1998;273(18):10823–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Stamos JL, et al. Structural basis of GSK-3 inhibition by N-terminal phosphorylation and by the Wnt receptor LRP6. Elife. 2014;3:e01998.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Azzolin L, et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell. 2014;158(1):157–70.PubMedCrossRefGoogle Scholar
  37. 37.
    Gammons MV, et al. Wnt signalosome assembly by DEP domain swapping of Dishevelled. Mol Cell. 2016;64(1):92–104.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Gammons MV, et al. Essential role of the Dishevelled DEP domain in a Wnt-dependent human-cell-based complementation assay. J Cell Sci. 2016;129(20):3892–902.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Zeng X, et al. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development. 2008;135(2):367–75.PubMedCrossRefGoogle Scholar
  40. 40.
    Fiedler M, et al. Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin. Proc Natl Acad Sci U S A. 2011;108(5):1937–42.Google Scholar
  41. 41.
    Schwarz-Romond T, et al. The Wnt signalling effector Dishevelled forms dynamic protein assemblies rather than stable associations with cytoplasmic vesicles. J Cell Sci. 2005;118(22):5269–77.PubMedCrossRefGoogle Scholar
  42. 42.
    Wong H-C, et al. Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of frizzled. Mol Cell. 2003;12(5):1251–60.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Jenny A, et al. Diego and Prickle regulate frizzled planar cell polarity signalling by competing for Dishevelled binding. Nat Cell Biol. 2005;7(7):691–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Mlodzik M. Chapter five-the Dishevelled protein family: still rather a mystery after over 20 years of molecular studies. Curr Top Dev Biol. 2016;117:75–91.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Hecht A, et al. The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J. 2000;19(8):1839–50.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kahn M. Symmetric division versus asymmetric division: a tale of two coactivators. Future Med Chem. 2011;3(14):1745–63.PubMedCrossRefGoogle Scholar
  47. 47.
    Chodaparambil JV, et al. Molecular functions of the TLE tetramerization domain in Wnt target gene repression. EMBO J. 2014;33(7):719–31.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kumar A, et al. Zfp703 is a Wnt/β-catenin feedback suppressor targeting the β-catenin/Tcf1 complex. Mol Cell Biol. 2016;36(12):1793–802.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    He X, et al. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development. 2004;131(8):1663–77.PubMedCrossRefGoogle Scholar
  50. 50.
    Lu X, et al. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature. 2004;430(6995):93–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Nishita M, et al. Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. J Cell Biol. 2006;175(4):555–62.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Adler PN. The frizzled/stan pathway and planar cell polarity in the Drosophila wing. Curr Top Dev Biol. 2012;101:1–31.Google Scholar
  53. 53.
    Habas R, Kato Y, He X. Wnt/frizzled activation of rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1. Cell. 2001;107(7):843–54.PubMedCrossRefGoogle Scholar
  54. 54.
    Simons M, Mlodzik M. Planar cell polarity signaling: from fly development to human disease. Annu Rev Genet. 2008;42:517–40.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Seifert JR, Mlodzik M. Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nat Rev Genet. 2007;8(2):126–38.Google Scholar
  56. 56.
    Wang Y, Nathans J. Tissue/planar cell polarity in vertebrates: new insights and new questions. Development. 2007;134(4):647–58.PubMedCrossRefGoogle Scholar
  57. 57.
    Kohn AD, Moon RT. Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium. 2005;38(3–4):439–46.PubMedCrossRefGoogle Scholar
  58. 58.
    Kühl SJ, Kühl M. On the role of Wnt/β-catenin signaling in stem cells. Biochim Biophys Acta. 2013;1830(2):2297–306.Google Scholar
  59. 59.
    Clevers H, Loh KM, Nusse R. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 2014;346(6205).Google Scholar
  60. 60.
    Barker N, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449(7165):1003–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Ten Berge D, et al. Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells. Nat Cell Biol. 2011;13(9):1070–5.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    O’Brien CA, Kreso A, Jamieson CHM. Cancer stem cells and self-renewal. Clin Cancer Res. 2010;16(12):3113–20.PubMedCrossRefGoogle Scholar
  63. 63.
    Medema JP. Cancer stem cells: the challenges ahead. Nat Cell Biol. 2013;15(4):338–44.PubMedCrossRefGoogle Scholar
  64. 64.
    Korinek V, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 1998;19(4):379–83.PubMedCrossRefGoogle Scholar
  65. 65.
    Pinto D, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 2003;17(14):1709–13.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Al-Hajj M, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983–8.Google Scholar
  67. 67.
    Li C, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Hermann PC, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1(3):313–23.PubMedCrossRefGoogle Scholar
  69. 69.
    Singh SK, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.PubMedCrossRefGoogle Scholar
  70. 70.
    Prince M, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104(3):973–8.Google Scholar
  71. 71.
    Yang ZF, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell. 2008;13(2):153–66.PubMedCrossRefGoogle Scholar
  72. 72.
    Eramo A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15(3):504–14.Google Scholar
  73. 73.
    Collins AT, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65(23):10946–51.PubMedCrossRefGoogle Scholar
  74. 74.
    Curley MD, et al. CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells. 2009;27(12):2875–83.PubMedGoogle Scholar
  75. 75.
    Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275–84.Google Scholar
  76. 76.
    Hadnagy A, et al. SP analysis may be used to identify cancer stem cell populations. Exp Cell Res. 2006;312(19):3701–10.Google Scholar
  77. 77.
    Chikazawa N, et al. Inhibition of Wnt signaling pathway decreases chemotherapy-resistant side-population colon cancer cells. Anticancer Res. 2010;30(6):2041–8.PubMedGoogle Scholar
  78. 78.
    Bao S, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.PubMedCrossRefGoogle Scholar
  79. 79.
    Su L-K, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science. 1993;262(5140):1734–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Harada N, et al. Hepatocarcinogenesis in mice with beta-catenin and ha-Ras gene mutations. Cancer Res. 2004;64(1):48–54.PubMedCrossRefGoogle Scholar
  81. 81.
    Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87(2):159–70.PubMedCrossRefGoogle Scholar
  82. 82.
    Network CGA. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.CrossRefGoogle Scholar
  83. 83.
    Verras M, et al. Wnt3a growth factor induces androgen receptor-mediated transcription and enhances cell growth in human prostate cancer cells. Cancer Res. 2004;64(24):8860–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Qiang YW, et al. Wnts induce migration and invasion of myeloma plasma cells. Blood. 2005;106(5):1786–93.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Chien AJ, et al. Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proc Natl Acad Sci U S A. 2009;106(4):1193–8.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Blanc E, et al. Low expression of Wnt-5a gene is associated with high-risk neuroblastoma. Oncogene. 2005;24(7):1277–83.PubMedCrossRefGoogle Scholar
  87. 87.
    Jonsson M, et al. Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas. Cancer Res. 2002;62(2):409–16.PubMedGoogle Scholar
  88. 88.
    Kremenevskaja N, et al. Wnt-5a has tumor suppressor activity in thyroid carcinoma. Oncogene. 2005;24(13):2144–54.PubMedCrossRefGoogle Scholar
  89. 89.
    Liang H, et al. Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell. 2003;4(5):349–60.PubMedCrossRefGoogle Scholar
  90. 90.
    Roman-Gomez J, et al. WNT5A, a putative tumour suppressor of lymphoid malignancies, is inactivated by aberrant methylation in acute lymphoblastic leukaemia. Eur J Cancer. 2007;43(18):2736–46.PubMedCrossRefGoogle Scholar
  91. 91.
    Da Forno PD, et al. WNT5A expression increases during melanoma progression and correlates with outcome. Clin Cancer Res. 2008;14(18):5825–32.PubMedCrossRefGoogle Scholar
  92. 92.
    Kurayoshi M, et al. Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Res. 2006;66(21):10439–48.PubMedCrossRefGoogle Scholar
  93. 93.
    Ripka S, et al. WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. Carcinogenesis. 2007;28(6):1178–87.PubMedCrossRefGoogle Scholar
  94. 94.
    Huang C-l, et al. Wnt5a expression is associated with the tumor proliferation and the stromal vascular endothelial growth factor—an expression in non–small-cell lung cancer. J Clin Oncol. 2005;23(34):8765–73.PubMedCrossRefGoogle Scholar
  95. 95.
    Mehdawi LM, et al. Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells. Mol Oncol. 2016;10(9):1415–29.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Bakker ER, et al. Wnt5a promotes human colon cancer cell migration and invasion but does not augment intestinal tumorigenesis in Apc1638N mice. Carcinogenesis. 2013;34(11):2629–38.PubMedCrossRefGoogle Scholar
  97. 97.
    Wang Q, et al. Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer. Oncogene. 2007;26(45):6560–5.PubMedCrossRefGoogle Scholar
  98. 98.
    Khaja ASS, et al. Elevated level of Wnt5a protein in localized prostate cancer tissue is associated with better outcome. PLoS One. 2011;6(10):e26539.CrossRefGoogle Scholar
  99. 99.
    Khaja ASS, et al. Emphasizing the role of Wnt5a protein expression to predict favorable outcome after radical prostatectomy in patients with low-grade prostate cancer. Cancer Medicine. 2012;1(1):96–104.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Mikels AJ, Nusse R. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol. 2006;4(4):e115.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Carmon KS, Loose DS. Secreted frizzled-related protein 4 regulates two Wnt7a signaling pathways and inhibits proliferation in endometrial cancer cells. Mol Cancer Res. 2008;6(6):1017–28.PubMedCrossRefGoogle Scholar
  102. 102.
    Satoh S, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000;24(3):245–50.PubMedCrossRefGoogle Scholar
  103. 103.
    Liu W, et al. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating β-catenin/TCF signalling. Nat Genet. 2000;26(2):146–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Cardona GM, et al. Identification of R-Spondin fusions in various types of human cancer. Cancer Res. 2014;74(19 Supplement):2408.Google Scholar
  105. 105.
    Madan B, Virshup DM. Targeting Wnts at the source--new mechanisms, new biomarkers, new drugs. Mol Cancer Ther. 2015;14(5):1087–94.PubMedCrossRefGoogle Scholar
  106. 106.
    Suzuki H, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet. 2004;36(4):417–22.PubMedCrossRefGoogle Scholar
  107. 107.
    Dahl E, et al. Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma. Oncogene. 2007;26(38):5680–91.PubMedCrossRefGoogle Scholar
  108. 108.
    Esteve P, Bovolenta P. The advantages and disadvantages of sfrp1 and sfrp2 expression in pathological events. Tohoku J Exp Med. 2010;221(1):11–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Joesting MS, et al. Identification of SFRP1 as a candidate mediator of stromal-to-epithelial signaling in prostate cancer. Cancer Res. 2005;65(22):10423–30.Google Scholar
  110. 110.
    Aguilera O, et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene. 2006;25(29):4116–21.PubMedCrossRefGoogle Scholar
  111. 111.
    Li S, et al. Dickkopf-1 is involved in invasive growth of esophageal cancer cells. J Mol Histol. 2011;42(6):491–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Sheng SL, et al. Clinical significance and prognostic value of serum Dickkopf-1 concentrations in patients with lung cancer. Clin Chem. 2009;55(9):1656–64.PubMedCrossRefGoogle Scholar
  113. 113.
    Sato N, et al. Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer Res. 2010;70(13):5326–36.PubMedCrossRefGoogle Scholar
  114. 114.
    Tian E, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349(26):2483–94.PubMedCrossRefGoogle Scholar
  115. 115.
    Wissmann C, et al. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J Pathol. 2003;201(2):204–12.PubMedCrossRefGoogle Scholar
  116. 116.
    Paluszczak J, et al. Frequent hypermethylation of WNT pathway genes in laryngeal squamous cell carcinomas. J Oral Pathol Med. 2014;43(9):652–7.Google Scholar
  117. 117.
    Nguyen DX, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell. 2009;138(1):51–62.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Medrek C, et al. Wnt-5a-CKI{alpha} signaling promotes {beta}-catenin/E-cadherin complex formation and intercellular adhesion in human breast epithelial cells. J Biol Chem. 2009;284(16):10968–79.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Easwaran V, et al. Beta-catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res. 2003;63(12):3145–53.PubMedGoogle Scholar
  120. 120.
    Chen MS, et al. Wnt/β-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line. J Cell Sci. 2007;120(3):468–77.PubMedCrossRefGoogle Scholar
  121. 121.
    Chang HW, et al. Wnt signaling controls radiosensitivity via cyclooxygenase-2-mediated Ku expression in head and neck cancer. Int J Cancer. 2008;122(1):100–7.PubMedCrossRefGoogle Scholar
  122. 122.
    Reya T, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423(6938):409–14.PubMedCrossRefGoogle Scholar
  123. 123.
    Van Den Berg DJ, et al. Role of members of the Wnt Gene family in human hematopoiesis. Blood. 1998;92(9):3189–202.Google Scholar
  124. 124.
    Tickenbrock L, et al. Activation of Wnt signalling in acute myeloid leukemia by induction of frizzled-4. Int J Oncol. 2008;33(6):1215–21.PubMedGoogle Scholar
  125. 125.
    Valencia A, et al. Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia. Leukemia. 2009;23(9):1658–66.PubMedCrossRefGoogle Scholar
  126. 126.
    Wang Y, et al. The Wnt/β-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327(5973):1650–3.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Jamieson CH, et al. Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351(7):657–67.PubMedCrossRefGoogle Scholar
  128. 128.
    Nygren MK, et al. Wnt3A activates canonical Wnt signalling in acute lymphoblastic leukaemia (ALL) cells and inhibits the proliferation of B-ALL cell lines. Br J Haematol. 2007;136(3):400–13.PubMedCrossRefGoogle Scholar
  129. 129.
    Ng O, et al. Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia. Blood Cancer J. 2014;4(3):e192.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Walker MP, et al. FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B-cell lymphoma. Sci Signal. 2015;8(362):ra12.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Nusse R, Varmus H. Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J. 2012;31(12):2670–84.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg. 2000;87(8):992–1005.PubMedCrossRefGoogle Scholar
  133. 133.
    Brown WA, et al. Inhibition of beta-catenin translocation in rodent colorectal tumors: a novel explanation for the protective effect of nonsteroidal antiinflammatory drugs in colorectal cancer. Dig Dis Sci. 2001;46(11):2314–21.PubMedCrossRefGoogle Scholar
  134. 134.
    Smith M-L, Hawcroft G, Hull M. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur J Cancer. 2000;36(5):664–74.PubMedCrossRefGoogle Scholar
  135. 135.
    Boon E, et al. Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. Br J Cancer. 2004;90(1):224–9.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov. 2006;5(12):997–1014.PubMedCrossRefGoogle Scholar
  137. 137.
    Castellone MD, et al. Prostaglandin E2 promotes Colon cancer cell growth through a Gs-Axin-ß-catenin signaling Axis. Science. 2005;310(5753):1504–10.PubMedCrossRefGoogle Scholar
  138. 138.
    Liu Y, et al. Retinoic acid receptor beta mediates the growth-inhibitory effect of retinoic acid by promoting apoptosis in human breast cancer cells. Mol Cell Biol. 1996;16(3):1138–49.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Houle B, Rochette-Egly C, Bradley W. Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells. Proc Natl Acad Sci U S A. 1993;90(3):985–9.Google Scholar
  140. 140.
    Soprano DR, Qin P, Soprano KJ. Retinoic acid receptors and cancers. Annu Rev Nutr. 2004;24:201–21.PubMedCrossRefGoogle Scholar
  141. 141.
    Easwaran V, et al. Cross-regulation of beta-catenin-LEF/TCF and retinoid signaling pathways. Curr Biol. 1999;9(23):1415–8.PubMedCrossRefGoogle Scholar
  142. 142.
    Akhter J, et al. Vitamin D3 analog, EB1089, inhibits growth of subcutaneous xenografts of the human colon cancer cell line, LoVo, in a nude mouse model. Dis Colon rectum. 1997;40(3):317–21.PubMedCrossRefGoogle Scholar
  143. 143.
    VanWeelden K, et al. Apoptotic regression of MCF-7 xenografts in nude mice treated with the vitamin D3 analog, EB1089 1. Endocrinology. 1998;139(4):2102–10.PubMedCrossRefGoogle Scholar
  144. 144.
    Pálmer HG, et al. Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling. J Cell Biol. 2001;154(2):369–88.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5(6):493–506.PubMedCrossRefGoogle Scholar
  146. 146.
    Chen H-J, et al. The β-catenin/TCF complex as a novel target of resveratrol in the Wnt/β-catenin signaling pathway. Biochem Pharmacol. 2012;84(9):1143–53.PubMedCrossRefGoogle Scholar
  147. 147.
    Badger TM, et al. Soy protein isolate and protection against cancer. J Am Coll Nutr. 2005;24(2):146S–9S.Google Scholar
  148. 148.
    Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr. 1995;125(3):777S–83S.PubMedGoogle Scholar
  149. 149.
    Zhang Y, et al. Genistein, a soya isoflavone, prevents azoxymethane-induced up-regulation of WNT/β-catenin signalling and reduces colon pre-neoplasia in rats. Br J Nutr. 2013;109(01):33–42.PubMedCrossRefGoogle Scholar
  150. 150.
    Zhang Y, Chen H. Genistein attenuates WNT signaling by up-regulating sFRP2 in a human colon cancer cell line. Exp Biol Med. 2011;236(6):714–22.CrossRefGoogle Scholar
  151. 151.
    Chen M, et al. The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry. 2009;48(43):10267–74.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Osada T, et al. Antihelminth compound Niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Res. 2011;71(12):4172–82.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Broome HE, et al. ROR1 is expressed on hematogones (non-neoplastic human B-lymphocyte precursors) and a minority of precursor-B acute lymphoblastic leukemia. Leuk Res. 2011;35(10):1390–4.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Klein U, et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med. 2001;194(11):1625–38.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Fukuda T, et al. Antisera induced by infusions of autologous ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc Natl Acad Sci U S A. 2008;105(8):3047–52.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Yang J, et al. Therapeutic potential and challenges of targeting receptor tyrosine kinase ROR1 with monoclonal antibodies in B-cell malignancies. PLoS One. 2011;6(6):e21018.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Daneshmanesh A, et al. Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells. Leukemia. 2012;26(6):1348–55.PubMedCrossRefGoogle Scholar
  158. 158.
    Choi MY, et al. Pre-clinical specificity and safety of UC-961, a first-in-class monoclonal antibody targeting ROR1. Clin Lymphoma Myeloma Leukemia. 2015;15:S167–9.CrossRefGoogle Scholar
  159. 159.
    Choi MY, et al. Immunotherapeutic Targeting of ROR1-Dependent, Non-Canonical Wnt5a-Signaling By Cirmtuzumab: A First-in-Human Phase I Trial for Patients with Intractable Chronic Lymphocytic Leukemia. Blood. 2016;128:3224.Google Scholar
  160. 160.
    Gurney A, et al. Wnt pathway inhibition via the targeting of frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci U S A. 2012;109(29):11717–22.Google Scholar
  161. 161.
    Smith DC, et al. First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors. J Clin Oncol. 2013;31(15 Supplement):2540.Google Scholar
  162. 162.
    Von Hoff DD, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.CrossRefGoogle Scholar
  163. 163.
    Zhang C, et al. Predictive biomarker identification for response to vantictumab (OMP-18R5; anti-Frizzled) using primary patient-derived human pancreatic tumor xenografts. Cancer Res. 2016;76(14 Supplement):3129.Google Scholar
  164. 164.
    Mita MM, et al. Phase 1b study of WNT inhibitor vantictumab (VAN, human monoclonal antibody) with paclitaxel (P) in patients (pts) with 1st-to 3rd-line metastatic HER2-negative breast cancer (BC). J Clin Oncol. 2016;34(15 Supplement):2516.Google Scholar
  165. 165.
    Zhang C, et al. Predictive biomarker identification for response to vantictumab (OMP-18R5; anti-frizzled) by mining gene expression data of human breast cancer xenografts. Cancer Res. 2014;74(19 Supplement):2830.Google Scholar
  166. 166.
    Nagayama S, et al. Therapeutic potential of antibodies against FZD10, a cell-surface protein, for synovial sarcomas. Oncogene. 2005;24(41):6201–12.PubMedCrossRefGoogle Scholar
  167. 167.
    Giraudet A.-L. et al. SYNFRIZZ-A phase Ia/Ib of a radiolabelled monoclonal AB for the treatment of relapsing synovial sarcoma. J Nucl Med. 2014;55(Supplement 1):223.Google Scholar
  168. 168.
    Pinzone JJ, et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood. 2009;113(3):517–25.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Xiang XJ, et al. Differential expression of Dickkopf-1 among non-small cell lung cancer cells. Mol Med Rep. 2015;12(2):1935–40.PubMedCrossRefGoogle Scholar
  170. 170.
    Edenfield WJ, et al. A phase 1 study evaluating the safety and efficacy of DKN-01, an investigational monoclonal antibody (Mab) in patients (pts) with advanced non-small cell lung cancer. J Clin Oncol. 2014;32(15 Supplement):8068.Google Scholar
  171. 171.
    Shepherd FA, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non–small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18(10):2095–103.PubMedCrossRefGoogle Scholar
  172. 172.
    Edenfield WJ, et al. A phase 1 study evaluating the safety and efficacy of DKN-01, an investigational monoclonal antibody (Mab) in patients (pts) with advanced non-small cell lung cancer. J Clin Oncol. 2014;32(15 Supplement):8068.Google Scholar
  173. 173.
    Bendell JC, et al. Phase I study of DKN-01, an anti-DKK1 antibody, in combination with paclitaxel (pac) in patients (pts) with DKK1+ relapsed or refractory esophageal cancer (EC) or gastro-esophageal junction tumors (GEJ). J Clin Oncol. 2016;34(4 Supplement):111.Google Scholar
  174. 174.
    Fulciniti M, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood. 2009;114(2):371–9.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Padmanabhan S, et al. A phase I/II study of BHQ880, a novel Osteoblat activating, anti-DKK1 human monoclonal antibody, in relapsed and refractory multiple myeloma (MM) patients treated with Zoledronic acid (Zol) and anti-myeloma therapy (MM Tx). Blood. 2009;114(22):750.Google Scholar
  176. 176.
    Munshi NC, et al. Early evidence of anabolic bone activity of BHQ880, a fully human anti-DKK1 neutralizing antibody: results of a phase 2 study in previously untreated patients with smoldering multiple myeloma at risk for progression. Blood. 2012;120(21):331.Google Scholar
  177. 177.
    Raje N, Roodman GD. Advances in the biology and treatment of bone disease in multiple myeloma. Clin Cancer Res. 2011;17(6):1278–86.PubMedCrossRefGoogle Scholar
  178. 178.
    Sonmez M, et al. Effect of pathologic fractures on survival in multiple myeloma patients: a case control study. J Exp Clin Cancer Res. 2008;27(1):11.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Hoey T. Development of FZD8-Fc (OMP-54F28), a Wnt signaling antagonist that inhibits tumor growth and reduces tumor initiating cell frequency. In: AACR Annual Meeting. 2013.Google Scholar
  180. 180.
    Jimeno A, et al. A first-in-human phase 1 study of anticancer stem cell agent OMP-54F28 (FZD8-Fc), decoy receptor for WNT ligands, in patients with advanced solid tumors. J Clin Oncol. 2014;32(15 Supplement):2505.Google Scholar
  181. 181.
    Weekes C, et al. Phase 1b study of WNT inhibitor ipafricept (IPA, decoy receptor for WNT ligands) with nab-paclitaxel (nab-P) and gemcitabine (G) in patients (pts) with previously untreated stage IV pancreatic cancer (PC). Ann Oncol. 2016;27(6 Supplement):367PD.Google Scholar
  182. 182.
    O’Cearbhaill RE, et al. Phase 1b of WNT inhibitor ipafricept (IPA, decoy receptor for WNT ligands) with carboplatin (C) and paclitaxel (P) in recurrent platinum-sensitive ovarian cancer (OC). J Clin Oncol. 2016;34(15 Supplement):2515.Google Scholar
  183. 183.
    Chen B, et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol. 2009;5(2):100–7.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Agarwal P, et al. Inhibition of CML stem cell growth by targeting WNT signaling using a porcupine inhibitor. Blood. 2014;124(21):3130.Google Scholar
  185. 185.
    Säfholm A, et al. The Wnt-5a–derived Hexapeptide Foxy-5 inhibits breast cancer metastasis <em>in vivo</em> by targeting cell motility. Clin Cancer Res. 2008;14(20):6556–63.PubMedCrossRefGoogle Scholar
  186. 186.
    Andersson T, et al. Abstract A116: targeting the Wnt-5a signaling pathway as a novel anti-metastatic therapy. Mol Cancer Ther. 2015;14(12 Supplement 2):A116.CrossRefGoogle Scholar
  187. 187.
    Ma H, et al. Differential roles for the coactivators CBP and p300 on TCF//[beta]-catenin-mediated survivin gene expression. Oncogene. 2005;24(22):3619–31.PubMedCrossRefGoogle Scholar
  188. 188.
    El-Khoueiry AB, et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. J Clin Oncol. 2013;31(15 Supplement):2501.Google Scholar
  189. 189.
    McWilliams RR, et al. A phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX. J Clin Oncol. 2015;33(15 Supplement):e15270.Google Scholar
  190. 190.
    Morishita EC, et al. Crystal structures of the armadillo repeat domain of adenomatous polyposis coli and its complex with the tyrosine-rich domain of Sam68. Structure. 2011;19(10):1496–508.PubMedCrossRefGoogle Scholar
  191. 191.
    Cortes JE, et al. Phase 1 study of CWP232291 in relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). J Clin Oncol. 2015;33(15 Supplement):7044.Google Scholar
  192. 192.
    Yoon S-S, et al. Ongoing Phase 1a/1b Dose-Finding Study of CWP232291 (CWP291) in Relapsed or Refractory Multiple Myeloma (MM). Blood. 2016;128:4501.Google Scholar
  193. 193.
    Hood J, et al. Discovery of a small molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying treatment for knee osteoarthritis. Osteoarthr Cartil. 2016;24:S14–5.CrossRefGoogle Scholar
  194. 194.
    Shou J, et al. Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Oncogene. 2002;21(6):878–89.PubMedCrossRefGoogle Scholar
  195. 195.
    Ohigashi T, et al. Inhibition of Wnt signaling downregulates Akt activity and induces chemosensitivity in PTEN-mutated prostate cancer cells. Prostate. 2005;62(1):61–8.PubMedCrossRefGoogle Scholar
  196. 196.
    Peng C, et al. Wnt5a as a predictor in poor clinical outcome of patients and a mediator in chemoresistance of ovarian cancer. Int J Gynecol Cancer. 2011;21(2):280–8.PubMedCrossRefGoogle Scholar
  197. 197.
    Lee M, et al. Use of WNT inhibitors to augment therapeutic index of chemotherapy. Google Patents; 2010.Google Scholar
  198. 198.
    Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19(2):179–92.PubMedCrossRefGoogle Scholar
  199. 199.
    Laine CM, et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med. 2013;368(19):1809–16.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Luke JJ, et al. Correlation of WNT/{beta}-catenin pathway activation with immune exclusion across most human cancers. J Clin Oncol. 2016;34(15 Supplement):3004.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of Hematology and OncologyCedars Sinai Medical CenterLos AngelesUSA

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