Skip to main content
SpringerLink
Log in

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

  • Review Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  4. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.

  5. Katoh M. WNT/PCP signaling pathway and human cancer (review). Oncol Rep. 2005;14(6):1583–8.

    CAS  PubMed  Google Scholar 

  6. Clevers H, Nusse R. Wnt/ β-catenin signaling and disease. Cell. 2012;149(6):1192–205.

    Article  CAS  PubMed  Google Scholar 

  7. Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13(12):767–79.

    Article  CAS  PubMed  Google Scholar 

  8. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434(7035):843–50.

    Article  CAS  PubMed  Google Scholar 

  9. Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14(15):1837–51.

    CAS  PubMed  Google Scholar 

  10. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13(7):513–32.

  11. Janda CY, et al. Structural basis of Wnt recognition by frizzled. Science. 2012;337(6090):59–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Takada R, et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell. 2006;11(6):791–801.

    Article  CAS  PubMed  Google Scholar 

  13. Proffitt KD, Virshup DM. Precise regulation of porcupine activity is required for physiological Wnt signaling. J Biol Chem. 2012;287(41):34167–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nile AH, Hannoush RN. Fatty acylation of Wnt proteins. Nat Chem Biol. 2016;12(2):60–9.

    Article  CAS  PubMed  Google Scholar 

  15. Langton PF, Kakugawa S, Vincent J-P. Making, exporting, and modulating Wnts. Trends Cell Biol. 2016;26(10):756–65.

    Article  CAS  PubMed  Google Scholar 

  16. Coombs GS, et al. WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification. J Cell Sci. 2010;123(19):3357–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  19. Madan B, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016;35(17):2197–207.

    Article  CAS  PubMed  Google Scholar 

  20. Bilic J, et al. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science. 2007;316(5831):1619–22.

    Article  CAS  PubMed  Google Scholar 

  21. Kikuchi A, et al. New insights into the mechanism of Wnt signaling pathway activation. Int Rev Cell Mol Biol. 2011;291:21–71.

  22. Cruciat C-M, Niehrs C. Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb Perspect Biol. 2013;5(3):a015081.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Mao B, Niehrs C. Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene. 2003;302(1):179–83.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  30. Esteve P, et al. SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis. Nat Neurosci. 2011;14(5):562–9.

    Article  CAS  PubMed  Google Scholar 

  31. Lee HX, et al. Embryonic dorsal-ventral signaling: secreted frizzled-related proteins as inhibitors of tolloid proteinases. Cell. 2006;124(1):147–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Aberle H, et al. β-catenin is a target for the ubiquitin–proteasome pathway. EMBO J. 1997;16(13):3797–804.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Azzolin L, et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell. 2014;158(1):157–70.

    Article  CAS  PubMed  Google Scholar 

  37. Gammons MV, et al. Wnt signalosome assembly by DEP domain swapping of Dishevelled. Mol Cell. 2016;64(1):92–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kahn M. Symmetric division versus asymmetric division: a tale of two coactivators. Future Med Chem. 2011;3(14):1745–63.

    Article  CAS  PubMed  Google Scholar 

  47. Chodaparambil JV, et al. Molecular functions of the TLE tetramerization domain in Wnt target gene repression. EMBO J. 2014;33(7):719–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  50. Lu X, et al. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature. 2004;430(6995):93–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Adler PN. The frizzled/stan pathway and planar cell polarity in the Drosophila wing. Curr Top Dev Biol. 2012;101:1–31.

  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.

    Article  CAS  PubMed  Google Scholar 

  54. Simons M, Mlodzik M. Planar cell polarity signaling: from fly development to human disease. Annu Rev Genet. 2008;42:517–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  56. Wang Y, Nathans J. Tissue/planar cell polarity in vertebrates: new insights and new questions. Development. 2007;134(4):647–58.

    Article  CAS  PubMed  Google Scholar 

  57. Kohn AD, Moon RT. Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium. 2005;38(3–4):439–46.

    Article  CAS  PubMed  Google Scholar 

  58. Kühl SJ, Kühl M. On the role of Wnt/β-catenin signaling in stem cells. Biochim Biophys Acta. 2013;1830(2):2297–306.

  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).

  60. Barker N, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449(7165):1003–7.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. O’Brien CA, Kreso A, Jamieson CHM. Cancer stem cells and self-renewal. Clin Cancer Res. 2010;16(12):3113–20.

    Article  PubMed  Google Scholar 

  63. Medema JP. Cancer stem cells: the challenges ahead. Nat Cell Biol. 2013;15(4):338–44.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  65. Pinto D, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 2003;17(14):1709–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  67. Li C, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030–7.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  69. Singh SK, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.

    Article  CAS  PubMed  Google Scholar 

  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.

  71. Yang ZF, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell. 2008;13(2):153–66.

    Article  CAS  PubMed  Google Scholar 

  72. Eramo A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15(3):504–14.

  73. Collins AT, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65(23):10946–51.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  75. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275–84.

  76. Hadnagy A, et al. SP analysis may be used to identify cancer stem cell populations. Exp Cell Res. 2006;312(19):3701–10.

  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.

    CAS  PubMed  Google Scholar 

  78. Bao S, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.

    Article  CAS  PubMed  Google Scholar 

  79. Su L-K, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science. 1993;262(5140):1734–7.

    Article  CAS  PubMed  Google Scholar 

  80. Harada N, et al. Hepatocarcinogenesis in mice with beta-catenin and ha-Ras gene mutations. Cancer Res. 2004;64(1):48–54.

    Article  CAS  PubMed  Google Scholar 

  81. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87(2):159–70.

    Article  CAS  PubMed  Google Scholar 

  82. Network CGA. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  84. Qiang YW, et al. Wnts induce migration and invasion of myeloma plasma cells. Blood. 2005;106(5):1786–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Blanc E, et al. Low expression of Wnt-5a gene is associated with high-risk neuroblastoma. Oncogene. 2005;24(7):1277–83.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  88. Kremenevskaja N, et al. Wnt-5a has tumor suppressor activity in thyroid carcinoma. Oncogene. 2005;24(13):2144–54.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  91. Da Forno PD, et al. WNT5A expression increases during melanoma progression and correlates with outcome. Clin Cancer Res. 2008;14(18):5825–32.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  97. Wang Q, et al. Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer. Oncogene. 2007;26(45):6560–5.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  104. Cardona GM, et al. Identification of R-Spondin fusions in various types of human cancer. Cancer Res. 2014;74(19 Supplement):2408.

  105. Madan B, Virshup DM. Targeting Wnts at the source--new mechanisms, new biomarkers, new drugs. Mol Cancer Ther. 2015;14(5):1087–94.

    Article  CAS  PubMed  Google Scholar 

  106. Suzuki H, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet. 2004;36(4):417–22.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  111. Li S, et al. Dickkopf-1 is involved in invasive growth of esophageal cancer cells. J Mol Histol. 2011;42(6):491–8.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  113. Sato N, et al. Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer Res. 2010;70(13):5326–36.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  117. Nguyen DX, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell. 2009;138(1):51–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Easwaran V, et al. Beta-catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res. 2003;63(12):3145–53.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  122. Reya T, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423(6938):409–14.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  129. Ng O, et al. Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia. Blood Cancer J. 2014;4(3):e192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Walker MP, et al. FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B-cell lymphoma. Sci Signal. 2015;8(362):ra12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov. 2006;5(12):997–1014.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  140. Soprano DR, Qin P, Soprano KJ. Retinoic acid receptors and cancers. Annu Rev Nutr. 2004;24:201–21.

    Article  CAS  PubMed  Google Scholar 

  141. Easwaran V, et al. Cross-regulation of beta-catenin-LEF/TCF and retinoid signaling pathways. Curr Biol. 1999;9(23):1415–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5(6):493–506.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  147. Badger TM, et al. Soy protein isolate and protection against cancer. J Am Coll Nutr. 2005;24(2):146S–9S.

  148. Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr. 1995;125(3):777S–83S.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  151. Chen M, et al. The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry. 2009;48(43):10267–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Daneshmanesh A, et al. Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells. Leukemia. 2012;26(6):1348–55.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

  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.

  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.

  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.

    Article  CAS  Google Scholar 

  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.

  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.

  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.

  166. Nagayama S, et al. Therapeutic potential of antibodies against FZD10, a cell-surface protein, for synovial sarcomas. Oncogene. 2005;24(41):6201–12.

    Article  CAS  PubMed  Google Scholar 

  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.

  168. Pinzone JJ, et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood. 2009;113(3):517–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

  174. Fulciniti M, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood. 2009;114(2):371–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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. Raje N, Roodman GD. Advances in the biology and treatment of bone disease in multiple myeloma. Clin Cancer Res. 2011;17(6):1278–86.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

  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.

  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.

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  197. Lee M, et al. Use of WNT inhibitors to augment therapeutic index of chemotherapy. Google Patents; 2010.

  198. Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19(2):179–92.

    Article  CAS  PubMed  Google Scholar 

  199. Laine CM, et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med. 2013;368(19):1809–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA

    Roya Tabatabai, Yuliya Linhares, David Bolos, Monica Mita & Alain Mita

Authors
  1. Roya Tabatabai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuliya Linhares
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Bolos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Monica Mita
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alain Mita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roya Tabatabai.

Ethics declarations

Funding

None.

Conflict of Interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tabatabai, R., Linhares, Y., Bolos, D. et al. Targeting the Wnt Pathway in Cancer: A Review of Novel Therapeutics. Targ Oncol 12, 623–641 (2017). https://doi.org/10.1007/s11523-017-0507-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-017-0507-4

Search

Navigation