The Canonical Wnt/β-catenin Pathway as a Therapeutic Target in Multiple Myeloma
Main Article Content
Abstract
It has been more than 30 years since Nusse and Varmus identified a new mouse proto-oncogene int1 (integration 1), conserved across multiple species, and already recognised in Drosophila as Wingless (Wg). Wnts are now known to activate multiple signalling pathways, the best understood and extensively investigated being the canonical/β-catenin dependent pathway. β-catenin signalling has been found dysregulated to varying degrees and via multiple mechanisms in both solid and haematologic cancers, including multiple myeloma (MM). Recently developed inhibitors of the Wnt canonical pathway have proven to be potentially effective against MM, with minimal side effects. There is cautious optimism that some of these inhibitors will be added in our armamentarium against MM in the not so distant future. In this review, we discuss the possible mechanisms of Wnt-canonical pathway dysregulation in the pathogenesis of MM. Furthermore, we summarise the pathway inhibitors that have been validated in the disease in pre-clinical models or clinical trials and their potential challenges.
Article Details
How to Cite
SAVVIDOU, Ioanna et al.
The Canonical Wnt/β-catenin Pathway as a Therapeutic Target in Multiple Myeloma.
Medical Research Archives, [S.l.], v. 6, n. 7, july 2018.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1821>. Date accessed: 17 apr. 2024.
doi: https://doi.org/10.18103/mra.v6i7.1821.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Palumbo A., Anderson K. Multiple Myeloma. N Engl J Med 2011;364: 1046-60.
2. Mitsiades C, Davies F, Laubach J, Joshua D, San Miguel J, Anderson K et al. Future directions of next genera-tion novel therapies, combination ap-proaches, and the development of per-sonalized medicine in myeloma. J Clin Oncol 2011;29: 1916-1923.
3. Pandey MK, Amin SG, Zangari M, Talamo G. Drug resistance in multiple myeloma: how to cross the border. Annals of Hematology & Oncology 2015; 2 (2):id1025.
4. Luis TC, Ichii M, Brugman MH, Kin-cade P, Staal FJT. Wnt signalling strength regulates normal hematopoi-esis and its deregulation is involved in leukaemia development. Leukemia 2012; 26 (3):414-21.
5. Anastas JN, Moon RT. WNT signal-ling pathways as therapeutic targets in cancer. Nature Reviews Cancer 2013; 13: 11-26.
6. Mikesch J-H, Steffen B, Berdel WE, Serve H, Müller-Tidow C. The emerg-ing role of Wnt signaling in the patho-genesis of acute myeloid leukemia. Leukemia 2007; 21: 1638–1647.
7. Coluccia AML, Vacca A, Dunach M, Mologni L, Redaelli S, Bustos VH et al. Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J 2007; 26(5): 1456–1466.
8. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM et al. Activa-tion of the Wnt signaling pathway in chronic lymphocytic leukemia. PNAS 2004; 101 (9): 3118–3123.
9. Derksen PW, Tjin E, Meijer HP, Klok MD, MacGillavry HD, van Oers MH et al. Illegitimate WNT signaling pro-motes proliferation of multiple mye-loma cells. PNAS 2004;101(16): 6122-7.
10. MacDonald BT, Tamai K, Xi He. Wnt /β-catenin signalling: components, mechanisms, and diseases. Develop-mental Cell 2009; 7: 9-26.
11. Katoh M, Katoh M. Wnt signalling pathway and stem cell signalling net-work. Clin Cancer Res 2007; 13 (14): 4042-45.
12. Moon RT, Kohn AD, De Ferrari GV, Kaykas A. Wnt and β-catenin signal-ling: diseases and therapies. Nature Reviews. 2004; 5: 689-699.
13. Staal FJT, Fodde R. Wnt signalling in adult stem-cells:tissue homeostasis and regeneration. Wnt signalling in development and disease: molecular mechanisms and biological functions. 2014; Chapter 25:329-37.
14. Luis TC, Naber BA, Roozen PP, Brugman MH, de Haas EF, Ghazvini M. Canonical Wnt signalling regulates hematopoiesis in a dosage-dependent fashion. Cell Stem Cell 2011; 9 (4):345-56.
15. Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M, Dimopoulos MA. Pathogenesis of bone disease in multi-ple myeloma: from bench to bedside. Blood cancer Journal. 2018; 8:7.
16. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001; 107(4):513-523.
17. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70(1):11-19.
18. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346(20):1513-1521.
19. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapou-los SE, Löwik CW et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005; 19(13):1842-1844.
20. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68(3):577-589.
21. Baron R, Kneissel M. WNT signalling in bone homeostasis and disease: from human mutations to treatments. Nature Medicine 2013; 19 (2):179-192.
22. Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mes-enchymal progenitors controls os-teoblast and chondrocyte differentia-tion during vertebrate skeletogenesis. Dev Cell. 2005;8(5):739-750.
23. Glass DA , Bialek P, Ahn JD, Star-buck M, Patel MS, Clevers H et al. Canonical Wnt signaling in differenti-ated osteoblasts controls osteoclast differentiation. Dev Cell. 2005;8(5):751-764.
24. Wei W, Zeve D, Suh J M, Wang X, Du Y, Zerwekh JE. Biphasic and Dos-age-Dependent Regulation of Osteo-clastogenesis by β-Catenin. Mol Cell Biol. 2011;31: 4706–4719.
25. Savvidou I, Khong T, Spencer A.
26. Sukhdeo K, Mani M, Zhang Y, Dutta J, Yasui H, Rooney MD, Carrasco DE, Zheng M, He H, Tai Y-T, Mitsiades C, Anderson KC, Carrasco DR. Tar-geting the β-catenin/TCF transcrip-tional complex in the treatment of multiple myeloma. PNAS 2007; 104 (18): 7516-21.
27. Kocemba KA, Groen RWJ, van An-del H, Kersten MJ, Mahtouk K, Spaargaren M, Pals ST. Transcrip-tional silencing of Wnt-antagonist DKK1 by promoter methylation is as-sociated with enhanced Wnt signalling in advanced multiple myeloma. PLoS ONE 2012; 7 (2):e30359.
28. Chim CS, Pang R, Fung TK, Choi CL, Liang R. Epigenetic dysregulation of Wnt signalling pathway in multiple myeloma. Leukemia 2007;21:2527-36.
29. Van Andel H, Ren Z, Koopmans I, Joosten SPJ, Kocemba KA, de Lau W, Kersten MJ, de Bruin AM, Guikema JEJ, Clevers H, Spaargaren M, Pals ST. Aberrantly expressed LGR4 em-powers Wnt signalling in multiple myeloma by hijacking osteoblast-derived R-spondins. PNAS 2017; 114(2):376-381.
30. Grumolato L, Liu G, Mong P, Mudbhary R, Biswas R, Arroyave R, Vijayakumar S, Economides AN, Aar-son SA. Canonical and noncanonical Wnts use a common mechanism to ac-tivate completely unrelated corecep-tors. Genes & Development 2010; 24: 2517-30.
31. Tung EK-K, Wong BY-C, Yau T-O, Ng IO-L. Upregulation of the Wnt co-receptor LRP6 promotes hepatocar-cinogenesis and enhances cell inva-sion. PLoS ONE 2012; 7(5):e36565.
32. Liua C-C, Priorb J, Piwnica-Wormsb D, Bua G. LRP6 overexpression de-fines a class of breast cancer subtype and is a target for therapy . PNAS 2010; 107 (11): 5136–41.
33. Qiang Y-W, Endo Y, Rubin JS, Rudikoff S. Wnt signalling in B-cell neoplasia. Oncogene 2003;22:1536-45.
34. Cruciat C-M, Niehrs C. Secreted and transmembrane Wnt inhibitors and ac-tivators. Cold Spring Harb Perspect Biol 2013;5:a015081.
35. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD. The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma. N Engl J Med. 2003;349:2483-2494.
36. Kaiser M, Mieth M, Liebisch P, Ober-lander R, Rademacher J, Jakob C, Kleeberg L, Fleissner C, Braendle, E, Peters M, Stover D, Sezer O, Heider U. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. European J Haematol. 2008;80(6): 490-494.
37. Politou MC, Heath DJ, Rahemtulla A, Szydlo R, Anagnostopoulos A, Di-mopoulos MA, Croucher PI, Terpos E. Serum concentrations of Dickkopf‐1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation. Int J Cancer 2006; 119: 1728-1731.
38. Terpos E, Heath DJ, Rahemtulla A, Zervas K, Chantry A, Anagnostopou-los A et al. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concen-trations and normalises indices of bone remodelling in patients with re-lapsed multiple myeloma. Br J Haematol. 2006;135(5):688-692.
39. Heider U, Kaiser M, Mieth M, Lamot-tke B, Rademacher J, Jakob C et al. Serum concentrations of DKK-1 de-crease in patients with multiple mye-loma responding to anti-myeloma treatment.Eur J Haematol. 2009 Jan;82(1):31-38.
40. Serman L, Matric TN, Serman A, Vranic S. Epigenetic alterations of the Wnt signalling pathway in cancer: a mini review. Bosn J Basic Med Sci. 2014; 14(4): 191-94.
41. Veeck J, Niederacher D, An H, Klopocki E, Wiesmann F, Betz B, et al. Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable progno-sis. Oncogene 2006; 25: 3479-88.
42. Suzuki H, Watkins DN, Jair KW Schuebel KE, Markowitz SD, Chen WD, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signalling in colorectal cancer. Nat Genet 2004; 36: 417-22.
43. Batra S, Shi Y, Kuchenbecker KM, He B, Reguart N, Mikami I, et al. Wnt inhibitory factor-1, a Wnt antagonist, is silenced by promoter hypermethyla-tion in malignant pleural meso-thelioma. Biochem Biophys Res Commun 2006; 342:1228-32.
44. Yu J, Tao Q, Cheng YY, Lee KY Ng SS, Cheung KF, et al. Promoter me-thylation of the Wnt/beta-catenin sig-nalling antagonist Dkk-3 is associated with poor survival in gastric cancer. Cancer 2009;115:49-60.
45. Sato N, Fukushima N, Maitra A, Ma-tsubayashi H, Yeo CJ, Cameron JL, et al. Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res 2003;63:3735-3742.
46. Griffiths EA, Gore SD, Hooker C, McDevitt MA, Karp JE, Smith BD, Mohammad HP, Ye Y, Herman JG, Carraway HE. Acute myeloid leuke-mia is characterized by Wnt pathway inhibitor promoter hypermethylation. Leuk Lymphoma 2010;51 (9):1711-19.
47. Román-Gómez J, Cordeu L, Agirre X, Jiménez -Velasco A, San José-Eneriz E, Garate L, Calasanz MJ, Heiniger A, Torres A, Prosper F. Epigenetic regu-lation of Wnt-signalling pathway in acute lymphoblastic leukemia. Blood 2007; 109:3462-69.
48. Chim CS, Pang R, Liang R. Epige-netic dysregulation of the Wnt signal-ling pathway in chronic lymphocytic leukemia (CLL). J Clin Pathol 2008; 61:1214-19.
49. Hall CL, Daignault SD, Shah RB, Pi-enta KJ, Keller ET. Dickkopf-1 ex-pression increases early in prostate cancer development and decreases during progression from primary tu-mor to metastasis. Prostate. 2008; 68:1396-13404.
50. Terpos E, Christoulas D, Katodritou E, Bratengeier C, Gkotzamanidou M, Michalis E et al.
Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symp-tomatic myeloma: reduction post-bortezomib monotherapy. Int J Can-cer. 2012;131(6):1466-1471.
51. Eda H, Santo L, Wein ML, Hu DZ, Cirstea DD, Nemani N.Regulation of sclerostin expression in multiple mye-loma by Dkk-1; a potential therapeutic strategy for myeloma bone disease. J Bone Miner Res. 2016; 31(6): 1225–1234.
52. Cejka D, Marculescu R, Kozakowski N, Plischke M, Reiter T, Gessl A et al. Renal elimination of sclerostin in-creases with declining kidney func-tion. J Clin Endocrinol Metab. 2014; 99 (1): 248-255.
53. Huang H-J, Zhou L-L, Fu W-J, Zhang C-Y, Jiang H, Du J, Hou J. β-catenin SUMOylataion in the dysregulated proliferation of myeloma cells. Am J Cancer Res 2015; 5 (1):309-20.
54. Yao H, Ashihara E, Maekawa T. Tar-geting the Wnt/β-catenin signaling pathway in human cancers. Expert Opin Ther Targets. 2011 Jul;15(7):873-87.
55. Chen W, Chen M, Barak LS. Devel-opment of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach. American Journal of Physiology - Gastrointestinal and Liver Physiology 2010;299 (2): 293-300.
56. Ashihara E, Takada T, Maekawa T. targeting the canonical Wnt/β-catenin pathway in haematological malignan-cies. Cancer Sci. 2015; 106 (6): 665-671.
57. Lepourcelet M, Chen YN, France DS, Wang H, Crews P, Petersen F et al. Small-molecule antagonists of the on-cogenic Tcf/beta-catenin protein com-plex. Cancer Cell. 2004; 5: 91–102.
58. Mink KS, Staib P, Puetter A, Gehrke I, Gandhirajan RK, Schlosser A et al. Small molecule inhibitors of Wnt sig-nalling effectively induce apoptosis in acute myeloid leukemia cells. Eur J Haematology. 2008; 82:165-175.
59. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, Moon RT, Teo J-L, Oh SW, Kim HY, Moon SH, Ha JR, Kahn M.. A small molecule in-hibitor of beta-catenin/CREB-binding protein transcription [corrected]. PNAS USA 2004; 101: 12682–87.
60. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009;461(7264):614-20.
61. Gang EJ, Hsieh Y-T, Pham J, Zhao Y, Nguyen C, Huantes S. Small molecule inhibition of CBP/catenin interactions eliminates drug resistant clones in acute lymphoblastic leukemia. Onco-gene. 2014; 33(17): 2169–2178.
62. Grigson ER, Ozerova M, Pisklakova A, Liu H, Sullivan DM, Nefedova Y. Canonical Wnt pathway inhibitor ICG-001 induces cytotoxicity of mul-tiple myeloma cells in Wnt-independent manner. PLoS ONE 2015; 10 (1):e0117693.
63. Andrew HK, Chiorean EG, Kwak EL, Lenz H-J, Nadler PI, Wood DL et al. Final results of 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. Journal of Clinical Oncology 2016 34:15_suppl, e15721-e15721.
64. Wu X, Luo F, Li J, Zhong X, Liu K. Tankyrase 1 inhibitior XAV939 in-creases chemosensitivity in colon can-cer cell lines via inhibition of the Wnt signalling pathway. International Journal of Oncology 2016;48(4):1333-1340.
65. Gonsalvez FC, Klein K, Carson BB, Katz S, Ekas LA, Evans S et al. An RNAi-based chemical genetic screen identifies three small-molecule inhibi-tors of the Wnt/wingless signaling pathway. . Proc Natl Acad Sci U S A. 2011; 108 (15): 5954-5963.
66. Narayanan BA, Doudican NA, Park J, Xu D, Narayanan NK, Dasgupta R et al. Antagonistic Effect of Small Mole-cule Inhibitors of Wnt/β-catenin in Multiple Myeloma. Anticancer Res. 2012 Nov; 32(11): 4697–4707.
67. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T et al. Targeting Wnt-driven cancer through the inhibition of Por-cupine by LGK974. Proc Natl Acad Sci U S A. 2013;110(50):20224-20229.
68. Richards MH, Seaton MS, Wallace J, Al-Harthi L. Porcupine Is Not Re-quired for the Production of the Ma-jority of Wnts from Primary Human Astrocytes and CD8+ T Cells. PLoS ONE. 2014; 9(3): e92159.
69. Yoon S-S, Min C-K, Kim JS, Mana-sanch EE, Hauptschein R, Choi J et al. Ongoing Phase 1a/1b Dose-Finding Study of CWP232291 (CWP291) in Relapsed or Refractory Multiple Mye-loma (MM). Blood 2016; 128:4501.
70. Frisone P, Pradella D, Di Matteo A, Belloni E, Ghigna C, and Paronetto MP. SAM68: Signal Transduction and RNA Metabolism in Human Cancer. BioMed Research International 2015: article ID 528954.
71. Bol D, Ebner R. Gene expression pro-filing in the discovery, optimization and development of novel drugs: one universal screening platform. Pharma-cogenomics. 2006; 7: 227–35.
72. Yao H, Ashihara E, Strovel JW, Na-kagawa Y, Kuroda J, Nagao R, et al.AV-65, a novel Wnt/beta-catenin signal inhibitor, successfully sup-presses progression of multiple mye-loma in a mouse model. Blood Cancer J 2011; 1: e43.
73. Fiskus W, Sharma S, Saha S, Shah B, Devaraj SGT, Sun B, Horrigan S, Leveque C, Zu Y, Iyer S, Bhalla KN. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone dacetylase inhibitor against AML cells. Leukemia 2015; 20: 1267-78.
74. Yoon H, Chan D, Huang Z‐Q, Li J, Fondell JD, Qin J, Wong J. Purifica-tion and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL 1 and TBLR1. EMBO J 2003; 22: 1336-446.
75. Li J, Wang C-Y. TBL1-TBLR1 and β-catenin recruit each other to Wnt tar-get-gene promoter for transcription activation and oncogenesis. Nature Cell Biology 2008; 10 (2): 160-69.
76. Donati G, Proserpio V, Lichtenberger BM, Natsuga K, Sinclair R, Fujiwara H. Epidermal Wnt/ β-catenin signal-ling regulates adipocyte differentiation via secretion of adipogenic factors. PNAS 2014 ;111 :E1501-E1509.
77. Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res. 2010; 25 (7): 1468-1486.
78. Lu B, Green BA, Farr JM, Lopes FCM, Van Raay TJ. Wnt drug discov-ery: weaving through the screens, pat-ents and clinical trials. Cancers. 2016; 8(9): 82.
79. Leucht P. Wnt Signalling: An Emerg-ing Target for Bone Regeneration. J Am Acad Orthop Surg 2015;23:67-8.
80. Munshi, NC, Abonour R, Beck JT, Bensinger W, Facon T, Stockerl-Goldstein K 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: 331.
2. Mitsiades C, Davies F, Laubach J, Joshua D, San Miguel J, Anderson K et al. Future directions of next genera-tion novel therapies, combination ap-proaches, and the development of per-sonalized medicine in myeloma. J Clin Oncol 2011;29: 1916-1923.
3. Pandey MK, Amin SG, Zangari M, Talamo G. Drug resistance in multiple myeloma: how to cross the border. Annals of Hematology & Oncology 2015; 2 (2):id1025.
4. Luis TC, Ichii M, Brugman MH, Kin-cade P, Staal FJT. Wnt signalling strength regulates normal hematopoi-esis and its deregulation is involved in leukaemia development. Leukemia 2012; 26 (3):414-21.
5. Anastas JN, Moon RT. WNT signal-ling pathways as therapeutic targets in cancer. Nature Reviews Cancer 2013; 13: 11-26.
6. Mikesch J-H, Steffen B, Berdel WE, Serve H, Müller-Tidow C. The emerg-ing role of Wnt signaling in the patho-genesis of acute myeloid leukemia. Leukemia 2007; 21: 1638–1647.
7. Coluccia AML, Vacca A, Dunach M, Mologni L, Redaelli S, Bustos VH et al. Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J 2007; 26(5): 1456–1466.
8. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM et al. Activa-tion of the Wnt signaling pathway in chronic lymphocytic leukemia. PNAS 2004; 101 (9): 3118–3123.
9. Derksen PW, Tjin E, Meijer HP, Klok MD, MacGillavry HD, van Oers MH et al. Illegitimate WNT signaling pro-motes proliferation of multiple mye-loma cells. PNAS 2004;101(16): 6122-7.
10. MacDonald BT, Tamai K, Xi He. Wnt /β-catenin signalling: components, mechanisms, and diseases. Develop-mental Cell 2009; 7: 9-26.
11. Katoh M, Katoh M. Wnt signalling pathway and stem cell signalling net-work. Clin Cancer Res 2007; 13 (14): 4042-45.
12. Moon RT, Kohn AD, De Ferrari GV, Kaykas A. Wnt and β-catenin signal-ling: diseases and therapies. Nature Reviews. 2004; 5: 689-699.
13. Staal FJT, Fodde R. Wnt signalling in adult stem-cells:tissue homeostasis and regeneration. Wnt signalling in development and disease: molecular mechanisms and biological functions. 2014; Chapter 25:329-37.
14. Luis TC, Naber BA, Roozen PP, Brugman MH, de Haas EF, Ghazvini M. Canonical Wnt signalling regulates hematopoiesis in a dosage-dependent fashion. Cell Stem Cell 2011; 9 (4):345-56.
15. Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M, Dimopoulos MA. Pathogenesis of bone disease in multi-ple myeloma: from bench to bedside. Blood cancer Journal. 2018; 8:7.
16. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001; 107(4):513-523.
17. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70(1):11-19.
18. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346(20):1513-1521.
19. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapou-los SE, Löwik CW et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 2005; 19(13):1842-1844.
20. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68(3):577-589.
21. Baron R, Kneissel M. WNT signalling in bone homeostasis and disease: from human mutations to treatments. Nature Medicine 2013; 19 (2):179-192.
22. Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mes-enchymal progenitors controls os-teoblast and chondrocyte differentia-tion during vertebrate skeletogenesis. Dev Cell. 2005;8(5):739-750.
23. Glass DA , Bialek P, Ahn JD, Star-buck M, Patel MS, Clevers H et al. Canonical Wnt signaling in differenti-ated osteoblasts controls osteoclast differentiation. Dev Cell. 2005;8(5):751-764.
24. Wei W, Zeve D, Suh J M, Wang X, Du Y, Zerwekh JE. Biphasic and Dos-age-Dependent Regulation of Osteo-clastogenesis by β-Catenin. Mol Cell Biol. 2011;31: 4706–4719.
25. Savvidou I, Khong T, Spencer A.
26. Sukhdeo K, Mani M, Zhang Y, Dutta J, Yasui H, Rooney MD, Carrasco DE, Zheng M, He H, Tai Y-T, Mitsiades C, Anderson KC, Carrasco DR. Tar-geting the β-catenin/TCF transcrip-tional complex in the treatment of multiple myeloma. PNAS 2007; 104 (18): 7516-21.
27. Kocemba KA, Groen RWJ, van An-del H, Kersten MJ, Mahtouk K, Spaargaren M, Pals ST. Transcrip-tional silencing of Wnt-antagonist DKK1 by promoter methylation is as-sociated with enhanced Wnt signalling in advanced multiple myeloma. PLoS ONE 2012; 7 (2):e30359.
28. Chim CS, Pang R, Fung TK, Choi CL, Liang R. Epigenetic dysregulation of Wnt signalling pathway in multiple myeloma. Leukemia 2007;21:2527-36.
29. Van Andel H, Ren Z, Koopmans I, Joosten SPJ, Kocemba KA, de Lau W, Kersten MJ, de Bruin AM, Guikema JEJ, Clevers H, Spaargaren M, Pals ST. Aberrantly expressed LGR4 em-powers Wnt signalling in multiple myeloma by hijacking osteoblast-derived R-spondins. PNAS 2017; 114(2):376-381.
30. Grumolato L, Liu G, Mong P, Mudbhary R, Biswas R, Arroyave R, Vijayakumar S, Economides AN, Aar-son SA. Canonical and noncanonical Wnts use a common mechanism to ac-tivate completely unrelated corecep-tors. Genes & Development 2010; 24: 2517-30.
31. Tung EK-K, Wong BY-C, Yau T-O, Ng IO-L. Upregulation of the Wnt co-receptor LRP6 promotes hepatocar-cinogenesis and enhances cell inva-sion. PLoS ONE 2012; 7(5):e36565.
32. Liua C-C, Priorb J, Piwnica-Wormsb D, Bua G. LRP6 overexpression de-fines a class of breast cancer subtype and is a target for therapy . PNAS 2010; 107 (11): 5136–41.
33. Qiang Y-W, Endo Y, Rubin JS, Rudikoff S. Wnt signalling in B-cell neoplasia. Oncogene 2003;22:1536-45.
34. Cruciat C-M, Niehrs C. Secreted and transmembrane Wnt inhibitors and ac-tivators. Cold Spring Harb Perspect Biol 2013;5:a015081.
35. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD. The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma. N Engl J Med. 2003;349:2483-2494.
36. Kaiser M, Mieth M, Liebisch P, Ober-lander R, Rademacher J, Jakob C, Kleeberg L, Fleissner C, Braendle, E, Peters M, Stover D, Sezer O, Heider U. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. European J Haematol. 2008;80(6): 490-494.
37. Politou MC, Heath DJ, Rahemtulla A, Szydlo R, Anagnostopoulos A, Di-mopoulos MA, Croucher PI, Terpos E. Serum concentrations of Dickkopf‐1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation. Int J Cancer 2006; 119: 1728-1731.
38. Terpos E, Heath DJ, Rahemtulla A, Zervas K, Chantry A, Anagnostopou-los A et al. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concen-trations and normalises indices of bone remodelling in patients with re-lapsed multiple myeloma. Br J Haematol. 2006;135(5):688-692.
39. Heider U, Kaiser M, Mieth M, Lamot-tke B, Rademacher J, Jakob C et al. Serum concentrations of DKK-1 de-crease in patients with multiple mye-loma responding to anti-myeloma treatment.Eur J Haematol. 2009 Jan;82(1):31-38.
40. Serman L, Matric TN, Serman A, Vranic S. Epigenetic alterations of the Wnt signalling pathway in cancer: a mini review. Bosn J Basic Med Sci. 2014; 14(4): 191-94.
41. Veeck J, Niederacher D, An H, Klopocki E, Wiesmann F, Betz B, et al. Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable progno-sis. Oncogene 2006; 25: 3479-88.
42. Suzuki H, Watkins DN, Jair KW Schuebel KE, Markowitz SD, Chen WD, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signalling in colorectal cancer. Nat Genet 2004; 36: 417-22.
43. Batra S, Shi Y, Kuchenbecker KM, He B, Reguart N, Mikami I, et al. Wnt inhibitory factor-1, a Wnt antagonist, is silenced by promoter hypermethyla-tion in malignant pleural meso-thelioma. Biochem Biophys Res Commun 2006; 342:1228-32.
44. Yu J, Tao Q, Cheng YY, Lee KY Ng SS, Cheung KF, et al. Promoter me-thylation of the Wnt/beta-catenin sig-nalling antagonist Dkk-3 is associated with poor survival in gastric cancer. Cancer 2009;115:49-60.
45. Sato N, Fukushima N, Maitra A, Ma-tsubayashi H, Yeo CJ, Cameron JL, et al. Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res 2003;63:3735-3742.
46. Griffiths EA, Gore SD, Hooker C, McDevitt MA, Karp JE, Smith BD, Mohammad HP, Ye Y, Herman JG, Carraway HE. Acute myeloid leuke-mia is characterized by Wnt pathway inhibitor promoter hypermethylation. Leuk Lymphoma 2010;51 (9):1711-19.
47. Román-Gómez J, Cordeu L, Agirre X, Jiménez -Velasco A, San José-Eneriz E, Garate L, Calasanz MJ, Heiniger A, Torres A, Prosper F. Epigenetic regu-lation of Wnt-signalling pathway in acute lymphoblastic leukemia. Blood 2007; 109:3462-69.
48. Chim CS, Pang R, Liang R. Epige-netic dysregulation of the Wnt signal-ling pathway in chronic lymphocytic leukemia (CLL). J Clin Pathol 2008; 61:1214-19.
49. Hall CL, Daignault SD, Shah RB, Pi-enta KJ, Keller ET. Dickkopf-1 ex-pression increases early in prostate cancer development and decreases during progression from primary tu-mor to metastasis. Prostate. 2008; 68:1396-13404.
50. Terpos E, Christoulas D, Katodritou E, Bratengeier C, Gkotzamanidou M, Michalis E et al.
Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symp-tomatic myeloma: reduction post-bortezomib monotherapy. Int J Can-cer. 2012;131(6):1466-1471.
51. Eda H, Santo L, Wein ML, Hu DZ, Cirstea DD, Nemani N.Regulation of sclerostin expression in multiple mye-loma by Dkk-1; a potential therapeutic strategy for myeloma bone disease. J Bone Miner Res. 2016; 31(6): 1225–1234.
52. Cejka D, Marculescu R, Kozakowski N, Plischke M, Reiter T, Gessl A et al. Renal elimination of sclerostin in-creases with declining kidney func-tion. J Clin Endocrinol Metab. 2014; 99 (1): 248-255.
53. Huang H-J, Zhou L-L, Fu W-J, Zhang C-Y, Jiang H, Du J, Hou J. β-catenin SUMOylataion in the dysregulated proliferation of myeloma cells. Am J Cancer Res 2015; 5 (1):309-20.
54. Yao H, Ashihara E, Maekawa T. Tar-geting the Wnt/β-catenin signaling pathway in human cancers. Expert Opin Ther Targets. 2011 Jul;15(7):873-87.
55. Chen W, Chen M, Barak LS. Devel-opment of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach. American Journal of Physiology - Gastrointestinal and Liver Physiology 2010;299 (2): 293-300.
56. Ashihara E, Takada T, Maekawa T. targeting the canonical Wnt/β-catenin pathway in haematological malignan-cies. Cancer Sci. 2015; 106 (6): 665-671.
57. Lepourcelet M, Chen YN, France DS, Wang H, Crews P, Petersen F et al. Small-molecule antagonists of the on-cogenic Tcf/beta-catenin protein com-plex. Cancer Cell. 2004; 5: 91–102.
58. Mink KS, Staib P, Puetter A, Gehrke I, Gandhirajan RK, Schlosser A et al. Small molecule inhibitors of Wnt sig-nalling effectively induce apoptosis in acute myeloid leukemia cells. Eur J Haematology. 2008; 82:165-175.
59. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, Moon RT, Teo J-L, Oh SW, Kim HY, Moon SH, Ha JR, Kahn M.. A small molecule in-hibitor of beta-catenin/CREB-binding protein transcription [corrected]. PNAS USA 2004; 101: 12682–87.
60. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009;461(7264):614-20.
61. Gang EJ, Hsieh Y-T, Pham J, Zhao Y, Nguyen C, Huantes S. Small molecule inhibition of CBP/catenin interactions eliminates drug resistant clones in acute lymphoblastic leukemia. Onco-gene. 2014; 33(17): 2169–2178.
62. Grigson ER, Ozerova M, Pisklakova A, Liu H, Sullivan DM, Nefedova Y. Canonical Wnt pathway inhibitor ICG-001 induces cytotoxicity of mul-tiple myeloma cells in Wnt-independent manner. PLoS ONE 2015; 10 (1):e0117693.
63. Andrew HK, Chiorean EG, Kwak EL, Lenz H-J, Nadler PI, Wood DL et al. Final results of 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. Journal of Clinical Oncology 2016 34:15_suppl, e15721-e15721.
64. Wu X, Luo F, Li J, Zhong X, Liu K. Tankyrase 1 inhibitior XAV939 in-creases chemosensitivity in colon can-cer cell lines via inhibition of the Wnt signalling pathway. International Journal of Oncology 2016;48(4):1333-1340.
65. Gonsalvez FC, Klein K, Carson BB, Katz S, Ekas LA, Evans S et al. An RNAi-based chemical genetic screen identifies three small-molecule inhibi-tors of the Wnt/wingless signaling pathway. . Proc Natl Acad Sci U S A. 2011; 108 (15): 5954-5963.
66. Narayanan BA, Doudican NA, Park J, Xu D, Narayanan NK, Dasgupta R et al. Antagonistic Effect of Small Mole-cule Inhibitors of Wnt/β-catenin in Multiple Myeloma. Anticancer Res. 2012 Nov; 32(11): 4697–4707.
67. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T et al. Targeting Wnt-driven cancer through the inhibition of Por-cupine by LGK974. Proc Natl Acad Sci U S A. 2013;110(50):20224-20229.
68. Richards MH, Seaton MS, Wallace J, Al-Harthi L. Porcupine Is Not Re-quired for the Production of the Ma-jority of Wnts from Primary Human Astrocytes and CD8+ T Cells. PLoS ONE. 2014; 9(3): e92159.
69. Yoon S-S, Min C-K, Kim JS, Mana-sanch EE, Hauptschein R, Choi J et al. Ongoing Phase 1a/1b Dose-Finding Study of CWP232291 (CWP291) in Relapsed or Refractory Multiple Mye-loma (MM). Blood 2016; 128:4501.
70. Frisone P, Pradella D, Di Matteo A, Belloni E, Ghigna C, and Paronetto MP. SAM68: Signal Transduction and RNA Metabolism in Human Cancer. BioMed Research International 2015: article ID 528954.
71. Bol D, Ebner R. Gene expression pro-filing in the discovery, optimization and development of novel drugs: one universal screening platform. Pharma-cogenomics. 2006; 7: 227–35.
72. Yao H, Ashihara E, Strovel JW, Na-kagawa Y, Kuroda J, Nagao R, et al.AV-65, a novel Wnt/beta-catenin signal inhibitor, successfully sup-presses progression of multiple mye-loma in a mouse model. Blood Cancer J 2011; 1: e43.
73. Fiskus W, Sharma S, Saha S, Shah B, Devaraj SGT, Sun B, Horrigan S, Leveque C, Zu Y, Iyer S, Bhalla KN. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone dacetylase inhibitor against AML cells. Leukemia 2015; 20: 1267-78.
74. Yoon H, Chan D, Huang Z‐Q, Li J, Fondell JD, Qin J, Wong J. Purifica-tion and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL 1 and TBLR1. EMBO J 2003; 22: 1336-446.
75. Li J, Wang C-Y. TBL1-TBLR1 and β-catenin recruit each other to Wnt tar-get-gene promoter for transcription activation and oncogenesis. Nature Cell Biology 2008; 10 (2): 160-69.
76. Donati G, Proserpio V, Lichtenberger BM, Natsuga K, Sinclair R, Fujiwara H. Epidermal Wnt/ β-catenin signal-ling regulates adipocyte differentiation via secretion of adipogenic factors. PNAS 2014 ;111 :E1501-E1509.
77. Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res. 2010; 25 (7): 1468-1486.
78. Lu B, Green BA, Farr JM, Lopes FCM, Van Raay TJ. Wnt drug discov-ery: weaving through the screens, pat-ents and clinical trials. Cancers. 2016; 8(9): 82.
79. Leucht P. Wnt Signalling: An Emerg-ing Target for Bone Regeneration. J Am Acad Orthop Surg 2015;23:67-8.
80. Munshi, NC, Abonour R, Beck JT, Bensinger W, Facon T, Stockerl-Goldstein K 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: 331.