Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

Nature Reviews Clinical Oncology volume 12, pages445–464(2015)Cite this article

Subjects

Key Points

  • Preclinical models provide evidence of cancer stem cells (CSCs) contributing to cancer proliferation, relapse and metastasis; this theory is being examined and validated in the clinical setting, currently in advanced malignancies

  • Over the past few years, new investigational agents have been developed to block the Notch, Hedgehog (HH) or Wnt signalling pathways for targeting CSCs

  • To date, robust antitumour activity has not been observed by targeting CSCs using Notch, HH or Wnt inhibitors, either as single agents or in combination with standard chemotherapy, in clinical trials

  • Combination approaches to overcome the crosstalk among Notch, HH and Wnt pathways, as well as other signalling pathways, has been examined mostly in preclinical models, with promising results

  • The success of the combination therapy in clinical trials might depend on CSC–tumour microenvironment interactions, perhaps in the context of the genotypes and phenotypes of the bulk tumour, CSCs, and the tumour microenvironment

  • A number of clinical trials have incorporated surrogate CSC assays to measure the effects of an investigational agent on CSCs, but further technological improvements in assays are needed

Abstract

During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

Figure 1: The canonical Notch signalling pathway and relevant pharmacological inhibitors under development in cancer.
Figure 2: The canonical HH-signalling pathway and pharmacological inhibitors targeting this pathway that are under ongoing development as anticancer therapies.
Figure 3: The canonical Wnt signalling pathway and pharmacological inhibitors under investigation in cancer.

References

  1. 1

    Vermeulen, L., Sprick, M. R., Kemper, K., Stassi, G. & Medema, J. P. Cancer stem cells—old concepts, new insights. Cell Death Differ. 15, 947–958 (2008).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Espinoza, I. & Miele, L. Deadly crosstalk: notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett. 341, 41–45 (2013).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Krivtsov, A. V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9. Nature 442, 818–822 (2006).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Pattabiraman, D. R. & Weinberg, R. A. Tackling the cancer stem cells—what challenges do they pose? Nat. Rev. Drug Discov. 13, 497–512 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

    Tirino, V. et al. Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization. FASEB J. 27, 13–24 (2013).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Lehmann, C., Jobs, G., Thomas, M., Burtscher, H. & Kubbies, M. Established breast cancer stem cell markers do not correlate with in vivo tumorigenicity of tumor-initiating cells. Int. J. Oncol. 41, 1932–1942 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Karsten, U. & Goletz, S. What makes cancer stem cell markers different? Springerplus 2, 301 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9

    Sachs, N. & Clevers, H. Organoid cultures for the analysis of cancer phenotypes. Curr. Opin. Genet. Dev. 24, 68–73 (2014).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522–526 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Driessens, G., Beck, B., Caauwe, A., Simons, B. D. & Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 488, 527–530 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Schepers, A. G. et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337, 730–735 (2012).

    CAS  Article  Google Scholar 

  13. 13

    Hoey, T. et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5, 168–177 (2009).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Varnat, F., Siegl-Cachedenier, I., Malerba, M., Gervaz, P. & Ruiz i Altaba, A. Loss of WNT–TCF addiction and enhancement of HH–GLI1 signalling define the metastatic transition of human colon carcinomas. EMBO Mol. Med. 2, 440–457 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    LaBarge, M. A. The difficulty of targeting cancer stem cell niches. Clin. Cancer Res. 16, 3121–3129 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Merchant, A. A. & Matsui, W. Targeting Hedgehog—a cancer stem cell pathway. Clin. Cancer Res. 16, 3130–3140 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Takebe, N., Harris, P. J., Warren, R. Q. & Ivy, S. P. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat. Rev. Clin. Oncol. 8, 97–106 (2011).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Espinoza, I. & Miele, L. Notch inhibitors for cancer treatment. Pharmacol. Ther. 139, 95–110 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Gomez-del Arco, P. et al. Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis. Immunity 33, 685–698 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Murthy, A. et al. Notch activation by the metalloproteinase ADAM17 regulates myeloproliferation and atopic barrier immunity by suppressing epithelial cytokine synthesis. Immunity 36, 105–119 (2012).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Gu, J. W. et al. Notch signals in the endothelium and cancer “stem-like” cells: opportunities for cancer therapy. Vasc. Cell 4, 7 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Andersson, E. R. & Lendahl, U. Therapeutic modulation of Notch signalling—are we there yet? Nat. Rev. Drug Discov. 13, 357–378 (2014).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Perumalsamy, L. R., Marcel, N., Kulkarni, S., Radtke, F. & Sarin, A. Distinct spatial and molecular features of notch pathway assembly in regulatory T cells. Sci. Signal. 5, ra53 (2012).

    PubMed  Article  CAS  Google Scholar 

  25. 25

    Perumalsamy, L. R., Nagala, M., Banerjee, P. & Sarin, A. A hierarchical cascade activated by non-canonical Notch signaling and the mTOR–Rictor complex regulates neglect-induced death in mammalian cells. Cell Death Differ. 16, 879–889 (2009).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Perumalsamy, L. R., Nagala, M. & Sarin, A. Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival. Proc. Natl Acad. Sci. USA 107, 6882–6887 (2010).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Raafat, A. et al. Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis. Oncogene 28, 219–230 (2009).

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Sade, H., Krishna, S. & Sarin, A. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. J. Biol. Chem. 279, 2937–2944 (2004).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Lee, K. S. et al. Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway. Genes Dev. 27, 2642–2647 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Takebe, N., Warren, R. Q. & Ivy, S. P. Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. Breast Cancer Res. 13, 211 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Deangelo, D. J. et al. A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias [abstract]. J. Clin. Oncol. 24 (Suppl.), a6585 (2006).

    Google Scholar 

  32. 32

    Pandya, K. et al. Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br. J. Cancer 105, 796–806 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Abel, E. V. et al. The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLoS ONE 9, e91983 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34

    Grudzien, P. et al. Inhibition of Notch signaling reduces the stem-like population of breast cancer cells and prevents mammosphere formation. Anticancer Res. 30, 3853–3867 (2010).

    CAS  PubMed  Google Scholar 

  35. 35

    Hassan, K. A. et al. Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clin. Cancer Res. 19, 1972–1980 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Saito, N. et al. A high Notch pathway activation predicts response to γ-secretase inhibitors in proneural subtype of glioma tumor-initiating cells. Stem Cells 32, 301–312 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Messersmith, W. A. et al. A phase I, dose-finding study in patients with advanced solid malignancies of the oral γ-secretase inhibitor PF-03084014. Clin. Cancer Res. 21, 60–67 (2015).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Milano, J. et al. Modulation of Notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol. Sci. 82, 341–358 (2004).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Searfoss, G. H. et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor. J. Biol. Chem. 278, 46107–46116 (2003).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Wong, G. T. et al. Chronic treatment with the γ-secretase inhibitor LY-411575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem. 279, 12876–12882 (2004).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    van Es, J. H. et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Krop, I. et al. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J. Clin. Oncol. 30, 2307–2313 (2012).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Dumortier, A. et al. Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin. PLoS ONE 5, e9258 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44

    Roderick, J. E. et al. Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia. J. Exp. Med. 210, 1311–1329 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Real, P. J. & Ferrando, A. A. NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 23, 1374–1377 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46

    Yun, J. et al. Crosstalk between PKCα and Notch-4 in endocrine-resistant breast cancer cells. Oncogenesis 2, e60 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Means-Powell, J. et al. A phase Ib dose escalation trial of RO4929097 (a γ-secretase inhibitor) in combination with exemestane in patients with ER+ metastatic breast cancer [abstract P2-14-04]. Cancer Res. 72 (Suppl.), 280s (2012).

    Google Scholar 

  48. 48

    Albain, K. Combination of Notch inhibitor MK-0752 and endocrine therapy for early stage ERα breast cancer in a pre-surgical window study. Cancer Res. 70 (Suppl.), 113s–114s (2010).

    Google Scholar 

  49. 49

    Tolcher, A. W. et al. Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J. Clin. Oncol. 30, 2348–2353 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Harrison, H. et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. 70, 709–718 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Hellstrom, M. et al. DLL4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52

    Jimeno, A. et al. Phase I study of REGN421/SAR153192, a fully-human delta-like ligand 4 (DLL4) monoclonal antibody (mAb), in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 31 (Suppl.), a2502 (2013).

    Google Scholar 

  53. 53

    Yan, M. Therapeutic promise and challenges of targeting DLL4/NOTCH1. Vasc. Cell 3, 17 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Xie, M., He, C. S., He, Z. & Lin, Q. Clinical and prognostic implications of delta-like ligand 4 and hypoxia-inducible factors in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib as first-line therapy [abstract]. J. Clin. Oncol. 31 (Suppl.), e15567 (2013).

    Google Scholar 

  55. 55

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  56. 56

    Sahebjam, S. et al. A phase I study of the combination of RO4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503). Br. J. Cancer 109, 943–949 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Sagert, J. et al. Tumor-specific inhibition of Jagged-dependent Notch signaling using a Probody™ therapeutic [abstract]. Mol. Cancer Ther. 12 (Suppl. 11), C158 (2013).

    Google Scholar 

  58. 58

    Mohammed, T. A. et al. A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma. Oncologist 16, 835–843 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Rajguru, S. et al. A phase II study of the histone deacetylase inhibitor panobinostat (LBH589) in low-grade neuroendocrine tumors [abstract]. J. Clin. Oncol. 30 (Suppl.), e14554 (2012).

    Google Scholar 

  60. 60

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  61. 61

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  62. 62

    Paryan, M. et al. Investigation of deregulated genes of Notch signaling pathway in human T cell acute lymphoblastic leukemia cell lines and clinical samples. Mol. Biol. Rep. 40, 5531–5540 (2013).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Fogelstrand, L. et al. Prognostic implications of mutations in NOTCH1 and FBXW7 in childhood T-ALL treated according to the NOPHO ALL-1992 and ALL-2000 protocols. Pediatr. Blood Cancer 61, 424–430 (2014).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Wang, H. et al. NOTCH1–RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. Proc. Natl Acad. Sci. USA 111, 705–710 (2014).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Takebe, N., Nguyen, D. & Yang, S. X. Targeting Notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol. Ther. 141, 140–149 (2014).

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Andersen, P., Uosaki, H., Shenje, L. T. & Kwon, C. Non-canonical Notch signaling: emerging role and mechanism. Trends Cell Biol. 22, 257–265 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67

    Stoeck, A. et al. Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma. Cancer Discov. 4, 1154–1167 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68

    Nguyen, D. et al. Notch1 phenotype and clinical stage progression in non-small cell lung cancer. J. Hematol. Oncol. 8, 9 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  70. 70

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  71. 71

    Rota, L. M., Lazzarino, D. A., Ziegler, A. N., LeRoith, D. & Wood, T. L. Determining mammosphere-forming potential: application of the limiting dilution analysis. J. Mammary Gland Biol. Neoplasia 17, 119–123 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Espinoza, I., Pochampally, R., Xing, F., Watabe, K. & Miele, L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther. 6, 1249–1259 (2013).

    PubMed  PubMed Central  Google Scholar 

  73. 73

    Fernandez-Majada, V. et al. Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer. Proc. Natl Acad. Sci. USA 104, 276–281 (2007).

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Fre, S. et al. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc. Natl Acad. Sci. USA 106, 6309–6314 (2009).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Kode, A. et al. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506, 240–244 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Sjolund, J. et al. The Notch and TGF-β signaling pathways contribute to the aggressiveness of clear cell renal cell carcinoma. PLoS ONE 6, e23057 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77

    Izrailit, J., Berman, H. K., Datti, A., Wrana, J. L. & Reedijk, M. High throughput kinase inhibitor screens reveal TRB3 and MAPK–ERK/TGFβ pathways as fundamental Notch regulators in breast cancer. Proc. Natl Acad. Sci. USA 110, 1714–1719 (2013).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Albain, K. et al. Modulation of cancer stem cell biomarkers by the Notch inhibitor MK0752 added to endocrine therapy for early stage ER+ breast cancer [abstract S1-5]. Cancer Res. 71 (Suppl.), (2011).

  79. 79

    Osipo, C. et al. ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a γ-secretase inhibitor. Oncogene 27, 5019–5032 (2008).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Zhang, C. C. et al. Synergistic effect of the γ-secretase inhibitor PF-03084014 and docetaxel in breast cancer models. Stem Cells Transl. Med. 2, 233–242 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Zhang, S., Chung, W. C., Miele, L. & Xu, K. Targeting Met and Notch in the Lfng-deficient, Met-amplified triple-negative breast cancer. Cancer Biol. Ther. 15, 633–642 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82

    Strosberg, J. R. et al. A phase II study of RO4929097 in metastatic colorectal cancer. Eur. J. Cancer 48, 997–1003 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83

    Beachy, P. A., Hymowitz, S. G., Lazarus, R. A., Leahy, D. J. & Siebold, C. Interactions between Hedgehog proteins and their binding partners come into view. Genes Dev. 24, 2001–2012 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84

    Odoux, C. et al. A stochastic model for cancer stem cell origin in metastatic colon cancer. Cancer Res. 68, 6932–6941 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85

    Amakye, D., Jagani, Z. & Dorsch, M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat. Med. 19, 1410–1422 (2013).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Ng, J. M. & Curran, T. The Hedgehog's tale: developing strategies for targeting cancer. Nat. Rev. Cancer 11, 493–501 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Kool, M. et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to Smoothened inhibition. Cancer Cell 25, 393–405 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88

    Johnson, R. L. et al. Human homolog of Patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Roma, J., Almazan-Moga, A., Sanchez de Toledo, J. & Gallego, S. Notch, Wnt, and Hedgehog pathways in rhabdomyosarcoma: from single pathways to an integrated network. Sarcoma 2012, 695603 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  90. 90

    Dennler, S. et al. Induction of Sonic hedgehog mediators by transforming growth factor-β: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 67, 6981–6986 (2007).

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Jagani, Z. et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog–Gli pathway. Nat. Med. 16, 1429–1433 (2010).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Ji, Z., Mei, F. C., Xie, J. & Cheng, X. Oncogenic KRAS activates Hedgehog signaling pathway in pancreatic cancer cells. J. Biol. Chem. 282, 14048–14055 (2007).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Riobo, N. A., Lu, K., Ai, X., Haines, G. M. & Emerson, C. P. Jr. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc. Natl Acad. Sci. USA 103, 4505–4510 (2006).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Wang, Y. et al. The crosstalk of mTOR/S6K1 and Hedgehog pathways. Cancer Cell 21, 374–87 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95

    Dirix, L. Discovery and exploitation of novel targets by approved drugs. J. Clin. Oncol. 32, 720–721 (2014).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Sekulic, A. et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med. 366, 2171–2179 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97

    Lewis, K. D. et al. Vismodegib in the treatment of patients with metastatic basal cell carcinoma (mBCC) and distant metastases: survival in the pivotal phase II and phase I studies [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a9012 (2014).

    Article  Google Scholar 

  98. 98

    Mortier, L. et al. A phase II study to assess vismodegib in the neoadjuvant treatment of locally advanced basal cell carcinoma (laBCC): the Vismodegib Neoadjuvant (VISMONEO) study [abstract]. J. Clin. Oncol. 32 (5s Suppl.), TPS9014 (2014).

    Google Scholar 

  99. 99

    Sloan, A. E. et al. Targeting glioma-initiating cells in GBM: ABTC-0904, a randomized phase 0/II study targeting the Sonic Hedgehog-signaling pathway [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a2026 (2014).

    Article  Google Scholar 

  100. 100

    Belani, C. P. et al. Three-arm randomized phase II study of cisplatin and etoposide (CE) versus CE with either vismodegib (V) or cixutumumab (Cx) for patients with extensive stage-small cell lung cancer (ES-SCLC) (ECOG 1508) [abstract]. J. Clin. Oncol. 31 (Suppl.), a7508 (2013).

    Google Scholar 

  101. 101

    Catenacci, D. V. T. et al. Final analysis of a phase IB/randomized phase II study of gemcitabine (G.) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer (PC): a University of Chicago phase II consortium study [abstract]. J. Clin. Oncol. 31 (Suppl.), a4012 (2013).

    Google Scholar 

  102. 102

    Cohen, D. J. et al. Vismodegib (V), a Hedgehog (HH) pathway inhibitor, combined with FOLFOX for first-line therapy of patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: a New York Cancer Consortium led phase II randomized study [abstract]. J. Clin. Oncol. 31 (Suppl.), a4011 (2013).

    Google Scholar 

  103. 103

    De Jesus-Acosta, A. et al. A phase II study of vismodegib, a Hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA) [abstract]. J. Clin. Oncol. 32 (Suppl. 3), a257 (2014).

    Article  Google Scholar 

  104. 104

    Von Hoff, D. E. et al. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT) [abstract]. J. Clin. Oncol. 30 (Suppl. 34), LBA148 (2012).

    Google Scholar 

  105. 105

    Berlin, J. et al. A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin. Cancer Res. 19, 258–267 (2013).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Kaye, S. B. et al. A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission. Clin. Cancer Res. 18, 6509–6518 (2012).

    CAS  PubMed  Article  Google Scholar 

  107. 107

    Madden, J. I. Infinity Reports Update from Phase 2 Study of Saridegib Plus Gemcitabine in Patients with Metastatic Pancreatic Cancer. Infinity Pharmaceuticals [online], (2012).

    Google Scholar 

  108. 108

    Madden, J. I. Infinity Stops Phase 2 Trials of Saridegib in Chondrosarcoma and Myelofibrosis. FierceBiotech [online], (2012).

    Google Scholar 

  109. 109

    US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  110. 110

    Migden, M. R. et al. Randomized, double-blind study of sonidegib (LDE225) in patients (pts) with locally advanced (La) or metastatic (m) basal-cell carcinoma (BCC) [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a9009a (2014).

    Article  Google Scholar 

  111. 111

    Pietanza, M. C. et al. Phase I trial of the Hedgehog (Hh) inhibitor, LDE225, in combination with etoposide and cisplatin (EP) for initial treatment of extensive stage small cell lung cancer (ES-SCLC) [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a7602 (2014).

    Article  Google Scholar 

  112. 112

    Zahreddine, H. A. et al. The Sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature 511, 90–93 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113

    US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  114. 114

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  115. 115

    US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  116. 116

    Yauch, R. L. et al. A paracrine requirement for Hedgehog signalling in cancer. Nature 455, 406–410 (2008).

    CAS  PubMed  Article  Google Scholar 

  117. 117

    Ellison, D. W. et al. Medulloblastoma: clinicopathological correlates of, SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 121, 381–396 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118

    Shou, Y. et al. A five-gene Hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma. Clin. Cancer Res. 21, 585–593 (2015).

    CAS  PubMed  Article  Google Scholar 

  119. 119

    Von Hoff, D. D. et al. Inhibition of the Hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 361, 1164–1172 (2009).

    CAS  PubMed  Article  Google Scholar 

  120. 120

    Graham, R. A. et al. Pharmacokinetics of Hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. Clin. Cancer Res. 17, 2512–2520 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121

    Ramaswamy, B. et al. Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res. 72, 5048–5059 (2012).

    CAS  PubMed  Article  Google Scholar 

  122. 122

    Yauch, R. L. et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326, 572–574 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123

    Buonamici, S. et al. Interfering with resistance to Smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med. 2, 51ra70 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. 124

    Yoon, J. W. et al. Noncanonical regulation of the Hedgehog mediator GLI1 by c-MYC in Burkitt lymphoma. Mol. Cancer Res. 11, 604–615 (2013).

    CAS  PubMed  Article  Google Scholar 

  125. 125

    Hollingshead, M. G. Antitumor efficacy testing in rodents. J. Natl Cancer Inst. 100, 1500–1510 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126

    Brennan, D., Chen, X., Cheng, L., Mahoney, M. & Riobo, N. A. Noncanonical Hedgehog signaling. Vitam. Horm. 88, 55–72 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127

    Gruber Filbin, M. et al. Coordinate activation of SHH and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. Nat. Med. 19, 1518–1523 (2013).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  128. 128

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  129. 129

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  130. 130

    Kim, D. J. et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J. Clin. Oncol. 32, 745–751 (2014).

    CAS  PubMed  Article  Google Scholar 

  131. 131

    Kim, J. et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17, 388–399 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132

    Kim, J., Lee, J. J., Kim, J., Gardner, D. & Beachy, P. A. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc. Natl Acad. Sci. USA 107, 13432–13437 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133

    Kim, J. et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to Smoothened antagonists. Cancer Cell 23, 23–34 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134

    Chien, A. J., Conrad, W. H. & Moon, R. T. A Wnt survival guide: from flies to human disease. J. Invest. Dermatol. 129, 1614–1627 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135

    Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452 (2003).

    CAS  PubMed  Article  Google Scholar 

  136. 136

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

    CAS  PubMed  Article  Google Scholar 

  137. 137

    Nusse, R. Wnt signaling in disease and in development. Cell Res. 15, 28–32 (2005).

    CAS  PubMed  Article  Google Scholar 

  138. 138

    He, X., Semenov, M., Tamai, K. & Zeng, X. LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: arrows point the way. Development 131, 1663–1677 (2004).

    CAS  PubMed  Article  Google Scholar 

  139. 139

    Logan, C. Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).

    CAS  PubMed  Article  Google Scholar 

  140. 140

    Itasaki, N. et al. Wise, a context-dependent activator and inhibitor of Wnt signalling. Development 130, 4295–4305 (2003).

    CAS  PubMed  Article  Google Scholar 

  141. 141

    Gao, C. & Chen, Y. G. Dishevelled: the hub of Wnt signaling. Cell Signal. 22, 717–727 (2010).

    CAS  PubMed  Article  Google Scholar 

  142. 142

    Habas, R. & Dawid, I. B. Dishevelled and Wnt signaling: is the nucleus the final frontier? J. Biol. 4, 2 (2005).

    PubMed  PubMed Central  Article  Google Scholar 

  143. 143

    Behrens, J. Control of β-catenin signaling in tumor development. Ann. N. Y. Acad. Sci. 910, 21–33 (2000).

    CAS  PubMed  Article  Google Scholar 

  144. 144

    Arce, L., Yokoyama, N. N. & Waterman, M. L. Diversity of LEF/TCF action in development and disease. Oncogene 25, 7492–7504 (2006).

    CAS  PubMed  Article  Google Scholar 

  145. 145

    Nguyen, L. V., Vanner, R., Dirks, P. & Eaves, C. J. Cancer stem cells: an evolving concept. Nat. Rev. Cancer 12, 133–143 (2012).

    CAS  Article  Google Scholar 

  146. 146

    Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on β-catenin signalling. Nature 452, 650–653 (2008).

    CAS  PubMed  Article  Google Scholar 

  147. 147

    Vincan, E. & Barker, N. The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. Clin. Exp. Metastasis 25, 657–663 (2008).

    CAS  PubMed  Article  Google Scholar 

  148. 148

    Lee, H. J., Wang, N. X., Shi, D. L. & Zheng, J. J. Sulindac inhibits canonical Wnt signaling by blocking the PDZ domain of the protein Dishevelled. Angew. Chem. Int. Ed. Engl. 48, 6448–6452 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149

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

    CAS  PubMed  Article  Google Scholar 

  150. 150

    Smith, M. L., Hawcroft, G. & Hull, M. A. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur. J. Cancer 36, 664–674 (2000).

    CAS  PubMed  Article  Google Scholar 

  151. 151

    Yoshizumi, T. et al. Thiazolidinedione, a peroxisome proliferator-activated receptor-γ ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects. Int. J. Oncol. 25, 631–639 (2004).

    CAS  PubMed  Google Scholar 

  152. 152

    Huang, S. M. et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614–620 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153

    Waaler, J. et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res. 72, 2822–2832 (2012).

    CAS  PubMed  Article  Google Scholar 

  154. 154

    Waaler, J. et al. Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth. Cancer Res. 71, 197–205 (2011).

    CAS  PubMed  Article  Google Scholar 

  155. 155

    Fujii, N. et al. An antagonist of dishevelled protein–protein interaction suppresses β-catenin-dependent tumor cell growth. Cancer Res. 67, 573–579 (2007).

    CAS  PubMed  Article  Google Scholar 

  156. 156

    Grandy, D. et al. Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. J. Biol. Chem. 284, 16256–16263 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. 157

    Su, Y., Ishikawa, S., Kojima, M. & Liu, B. Eradication of pathogenic β-catenin by Skp1/Cullin/F box ubiquitination machinery. Proc. Natl Acad. Sci. USA 100, 12729–12734 (2003).

    CAS  PubMed  Article  Google Scholar 

  158. 158

    Yao, H. et al. AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model. Blood Cancer J. 1, e43 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159

    El-Khoueiry, A. B. et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 31 (Suppl.), a2501 (2013).

    Google Scholar 

  160. 160

    Ma, H., Nguyen, C., Lee, K. S. & Kahn, M. Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression. Oncogene 24, 3619–3631 (2005).

    CAS  PubMed  Article  Google Scholar 

  161. 161

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  162. 162

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  163. 163

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  164. 164

    US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  165. 165

    Li, X. et al. Prostate tumor progression is mediated by a paracrine TGF- β/Wnt3a signaling axis. Oncogene 27, 7118–7130 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. 166

    Kahn, M. Can we safely target the WNT pathway? Nat. Rev. Drug Discov. 13, 513–532 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167

    Smith, D. C. 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 [abstract]. J. Clin. Oncol. 31 (Suppl.), a2540 (2013).

    Google Scholar 

  168. 168

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  169. 169

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  170. 170

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  171. 171

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  172. 172

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  173. 173

    US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  174. 174

    US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  175. 175

    Smith, D. C. et al. A first-in-human phase I study of anti-cancer stem cell (CSC) agent OMP-54F28 (FZD8-Fc) targeting the Wnt pathway in patients with advanced solid tumors [abstract]. Mol. Cancer Ther. 12 (11 Suppl.), B79 (2013).

    Google Scholar 

  176. 176

    Jimeno, A. et al. A first-in-human phase I study of anticancer stem cell agent OMP-54F28 (FZD8-Fc), decoy receptor for Wnt ligands, in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 32 (5s Suppl.), a2505 (2014).

    Article  Google Scholar 

  177. 177

    Katoh, M. Networking of Wnt, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. Stem Cell Rev. 3, 30–38 (2007).

    CAS  PubMed  Article  Google Scholar 

  178. 178

    Kwon, C. et al. Notch post-translationally regulates β-catenin protein in stem and progenitor cells. Nat. Cell Biol. 13, 1244–1251 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179

    Rodilla, V. et al. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc. Natl Acad. Sci. USA 106, 6315–6320 (2009).

    CAS  PubMed  Article  Google Scholar 

  180. 180

    Arcaroli, J. J. et al. Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model. Br. J. Cancer 109, 667–675 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. 181

    Escobar, C., Munker, R., Thomas, J. O., Li, B. D. & Burton, G. V. Update on desmoid tumors. Ann. Oncol. 23, 562–569 (2012).

    CAS  PubMed  Article  Google Scholar 

  182. 182

    Messersmith, W. A. et al. First-in-patient phase I study of the novel gamma secretase inhibitor PF-03084014 in patients with advanced solid tumor malignancies [abstract 588]. Eur. J. Cancer 48 (Suppl. 6), 180 (2012).

    Article  Google Scholar 

  183. 183

    Carothers, A. M. et al. Mesenchymal stromal cell mutations and wound healing contribute to the etiology of desmoid tumors. Cancer Res. 72, 346–355 (2012).

    CAS  PubMed  Article  Google Scholar 

  184. 184

    Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369, 341–350 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185

    He, J. et al. Suppressing Wnt signaling by the Hedgehog pathway through sFRP-1. J. Biol. Chem. 281, 35598–35602 (2006).

    CAS  PubMed  Article  Google Scholar 

  186. 186

    Schneider, F. T. et al. Sonic hedgehog acts as a negative regulator of β-catenin signaling in the adult tongue epithelium. Am. J. Pathol. 177, 404–414 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  187. 187

    Rabadan, M. A. et al. Jagged2 controls the generation of motor neuron and oligodendrocyte progenitors in the ventral spinal cord. Cell Death Differ. 19, 209–219 (2012).

    CAS  PubMed  Article  Google Scholar 

  188. 188

    US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  189. 189

    Dakubo, G. D., Mazerolle, C. J. & Wallace, V. A. Expression of Notch and Wnt pathway components and activation of Notch signaling in medulloblastomas from heterozygous patched mice. J. Neurooncol. 79, 221–227 (2006).

    CAS  PubMed  Article  Google Scholar 

  190. 190

    Ingram, W. J., McCue, K. I., Tran, T. H., Hallahan, A. R. & Wainwright, B. J. Sonic hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling. Oncogene 27, 1489–1500 (2008).

    CAS  PubMed  Article  Google Scholar 

  191. 191

    Di Marcotullio, L. et al. Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Nat. Cell Biol. 8, 1415–1423 (2006).

    CAS  PubMed  Article  Google Scholar 

  192. 192

    Domingo-Domenech, J. et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of Notch- and Hedgehog-dependent tumor-initiating cells. Cancer Cell 22, 373–388 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. 193

    Cilloni, D. & Saglio, G. Molecular pathways: BCR–ABL. Clin. Cancer Res. 18, 930–937 (2012).

    CAS  PubMed  Article  Google Scholar 

  194. 194

    Chau, W. K., Ip, C. K., Mak, A. S., Lai, H. C. & Wong, A. S. c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/β-catenin-ATP-binding cassette G2 signaling. Oncogene 32, 2767–2781 (2013).

    CAS  PubMed  Article  Google Scholar 

  195. 195

    Espinosa, L., Ingles-Esteve, J., Aguilera, C. & Bigas, A. Phosphorylation by glycogen synthase kinase-3β down-regulates Notch activity, a link for Notch and Wnt pathways. J. Biol. Chem. 278, 32227–32235 (2003).

    CAS  PubMed  Article  Google Scholar 

  196. 196

    Saint Just Ribeiro, M., Hansson, M. L., Lindberg, M. J., Popko-Scibor, A. E. & Wallberg, A. E. GSK3β is a negative regulator of the transcriptional coactivator MAML1. Nucleic Acids Res. 37, 6691–6700 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197

    Foltz, D. R., Santiago, M. C., Berechid, B. E. & Nye, J. S. Glycogen synthase kinase-3β modulates Notch signaling and stability. Curr. Biol. 12, 1006–1011 (2002).

    CAS  PubMed  Article  Google Scholar 

  198. 198

    Rizzo, P. et al. Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res. 68, 5226–5235 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199

    Hao, L. et al. Notch-1 activates estrogen receptor-α-dependent transcription via IKKα in breast cancer cells. Oncogene 29, 201–213 (2010).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge Dr Richard Swerdlow of PSI INTERNATIONAL, Inc., Rockville, MD, USA, for his assistance in organizing the references and formatting the manuscript, and Melissa Maher at Technical Resources International, Inc., Bethesda, MD, USA, for drafting the Figures.

Author information

Affiliations

  1. Division of Cancer Treatment and Diagnosis, Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institute of Health, 9609 Medical Center Drive MSC9739, Bethesda, 20852, MD, USA

    Naoko Takebe, Pamela Jo Harris & S. Percy Ivy

  2. Stanley Scott Cancer Center, Louisiana State University Health Sciences Center and Louisiana Cancer Research Consortium, USA

    Lucio Miele

  3. Cancer Therapy and Research Center, University of Texas, USA

    Woondong Jeong

  4. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Japan

    Hideaki Bando

  5. Norris Comprehensive Cancer Research Center, University of Southern California, USA

    Michael Kahn

  6. Division of Cancer Treatment and Diagnosis, National Clinical Target Validation Laboratory, National Cancer Institute, USA

    Sherry X. Yang

Authors
  1. Naoko Takebe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucio Miele
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pamela Jo Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Woondong Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hideaki Bando
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Kahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sherry X. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. Percy Ivy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed substantially to researching the data for the article, discussions of content, writing the article, and review/editing of the manuscript before submission.

Corresponding authors

Correspondence to Naoko Takebe or S. Percy Ivy.

Ethics declarations

Competing interests

L.M. has participated in collaborative research on Notch inhibitors with CytoMX and Merck Oncology. M.K. is an equity holder in Prism Pharma. The other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Takebe, N., Miele, L., Harris, P. et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12, 445–464 (2015). https://doi.org/10.1038/nrclinonc.2015.61

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing