Anti-cancer stem-like cell compounds in clinical development - an overview and critical appraisal

Frontiers in Oncology

Volumn 6, Issue MAY, 2016, Pages

  Marcucci, Fabrizio ^a   Rumio, Cristiano ^a   Lefoulon, François ^b  

^a UNIVERSITY OF MILAN   (Italy)

^b INSTITUT DE RECHERCHES INTERNATIONALES SERVIER   (France)

Author keywords

Biomarkers; Cancer stem like cells; Classification; Clinical development; Epithelial mesenchymal transition; Therapy

Indexed keywords

ANTIBODY; ANTINEOPLASTIC AGENT; BIOLOGICAL MARKER; BRONTICTUZUMAB; CD33 ANTIGEN; CD47 ANTIGEN; CHEMOKINE RECEPTOR CXCR1; CHEMOKINE RECEPTOR CXCR1 ANTAGONIST; CHEMOKINE RECEPTOR CXCR4; CLUSTERIN ANTIBODY; DASATINIB; DEFACTINIB; DEMCIZUMAB; DIPEPTIDYL PEPTIDASE IV; FRIZZLED PROTEIN; GEMCITABINE; HERMES ANTIGEN; INTERLEUKIN 8; IPAFRICEPT; NOTCH RECEPTOR; ONCOLYTIC ADENOVIRUS; PATIDEGIB; REPARIXIN; ROVALPITUZUMAB TESIRINE; SONIC HEDGEHOG PROTEIN; TAREXTUMAB; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; VANTICTUMAB; VISMODEGIB; WNT PROTEIN;

ANTINEOPLASTIC ACTIVITY; BREAST CANCER; CANCER STEM CELL; CELL ADHESION; CELL DIFFERENTIATION; CELL PLASTICITY; CELL POLARITY; CLINICAL TRIAL (TOPIC); DRUG TARGETING; EPITHELIAL MESENCHYMAL TRANSITION; GENE EXPRESSION PROFILING; HUMAN; LUNG METASTASIS; LYMPHATIC LEUKEMIA; NONHUMAN; PATIENT SELECTION; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPE; REVIEW; TUMOR MICROENVIRONMENT; WNT SIGNALING PATHWAY;

EID: 84973572991     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2016.00115     Document Type: Review

References (217)

1. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature (2001) 414:105-11. doi: 10.1038/35102167
2. Ghisolfi L, Keates AC, Hu X, Lee DK, Li CJ. Ionizing radiation induces stemness in cancer cells. PLoS One (2012) 7:e43628. doi:10.1371/journal.pone.0043628
3. Hu X, Ghisolfi L, Keates AC, Zhang J, Xiang S, Lee DK, et al. Induction of cancer cell stemness by chemotherapy. Cell Cycle (2012) 11:2691-8. doi:10.4161/cc.21021
4. Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells-what challenges do they pose? Nat Rev Drug Discov (2014) 13:497-512. doi:10.1038/nrd4253
5. Sun S, Liu S, Duan SZ, Zhang L, Zhou H, Hu Y, et al. Targeting the c-Met/FZD8 signaling axis eliminates patient-derived cancer stem-like cells in head and neck squamous carcinomas. Cancer Res (2014) 74:7546-59. doi:10.1158/0008-5472.CAN-14-0826
6. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature (1994) 367:645-8. doi:10.1038/367645a0
7. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A (2003) 100:3983-8. doi:10.1073/pnas.0530291100
8. Bapat SA, Mali AM, Koppikar CB, Kurrey NK. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res (2005) 65:3025-9. doi:10.1158/0008-5472.CAN-04-3931
9. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res (2005) 65:10946-51. doi:10.1158/0008-5472.CAN-05-2018
10. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature (2007) 445:111-5. doi:10.1038/nature05384
11. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res (2003) 63:5821-8
12. Visvader JE. Cells of origin in cancer. Nature (2011) 469:314-22. doi:10.1038/nature09781
13. Martinez-Climent JA, Andreu EJ, Prosper F. Somatic stem cells and the origin of cancer. Clin Transl Oncol (2006) 8:647-63. doi:10.1007/s12094-006-0035-7
14. Vaz AP, Deb S, Rachagani S, Dey P, Muniyan S, Lakshmanan I, et al. Overexpression of PD2 leads to increased tumorigenicity and metastasis in pancreatic ductal adenocarcinoma. Oncotarget (2016) 7:3317-31. doi:10.18632/oncotarget.6580
15. Wang Y, Cardenas H, Fang F, Condello S, Taverna P, Segar M, et al. Epigenetic targeting of ovarian cancer stem cells. Cancer Res (2014) 74:4922-36. doi:10.1158/0008-5472.CAN-14-1022
16. Marcucci F, Bellone M, Caserta CA, Corti A. Pushing tumor cells towards a malignant phenotype: stimuli from the microenvironment, intercellular communications and alternative roads. Int J Cancer (2014) 135:1265-76. doi:10.1002/ijc.28572
17. Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest (2011) 121:3804-9. doi:10.1172/JCI57099
18. Lu T, Stark GR. Cytokine overexpression and constitutive NF-κB in cancer. Cell Cycle (2004) 3:1114-7. doi:10.4161/cc.3.9.1130
19. Catanzaro JM, Sheshadri N, Pan JA, Sun Y, Shi C, Li J, et al. Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4. Nat Commun (2014) 5:3729. doi:10.1038/ncomms4729
20. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer (2008) 8:755-68. doi:10.1038/nrc2499
21. Vermeulen L, de Sousae Melo F, Richel DJ, Medema JP. The developing cancer stem-cell model: clinical challenges and opportunities. Lancet Oncol (2012) 13:e83-9. doi:10.1016/S1470-2045(11)70257-1
22. Poleszczuk J, Hahnfeldt P, Enderling H. Evolution and phenotypic selection of cancer stem cells. PLoS Comput Biol (2015) 11:e1004025. doi:10.1371/journal.pcbi.1004025
23. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol (2015) 12:445-64. doi:10.1038/nrclinonc.2015.61
24. Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell (2008) 133:704-15. doi:10.1016/j.cell.2008.03.027
25. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, et al. EMT and dissemination precede pancreatic tumor formation. Cell (2012) 148:349-61. doi:10.1016/j.cell.2011.11.025
26. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell (2009) 139:871-90. doi:10.1016/j.cell.2009.11.007
27. Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest (2009) 119:1417-9. doi:10.1172/JCI39675
28. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer (2009) 9:265-73. doi:10.1038/nrc2620
29. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene (2010) 29:4741-51. doi:10.1038/onc.2010.215
30. Yen WC, Fischer MM, Axelrod F, Bond C, Cain J, Cancilla B, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res (2015) 21:2084-95. doi:10.1158/1078-0432.CCR-14-2808
31. Marcucci F, Stassi G, De Maria R. Epithelial-mesenchymal transition: a new target in anticancer drug discovery. Nat Rev Drug Discov (2016). doi:10.1038/nrd.2015.13
32. Frisch SM, Schaller M, Cieply B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J Cell Sci (2013) 126:21-9. doi:10.1242/jcs.120907
33. Ocaña OH, Córcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S, et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell (2012) 22:709-24. doi:10.1016/j.ccr.2012.10.012
34. Tan TZ, Miow QH, Miki Y, Noda T, Mori S, Huang RY, et al. Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med (2014) 6:1279-93. doi:10.15252/emmm.201404208
35. Kuo SZ, Blair KJ, Rahimy E, Kiang A, Abhold E, Fan JB, et al. Salinomycin induces cell death and differentiation in head and neck squamous cell carcinoma stem cells despite activation of epithelial-mesenchymal transition and Akt. BMC Cancer (2012) 12:556. doi:10.1186/1471-2407-12-556
36. Wiener Z, Högström J, Hyvönen V, Band AM, Kallio P, Holopainen T, et al. Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance. Cell Rep (2014) 8:1943-56. doi:10.1016/j.celrep.2014.08.034
37. Ojha R, Bhattacharyya S, Singh SK. Autophagy in cancer stem cells: a potential link between chemoresistance, recurrence, and metastasis. Biores Open Access (2015) 4:97-108. doi:10.1089/biores.2014.0035
38. Yang MC, Wang HC, Hou YC, Tung HL, Chiu TJ, Shan YS. Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine. Mol Cancer (2015) 14:179. doi:10.1186/s12943-015-0449-3
39. Papadaki MA, Kallergi G, Zafeiriou Z, Manouras L, Theodoropoulos PA, Mavroudis D, et al. Co-expression of putative stemness and epithelial-to-mesenchymal transition markers on single circulating tumour cells from patients with early and metastatic breast cancer. BMC Cancer (2014) 14:651. doi:10.1186/1471-2407-14-651
40. Diessner J, Bruttel V, Stein RG, Horn E, Häusler SF, Dietl J, et al. Targeting of preexisting and induced breast cancer stem cells with trastuzumab and trastuzumab emtansine (T-DM1). Cell Death Dis (2014) 5:e1149. doi:10.1038/cddis.2014.115
41. Herrmann H, Sadovnik I, Cerny-Reiterer S, Rülicke T, Stefanzl G, Willmann M, et al. Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood (2014) 123:3951-62. doi:10.1182/blood-2013-10-536078
42. Cioffi M, Trabulo S, Hidalgo M, Costello E, Greenhalf W, Erkan M, et al. Inhibition of CD47 effectively targets pancreatic cancer stem cells via dual mechanisms. Clin Cancer Res (2015) 21:2325-37. doi:10.1158/1078-0432.CCR-14-1399
43. Emlet DR, Gupta P, Holgado-Madruga M, Del Vecchio CA, Mitra SS, Han SY, et al. Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III. Cancer Res (2014) 74:1238-49. doi:10.1158/0008-5472.CAN-13-1407
44. Shiota M, Zardan A, Takeuchi A, Kumano M, Beraldi E, Naito S, et al. Clusterin mediates TGF-β-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer Res (2012) 72:5261-72. doi:10.1158/0008-5472.CAN-12-0254
45. Lenferink AE, Cantin C, Nantel A, Wang E, Durocher Y, Banville M, et al. Transcriptome profiling of a TGF-β-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies. Oncogene (2010) 29:831-44. doi:10.1038/onc.2009.399
46. Wang C, Jiang K, Kang X, Gao D, Sun C, Li Y, et al. Tumor-derived secretory clusterin induces epithelial-mesenchymal transition and facilitates hepatocellular carcinoma metastasis. Int J Biochem Cell Biol (2012) 44:2308-20. doi:10.1016/j.biocel.2012.09.012
47. Brandolini L, Cristiano L, Fidoamore A, De Pizzol M, Di Giacomo E, Florio TM, et al. Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling. Oncotarget (2015) 6:43375-94. doi:10.18632/oncotarget.6234
48. Zhang S, Cui B, Lai H, Liu G, Ghia EM, Widhopf GF II, et al. Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy. Proc Natl Acad Sci U S A (2014) 111:17266-71. doi:10.1073/pnas.1419599111
49. Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res (2009) 69:1302-13. doi:10.1158/0008-5472.CAN-08-2741
50. Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest (2010) 120:485-97. doi:10.1172/JCI39397
51. Cui B, Zhang S, Chen L, Yu J, Widhopf GF II, Fecteau J-F, et al. Targeting ROR1 inhibits epithelial-mesenchymal transition and metastasis. Cancer Res (2013) 73:3649-60. doi:10.1158/0008-5472.CAN-12-3832
52. Park SY, Kim MJ, Park SA, Kim JS, Min KN, Kim DK, et al. Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells. Oncotarget (2015) 6:37526-43. doi:10.18632/oncotarget.6063
53. Ohnuki H, Jiang K, Wang D, Salvucci O, Kwak H, Sánchez-Martín D, et al. Tumor-infiltrating myeloid cells activate Dll4/Notch/TGF-β signaling to drive malignant progression. Cancer Res (2014) 74:2038-49. doi:10.1158/0008-5472.CAN-13-3118
54. Asiedu MK, Ingle JN, Behrens MD, Radisky DC, Knutson KL. TGFβ/TNFa-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res (2011) 71:4707-19. doi:10.1158/0008-5472.CAN-10-4554
55. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell (2011) 145:926-40. doi:10.1016/j.cell.2011.04.029
56. Fan QM, Jing YY, Yu GF, Kou XR, Ye F, Gao L, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett (2014) 352:160-8. doi:10.1016/j.canlet.2014.05.008
57. Park CY, Min KN, Son JY, Park SY, Nam JS, Kim DK, et al. An novel inhibitor of TGF-β type I receptor, IN-1130, blocks breast cancer lung metastasis through inhibition of epithelial-mesenchymal transition. Cancer Lett (2014) 351:72-80. doi:10.1016/j.canlet.2014.05.006
58. Zhong Z, Driscoll Carroll K, Policarpio D, Osborn C, Gregory M, Bassi R, et al. Anti-transforming growth factor β receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells. Clin Cancer Res (2010) 16:1191-205. doi:10.1158/1078-0432.CCR-09-1634
59. Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, Naxerova K, et al. TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci U S A (2012) 109:16618-23. doi:10.1073/pnas.1117610109
60. Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One (2014) 9:e90353. doi:10.1371/journal.pone.0090353
61. Bhola NE, Balko JM, Dugger TC, Kuba MG, Sánchez V, Sanders M, et al. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest (2013) 123:1348-58. doi:10.1172/JCI65416
62. Akhurst RJ, Hata A. Targeting the TGF-β signalling pathway. Nat Rev Drug Discov (2012) 11:790-811. doi:10.1038/nrd3810
63. Anderton MJ, Mellor HR, Bell A, Sadler C, Pass M, Powell S, et al. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol Pathol (2011) 39:916-24. doi:10.1177/0192623311416259
64. Gueorguieva I, Cleverly AL, Stauber A, Sada Pillay N, Rodon JA, Miles CP, et al. Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model. Br J Clin Pharmacol (2014) 77:796-807. doi:10.1111/bcp.12256
65. Yoon C, Park do J, Schmidt B, Thomas NJ, Lee HJ, Kim TS, et al. CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin Cancer Res (2014) 20:3974-88. doi:10.1158/1078-0432.CCR-14-0011
66. Singh BN, Fu J, Srivastava RK, Shankar S. Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One (2011) 6:e27306. doi:10.1371/journal.pone.0027306
67. Kim EJ, Sahai V, Abel EV, Griffith KA, Greenson JK, Takebe N, et al. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin Cancer Res (2014) 20:5937-45. doi:10.1158/1078-0432.CCR-14-1269
68. Kim G, McKee AE, Ning YM, Hazarika M, Theoret M, Johnson JR, et al. FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation. Clin Cancer Res (2014) 20:4994-5000. doi:10.1158/1078-0432.CCR-14-0776
69. Jimeno A, Weiss GJ, Miller WH Jr, Gettinger S, Eigl BJ, Chang AL, et al. Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res (2013) 19:2766-74. doi:10.1158/1078-0432.CCR-12-3654
70. Bowles DW, Keysar SB, Eagles JR, Wang G, Glogowska MJ, McDermott JD, et al. A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma. Oral Oncol (2016) 53:74-9. doi:10.1016/j.oraloncology.2015.11.014
71. Storm EE, Durinck S, de Sousae Melo F, Tremayne J, Kljavin N, Tan C, et al. Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function. Nature (2016) 529:97-100. doi:10.1038/nature16466
72. Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, 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) 109:11717-22. doi:10.1073/pnas.1120068109
73. Le PN, McDermott JD, Jimeno A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther (2015) 146:1-11. doi:10.1016/j.pharmthera.2014.08.005
74. Jang G-B, Hong I-S, Kim R-J, Lee S-Y, Park S-J, Lee E-S, et al. Wnt/β-catenin small-molecule inhibitor CWP232228 preferentially inhibits the growth of breast cancer stem-like cells. Cancer Res (2015) 75:1691-702. doi:10.1158/0008-5472.CAN-14-2041
75. Nagaraj AB, Joseph P, Kovalenko O, Singh S, Armstrong A, Redline R, et al. Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance. Oncotarget (2015) 6:23720-34. doi:10.18632/oncotarget.4690
76. Lenz H-J, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci (2014) 105:1087-92. doi:10.1111/cas.12471
77. Lee K-M, Nam K, Oh S, Lim J, Kim RK, Shim D, et al. ECM1 regulates tumor metastasis and CSC-like property through stabilization of β-catenin. Oncogene (2015) 34:6055-65. doi:10.1038/onc.2015.54
78. Ponnusamy MP, Seshacharyulu P, Lakshmanan I, Vaz AP, Chugh S, Batra SK. Emerging role of mucins in epithelial to mesenchymal transition. Curr Cancer Drug Targets (2013) 13:945-56. doi:10.2174/15680096113136660100
79. Smith DC, Eisenberg PD, Manikhas G, Chugh R, Gubens MA, Stagg RJ, et al. A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clin Cancer Res (2014) 20:6295-303. doi:10.1158/1078-0432.CCR-14-1373
80. Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med (2015) 7:302ra136. doi:10.1126/scitranslmed.aac9459
81. Damelin M, Bankovich A, Park A, Aguilar J, Anderson W, Santaguida M, et al. Anti-EFNA4 calicheamicin conjugates effectively target triple-negative breast and ovarian tumor-initiating cells to result in sustained tumor regressions. Clin Cancer Res (2015) 21:4165-73. doi:10.1158/1078-0432.CCR-15-0695
82. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer (2013) 13:11-26. doi:10.1038/nrc3419
83. Rudin CM. Vismodegib. Clin Cancer Res (2012) 18:3218-22. doi:10.1158/1078-0432.CCR-12-0568
84. Justilien V, Fields AP. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clin Cancer Res (2015) 21:505-13. doi:10.1158/1078-0432.CCR-14-0507
85. Sharma N, Nanta R, Sharma J, Gunewardena S, Singh KP, Shankar S, et al. PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth. Oncotarget (2015) 6:32039-60. doi:10.18632/oncotarget.5055
86. Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn A, Rodriguez-Barrueco R, et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of Notch and Hedgehog-dependent tumor-initiating cells. Cancer Cell (2012) 22:373-88. doi:10.1016/j.ccr.2012.07.016
87. Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells (2007) 25:2524-33. doi:10.1634/stemcells.2007-0166
88. Justilien V, Walsh MP, Ali SA, Thompson EA, Murray NR, Fields AP. The PRKCI and SOX2 oncogenes are coamplified and cooperate to activate Hedgehog signaling in lung squamous cell carcinoma. Cancer Cell (2014) 25:139-51. doi:10.1016/j.ccr.2014.01.008
89. Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res (2006) 66:6063-71. doi:10.1158/0008-5472.CAN-06-0054
90. Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, Gervaz P, et al. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med (2009) 1:338-51. doi:10.1002/emmm.200900039
91. Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell (2008) 14:238-49. doi:10.1016/j.ccr.2008.08.003
92. Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci U S A (2007) 104:4048-53. doi:10.1073/pnas.0611682104
93. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, et al. A paracrine requirement for hedgehog signalling in cancer. Nature (2008) 455:406-10. doi:10.1038/nature07275
94. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature (2000) 406:1005-9. doi:10.1038/35023008
95. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med (2012) 366:2171-9. doi:10.1056/NEJMoa1113713
96. Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science (2009) 326:572-4. doi:10.1126/science.1179386
97. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med (2009) 361:1173-8. doi:10.1056/NEJMoa0902903
98. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov (2014) 13:513-32. doi:10.1038/nrd4233
99. Eaves CJ, Humphries RK. Acute myeloid leukemia and the Wnt pathway. N Engl J Med (2010) 362:2326-7. doi:10.1056/NEJMcibr1003522
100. Monteiro J, Gaspar C, Richer W, Franken PF, Sacchetti A, Joosten R, et al. Cancer stemness in Wnt-driven mammary tumorigenesis. Carcinogenesis (2014) 35:2-13. doi:10.1093/carcin/bgt279
101. White BD, Chien AJ, Dawson DW. Dysregulation of Wnt/beta-catenin signaling in gastrointestinal cancers. Gastroenterology (2012) 142:219-32. doi:10.1053/j.gastro.2011.12.001
102. Yoon JK, Lee JS. Cellular signaling and biological functions of R-spondins. Cell Signal (2012) 24:369-77. doi:10.1016/j.cellsig.2011.09.023
103. Andersson ER, Ledahl U. Therapeutic modulation of Notch signalling-are we there yet? Nat Rev Drug Discov (2014) 13:357-78. doi:10.1038/nrd4252
104. Huynh C, Poliseno L, Segura MF, Medicherla R, Haimovic A, Menendez S, et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One (2011) 6:e25264. doi:10.1371/journal.pone.0025264
105. Takebe N, Nguyen D, Yang SX. Targeting Notch pathway in cancer: clinical development advances and challenges. Pharmacol Ther (2014) 141:140-9. doi:10.1016/j.pharmthera.2013.09.005
106. Hellström M, Phng L-K, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature (2007) 445:776-80. doi:10.1038/nature05571
107. Kuhnert F, Chen G, Coetzee S, Thambi N, Hickey C, Shan J, et al. Dll4 blockade in stromal cells mediates antitumor effects in preclinical models of ovarian cancer. Cancer Res (2015) 75:4086-96. doi:10.1158/0008-5472.CAN-14-3773
108. Chiorean EG, LoRusso P, Strother RM, Diamond JR, Younger A, Messersmith WA, et al. A phase I first-in-human study of enoticumab (REGN421), a fully human Delta-like ligand 4 (Dll4) monoclonal antibody in patients with advanced solid tumors. Clin Cancer Res (2015) 21:2695-703. doi:10.1158/1078-0432.CCR-14-2797
109. Geffers I, Serth K, Chapman G, Jaekel R, Schuster-Gossler K, Cordes R, et al. Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo. J Cell Biol (2007) 178:465-76. doi:10.1083/jcb.200702009
110. Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL. Notch inhibition by the ligand Delta-like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet (2011) 20:905-16. doi:10.1093/hmg/ddq529
111. Boyd AW, Bartlett PF, Lackmann M. Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov (2014) 13:39-62. doi:10.1038/nrd4175
112. Marquardt JU, Raggi C, Andersen JB, Seo D, Avital I, Geller D, et al. Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology (2011) 54:1031-42. doi:10.1002/hep.24454
113. Duong HQ, Yi YW, Kang HJ, Bae I, Jang YJ, Kwak SJ, et al. Combination of dasatinib and gemcitabine reduces the ALDH1A1 expression and the proliferation of gemcitabine-resistant pancreatic cancer MIA PaCa-2 cells. Int J Oncol (2014) 44:2132-8. doi:10.3892/ijo.2014.2357
114. Thakur R, Trivedi R, Rastogi N, Singh M, Mishra DP. Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer. Sci Rep (2015) 5:10194. doi:10.1038/srep10194
115. Williams KE, Bundred NJ, Landberg G, Clarke RB, Farnie G. Focal adhesion kinase and Wnt signaling regulate human ductal carcinoma in situ stem cell activity and response to radiotherapy. Stem Cells (2015) 33:327-41. doi:10.1002/stem.1843
116. Schober M, Fuchs E. Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling. Proc Natl Acad Sci U S A (2011) 108:10544-9. doi:10.1073/pnas.1107807108
117. Mustjoki S, Richter J, Barbany G, Ehrencrona H, Fioretos T, Gedde-Dahl T, et al. Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients. Leukemia (2013) 27:1520-6. doi:10.1038/leu.2013.19
118. Jones SF, Siu LL, Bendell JC, Cleary JM, Razak AR, Infante JR, et al. A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors. Invest New Drugs (2015) 33:1100-7. doi:10.1007/s10637-015-0282-y
119. O'Brien S, Golubovskaya VM, Conroy J, Liu S, Wang D, Liu B, et al. FAK inhibition with small molecule inhibitor Y15 decreases viability, clonogenicity, and cell attachment in thyroid cancer cell lines and synergizes with targeted therapeutics. Oncotarget (2014) 5:7945-59. doi:10.18632/oncotarget.2381
120. Shapiro IM, Kolev VN, Vidal CM, Kadariya Y, Ring JE, Wright Q, et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med (2014) 6:237ra68. doi:10.1126/scitranslmed.3008639
121. Kolev VN, Wright QG, Vidal CM, Ring JE, Shapiro IM, Ricono J, et al. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res (2015) 75:446-55. doi:10.1158/0008-5472.CAN-14-1223
122. Chiarini F, Lonetti A, Teti G, Orsini E, Bressanin D, Cappellini A, et al. A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia. Oncotarget (2012) 3:1615-28. doi:10.18632/oncotarget.762
123. Judd NP, Winkler AE, Murillo-Sauca O, Brotman JJ, Law JH, Lewis JS Jr, et al. ERK1/2 regulation of CD44 modulates oral cancer aggressiveness. Cancer Res (2012) 72:365-74. doi:10.1158/0008-5472.CAN-11-1831
124. Li Y, Rogoff HA, Keates S, Gao Y, Murikipudi S, Mikule K, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A (2015) 112:1839-44. doi:10.1073/pnas.1424171112
125. Iv Santaliz-Ruiz LE, Xie X, Old M, Teknos TN, Pan Q. Emerging role of nanog in tumorigenesis and cancer stem cells. Int J Cancer (2014) 135:2741-8. doi:10.1002/ijc.28690
126. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res (2009) 69:7507-11. doi:10.1158/0008-5472.CAN-09-2994
127. Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer (2009) 9:563-75. doi:10.1038/nrc2676
128. Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC, Struhl K. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci U S A (2014) 111:10574-9. doi:10.1073/pnas.1409844111
129. Liu P, Brown S, Goktug T, Channathodiyil P, Kannappan V, Hugnot JP, et al. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br J Cancer (2012) 107:1488-97. doi:10.1038/bjc.2012.442
130. Liu P, Wang Z, Brown S, Kannappan V, Tawari PE, Jiang W, et al. Liposome encapsulated Disulfiram inhibits NF-κB pathway and targets breast cancer stem cells in vitro and in vivo. Oncotarget (2014) 5:7471-85. doi:10.18632/oncotarget.2166
131. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez JA. Metformin against TGFβ-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell Cycle (2010) 9:4461-8. doi:10.4161/cc.9.22.14048
132. Li L, Han R, Xiao H, Lin C, Wang Y, Liu H, et al. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res (2014) 20:2714-26. doi:10.1158/1078-0432.CCR-13-2613
133. Vasamsetti SB, Karnewar S, Kanugula AK, Thatipalli AR, Kumar JM, Kotamraju S. Metformin inhibits monocyte-to-macrophage differentiation via AMPK mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes (2015) 64:2028-41. doi:10.2337/db14-1225
134. Lee BY, Hochgräfe F, Lin HM, Castillo L, Wu J, Raftery MJ, et al. Phosphoproteomic profiling identifies focal adhesion kinase as a mediator of docetaxel resistance in castrate-resistant prostate cancer. Mol Cancer Ther (2014) 13:190-201. doi:10.1158/1535-7163.MCT-13-0225-T
135. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer (2015) 15:7-24. doi:10.1038/nrc3860
136. Slomovitz BM, Coleman RL. The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res (2012) 18:5856-64. doi:10.1158/1078-0432.CCR-12-0662
137. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature (2006) 441:475-82. doi:10.1038/nature04703
138. He K, Xu T, Xu Y, Ring A, Kahn M, Goldkorn A. Cancer cells acquire a drug resistant, highly tumorigenic, cancer stem-like phenotype through modulation of the PI3K/Akt/β-catenin/CBP pathway. Int J Cancer (2014) 134:43-54. doi:10.1002/ijc.28341
139. Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A (2007) 104:16158-63. doi:10.1073/pnas.0702596104
140. Chen J, Shao R, Li F, Monteiro M, Liu JP, Xu ZP, et al. PI3K/Akt/mTOR pathway dual inhibitor BEZ235 suppresses the stemness of colon cancer stem cells. Clin Exp Pharmacol Physiol (2015) 42:1317-26. doi:10.1111/1440-1681.12493
141. Sarvi S, Mackinnon AC, Avlonitis N, Bradley M, Rintoul RC, Rassl DM, et al. CD133+ cancer stem-like cells in small cell lung cancer are highly tumorigenic and chemoresistant but sensitive to a novel neuropeptide antagonist. Cancer Res (2014) 74:1554-65. doi:10.1158/0008-5472.CAN-13-1541
142. Luchman HA, Stechishin OD, Nguyen SA, Lun XQ, Cairncross JG, Weiss S. Dual mTORC1/2 blockade inhibits glioblastoma brain tumor initiating cells in vitro and in vivo and synergizes with temozolomide to increase orthotopic xenograft survival. Clin Cancer Res (2014) 20:5756-67. doi:10.1158/1078-0432.CCR-13-3389
143. Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol (2013) 10:143-53. doi:10.1038/nrclinonc.2013.10
144. Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis (2013) 4:e875. doi:10.1038/cddis.2013.407
145. Samatar AA, Pulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov (2014) 13:928-42. doi:10.1038/nrd4281
146. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet (2012) 380:358-65. doi:10.1016/S0140-6736(12)60868-X
147. Balko JM, Schwarz LJ, Bhola NE, Kurupi R, Owens P, Miller TW, et al. Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. Cancer Res (2013) 73:6346-58. doi:10.1158/0008-5472.CAN-13-1385
148. Hepburn AC, Veeratterapillay R, Williamson SC, El-Sherif A, Sahay N, Thomas HD, et al. Side population in human non-muscle invasive bladder cancer enriches for cancer stem cells that are maintained by MAPK signalling. PLoS One (2012) 7:e50690. doi:10.1371/journal.pone.0050690
149. Fischer M, Yen WC, Kapoun AM, Wang M, O'Young G, Lewicki J, et al. Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations. Cancer Res (2011) 71:1520-5. doi:10.1158/0008-5472.CAN-10-2817
150. Sette G, Salvati V, Memeo L, Fecchi K, Colarossi C, Di Matteo P, et al. EGFR inhibition abrogates leiomyosarcoma cell chemoresistance through inactivation of survival pathways and impairment of CSC potential. PLoS One (2012) 7:e46891. doi:10.1371/journal.pone.0046891
151. Wang YK, Zhu YL, Qiu FM, Zhang T, Chen ZG, Zheng S, et al. Activation of Akt and MAPK pathways enhances the tumorigenicity of CD133+ primary colon cancer cells. Carcinogenesis (2010) 31:1376-80. doi:10.1093/carcin/bgq120
152. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget (2011) 2:135-64. doi:10.18632/oncotarget.240
153. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science (1994) 264:95-8
154. Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, et al. Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci U S A (2001) 98:7319-24
155. Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science (1995) 269:81-3
156. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer (2014) 14:736-46. doi:10.1038/nrc3818
157. Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C, et al. STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res (2011) 71:7226-37. doi:10.1158/0008-5472.CAN-10-4660
158. van der Zee M, Sacchetti A, Cansoy M, Joosten R, Teeuwssen M, Heijmans-Antonissen C, et al. IL6/JAK1/STAT3 signaling blockade in endometrial cancer affects the ALDHhi/CD126+ stem-like component and reduces tumor burden. Cancer Res (2015) 75:3608-22. doi:10.1158/0008-5472.CAN-14-2498
159. Schroeder A, Herrmann A, Cherryholmes G, Kowolik C, Buettner R, Pal S, et al. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res (2014) 74:1227-37. doi:10.1158/0008-5472.CAN-13-0594
160. Shao C, Sullivan JP, Girard L, Augustyn A, Yenerall P, Rodriguez-Canales J, et al. Essential role of aldehyde dehydrogenase 1A3 for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway. Clin Cancer Res (2014) 20:4154-66. doi:10.1158/1078-0432.CCR-13-3292
161. Li L, Tang W, Wu X, Karnak D, Meng X, Thompson R, et al. HAb18G/CD147 promotes pSTAT3-mediated pancreatic cancer development via CD44s. Clin Cancer Res (2013) 19:6703-15. doi:10.1158/1078-0432.CCR-13-0621
162. Moon SH, Kim DK, Cha Y, Jeon I, Song J, Park KS. PI3K/Akt and Stat3 signaling regulated by PTEN control of the cancer stem cell population, proliferation and senescence in a glioblastoma cell line. Int J Oncol (2013) 42:921-8. doi:10.3892/ijo.2013.1765
163. Baell JB. Feeling nature's PAINS: natural products, natural product drugs, and pan assay interference compounds (PAINS). J Nat Prod (2016) 79(3):616-28. doi:10.1021/acs.jnatprod.5b00947
164. Senger MR, Fraga CA, Dantas RF, Silva FP. Filtering promiscuous compounds in early drug discovery: is it a good idea? Drug Discov Today (2016). doi:10.1016/j.drudis.2016.02.004
165. Liu X, Chhipa RR, Pooya S, Wortman M, Yachyshin S, Chow LM, et al. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sci U S A (2014) 111:E435-44. doi:10.1073/pnas.1311121111
166. Schenk T, Chen WC, Göllner S, Howell L, Jin L, Hebestreit K, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med (2012) 18:605-11. doi:10.1038/nm.2661
167. Zhang KZ, Zhang QB, Zhang QB, Sun HC, Ao JY, Chai ZT, et al. Arsenic trioxide induces differentiation of CD133+ hepatocellular carcinoma cells and prolongs posthepatectomy survival by targeting GLI1 expression in a mouse model. J Hematol Oncol (2014) 7:28. doi:10.1186/1756-8722-7-28
168. Sachlos E, Risueño EM, Laronde S, Shapovalova Z, Lee J-H, Russell J, et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell (2012) 149:1284-97. doi:10.1016/j.cell.2012.03.049
169. Ogawa K, Yoshioka Y, Isohashi F, Seo Y, Yoshida K, Yamazaki H. Radiotherapy targeting cancer stem cells: current views and future perspectives. Anticancer Res (2013) 33:747-54
170. Gupta T, Nair V, Paul SN, Kannan S, Moiyadi A, Epari S, et al. Can irradiation of potential cancer stem-cell niche in the subventricular zone influence survival in patients with newly diagnosed glioblastoma? J Neurooncol (2012) 109:195-203. doi:10.1007/s11060-012-0887-3
171. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell (2009) 138:645-59. doi:10.1016/j.cell.2009.06.034
172. Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U S A (2011) 108:13253-7. doi:10.1073/pnas.1110431108
173. Lu Y, Ma W, Mao J, Yu X, Hou Z, Fan S, et al. Salinomycin exerts anticancer effects on human breast carcinoma MCF-7 cancer stem cells via modulation of Hedgehog signaling. Chem Biol Interact (2015) 228:100-7. doi:10.1016/j.cbi.2014.12.002
174. Zhou J, Li P, Xue X, He S, Kuang Y, Zhao H, et al. Salinomycin induces apoptosis in cisplatin-resistant colorectal cancer cells by accumulation of reactive oxygen species. Toxicol Lett (2013) 222:139-45. doi:10.1016/j.toxlet.2013.07.022
175. An H, Kim JY, Oh E, Lee N, Cho Y, Seo JH. Salinomycin promotes anoikis and decreases the CD44+/CD24-stem-like population via inhibition of STAT3 activation in MDA-MB-231 Cells. PLoS One (2015) 10:e0141919. doi:10.1371/journal.pone.0141919
176. Naujokat C, Steinhart R. Salinomycin as a drug for targeting human cancer stem cells. J Biomed Biotechnol (2012) 2012:950658. doi:10.1155/2012/950658
177. Wright C, Moore R. Disulfiram treatment of alcoholism. Am J Med (1990) 88:647-55. doi:10.1016/0002-9343(90)90534-K
178. Dufour P, Lang JM, Giron C, Duclos B, Haehnel P, Jaeck D, et al. Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study. Biotherapy (1993) 6:9-12. doi:10.1007/BF01877380
179. Han D, Wu G, Chang C, Zhu F, Xiao Y, Li Q, et al. Disulfiram inhibits TGF-β-induced epithelial-mesenchymal transition and stem-like features in breast cancer via ERK/NF-κB/Snail pathway. Oncotarget (2015) 6:40907-19. doi:10.18632/oncotarget.5723
180. Hothi P, Martins TJ, Chen L, Deleyrolle L, Yoon JG, Reynolds B, et al. High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells. Oncotarget (2012) 3:1124-36. doi:10.18632/oncotarget.707
181. Nechushtan H, Hamamreh Y, Nidal S, Gotfried M, Baron A, Shalev YI, et al. A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist (2015) 20:366-7. doi:10.1634/theoncologist.2014-0424
182. Firat E, Weyerbrock A, Gaedicke S, Grosu AL, Niedermann G. Chloroquine or chloroquine-PI3K/Akt pathway inhibitor combinations strongly promote gamma-irradiation-induced cell death in primary stem-like glioma cells. PLoS One (2012) 7:e47357. doi:10.1371/journal.pone.0047357
183. Balic A, Sørensen MD, Trabulo SM, Sainz B Jr, Cioffi M, Vieira CR, et al. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling. Mol Cancer Ther (2014) 13:1758-71. doi:10.1158/1535-7163.MCT-13-0948
184. Jiang H, Gomez-Manzano C, Lang FF, Alemany R, Fueyo J. Oncolytic adenovirus: preclinical and clinical studies in patients with human malignant gliomas. Curr Gene Ther (2009) 9:422-7. doi:10.2174/156652309789753356
185. Choi DS, Blanco E, Kim YS, Rodriguez AA, Zhao H, Huang TH, et al. Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells (2014) 32:2309-23. doi:10.1002/stem.1746
186. Fueyo J, Gomez-Manzano C, Alemany R, Lee PS, McDonnell TJ, Mitlianga P, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene (2000) 19:2-12. doi:10.1038/sj.onc.1203251
187. Alonso MM, Gomez-Manzano C, Bekele BN, Yung WK, Fueyo J. Adenovirus-based strategies overcome temozolomide resistance by silencing the O6-methylguanine-DNA methyltransferase promoter. Cancer Res (2007) 67:11499-504. doi:10.1158/0008-5472.CAN-07-5312
188. Ning N, Pan Q, Zheng F, Teitz-Tennenbaum S, Egenti M, Yet J, et al. Cancer stem cell vaccination confers significant antitumor immunity. Cancer Res (2012) 72:1853-64. doi:10.1158/0008-5472.CAN-11-1400
189. Favaro R, Appolloni I, Pellegatta S, Sanga AB, Pagella P, Gambini E, et al. Sox2 is required to maintain cancer stem cells in a mouse model of high-grade oligodendroglioma. Cancer Res (2014) 74:1833-44. doi:10.1158/0008-5472.CAN-13-1942
190. Lanzardo S, Conti L, Rooke R, Ruiu R, Accart N, Bolli E, et al. Immunotargeting of antigen xCT attenuates stem-like cell behavior and metastatic progression in breast cancer. Cancer Res (2016) 76:62-72. doi:10.1158/0008-5472.CAN-15-1208
191. Vik-Mo EO, Nyakas M, Mikkelsen BV, Moe MC, Due-Tønnesen P, Suso EM, et al. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol Immunother (2013) 62:1499-509. doi:10.1007/s00262-013-1453-3
192. Xu M, Yao Y, Hua W, Wu Z, Zhong P, Mao Y, et al. Mouse glioma immunotherapy mediated by A2B5+ GL261 cell lysate-pulsed dendritic cells. J Neurooncol (2014) 116:497-504. doi:10.1007/s11060-013-1334-9
193. Rezvani K, Yong AS, Mielke S, Jafarpour B, Savani BN, Le RQ, et al. Repeated PR1 and WT1 peptide vaccination in Montanide-adjuvant fails to induce sustained high-avidity, epitope-specific CD8+ T cells in myeloid malignancies. Haematologica (2011) 96:432-40. doi:10.3324/haematol.2010.031674
194. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis (2010) 31:27-36. doi:10.1093/carcin/bgp220
195. Lu S, Labhasetwar V. Drug resistant breast cancer cell line displays cancer stem cell phenotype and responds sensitively to epigenetic drug SAHA. Drug Deliv Transl Res (2013) 3:183-94. doi:10.1007/s13346-012-0113-z
196. Nalls D, Tang S-N, Rodova M, Srivastava RK, Shankar S. Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS One (2011) 6:e24099. doi:10.1371/journal.pone.0024099
197. Peitzsch C, Cojoc M, Hein L, Kurth I, Mäbert K, Trautmann F, et al. An epigenetic reprogramming strategy to re-sensitize radioresistant prostate cancer cells. Cancer Res (2016). doi:10.1158/0008-5472
198. Bao B, Azmi AS, Ali S, Ahmad A, Li Y, Banerjee S, et al. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness. Biochim Biophys Acta (2012) 1826:272-96. doi:10.1016/j.bbcan.2012.04.008
199. Marcucci F, Corti A. How to improve exposure of tumor cells to drugs-promoter drugs increase tumor uptake and penetration of effector drugs. Adv Drug Deliv Rev (2012) 64:53-68. doi:10.1016/j.addr.2011.09.007
200. Marcucci F, Corti A. Improving drug penetration to curb tumor drug resistance. Drug Discov Today (2012) 17:1139-47. doi:10.1016/j.drudis.2012.06.004
201. Markman JL, Rekechenetskiy A, Holler E, Ljubimova JY. Nanomedicine therapeutic approaches to overcome cancer drug resistance. Adv Drug Deliv Rev (2013) 65:1866-79. doi:10.1016/j.addr.2013.09.019
202. Marcucci F, Lefoulon F. Active targeting with particulate drug carriers in tumor therapy: fundamentals and recent progresses. Drug Discov Today (2004) 9:219-28. doi:10.1016/S1359-6446(03)02988-X
203. Marcucci F, Bellone M, Rumio C, Corti A. Approaches to improve tumor accumulation and interactions between monoclonal antibodies and immune cells. MAbs (2013) 5:34-46. doi:10.4161/mabs.22775
204. Zhang Y, Zhang H, Wang X, Wang J, Zhang X, Zhang Q. The eradication of breast cancer and cancer stem cells using octreotide modified paclitaxel active targeting micelles and salinomycin passive targeting micelles. Biomaterials (2012) 33:679-91. doi:10.1016/j.biomaterials.2011.09.072
205. Zhou J, Patel TR, Sirianni RW, Strohbehn G, Zheng MQ, Duong N, et al. Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. Proc Natl Acad Sci U S A (2013) 110:11751-6. doi:10.1073/pnas.1304504110
206. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science (2009) 324:1457-61. doi:10.1126/science.1171362
207. Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res (2008) 14:5995-6004. doi:10.1158/1078-0432.CCR-08-0291
208. Krawczyk N, Meier-Stiegen F, Banys M, Neubauer H, Ruckhaeberle E, Fehm T. Expression of stem cell and epithelial-mesenchymal transition markers in circulating tumor cells of breast cancer patients. Biomed Res Int (2014) 2014:415721. doi:10.1155/2014/415721
209. Korkaya H, Wicha MS. HER2 and breast cancer stem cells: more than meets the eye. Cancer Res (2013) 73:3489-93. doi:10.1158/0008-5472.CAN-13-0260
210. Lobry C, Oh P, Mansour MR, Look AT, Aifantis I. Notch signaling: switching an oncogene to a tumor suppressor. Blood (2014) 123:2451-9. doi:10.1182/blood-2013-08-355818
211. Rampias T, Vgenopoulou P, Avgeris M, Polyzos A, Stravodimos K, Valavanis C, et al. A new tumor suppressor role for the Notch pathway in bladder cancer. Nat Med (2014) 20:1199-207. doi:10.1038/nm.3678
212. Massagué J. TGF-β signalling in context. Nat Rev Mol Cell Biol (2012) 13:616-30. doi:10.1038/nrm3434
213. Chen EY, DeRan MT, Ignatius MS, Grandinetti KB, Clagg R, McCarthy KM, et al. Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Proc Natl Acad Sci U S A (2014) 111:5349-54. doi:10.1073/pnas.1317731111
214. Couto JP, Daly L, Almeida A, Knauf JA, Fagin JA, Sobrinho-Simões M, et al. STAT3 negatively regulates thyroid tumorigenesis. Proc Natl Acad Sci U S A (2012) 109:E2361-70. doi:10.1073/pnas.1201232109
215. Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov (2015) 5:1282-9. doi:10.1158/2159-8290.CD-15-1020
216. He Y-C, Zhou F-L, Shen Y, Liao D-F, Cao D. Apoptotic death of cancer stem cells for cancer therapy. Int J Mol Sci (2014) 15:8335-51. doi:10.3390/ijms15058335
217. Xiao Z, Sperl B, Ullrich A, Knyazev P. Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status. Oncotarget (2014) 5:12877-90. doi:10.18632/oncotarget.2657