Therapeutic target discovery and drug development in cancer stem cells for leukemia and lymphoma: from bench to the clinic

References

• Estimated Number * of New Cancer Cases and Deaths by Sex, US, 2016. Estimated new cases are based on 1988-2012 incidence data reported by the North American Association of Central Cancer Registries (NAACCR). Estimated deaths are based on 1998-2012 US mortality data, National Center for Health Statistics, Centers for Disease Control and Prevention.American Cancer Society, Inc., Surveillance Research; ©2016 [cited 2016 Aug 26] Available from: http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016/index f
   Google Scholar
• Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001;98(8):2301–2307.
   PubMed Web of Science ®Google Scholar
• Costello RT, Mallet F, Gaugler B, et al. Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res. 2000;60(16):4403–4411.
   PubMed Web of Science ®Google Scholar
• Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730–737.
   PubMed Web of Science ®Google Scholar
• Ishikawa F, Yoshida S, Saito Y, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25(11):1315–1321. DOI:10.1038/nbt1350
   PubMed Web of Science ®Google Scholar
• Taussig DC, Miraki-Moud F, Anjos-Afonso F, et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood. 2008;112(3):568–575. DOI:10.1182/blood-2007-10-118331
   PubMed Web of Science ®Google Scholar
• Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, et al. FLT3-IDT up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-IDT-specific STAT5 activation. Blood. 2009;114(24):5034–5043. DOI:10.1182/blood-2008-12-196055
   PubMed Web of Science ®Google Scholar
• Martelli MP, Pettirossi V, Thiede C, et al. CD34+ cells from AML with mutated NPM1 harbor cytoplasmatic mutated nucleophosmin and generated leukemia in immunocompromised mice. Blood. 2010;116(19):3907–3922. DOI:10.1182/blood-2009-08-238899
   PubMed Web of Science ®Google Scholar
• Taussig DC, Vargaftig J, Miraki-Moud F, et al. Leukemia-initiating cells from some acute leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood. 2010;115(10):1976–1984. DOI:10.1182/blood-2009-02-206565
   PubMed Web of Science ®Google Scholar
• Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast crisis CML. N Engl J Med. 2004;351(7):657–667. DOI:10.1056/NEJMoa040258
   PubMed Web of Science ®Google Scholar
• Goardon N, Marchi E, Atzberger A, et al. Coexistance of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell. 2011;19(1):138–152. DOI:10.1016/j.ccr.2010.12.012
   PubMed Web of Science ®Google Scholar
• Quek L, Otto GW, Garnett C, et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. J Exp Med. 2016;213(8):1513–1535. DOI:10.1084/jem.20151775
   PubMed Web of Science ®Google Scholar
• Lee CG, Das B, Lin TL, et al. A rare fraction of drug-resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells to maintain tumorigenic potential. Br J Haematol. 2012;158(1):79–90. DOI:10.1111/j.1365-2141.2012.09123.x
   PubMed Web of Science ®Google Scholar
• Gorss E, Quillet-Mary A, Ysebaert L, et al. Cancer stem cells of differentiated B-cell malignancies: models and consequences. Cancers. 2011;3(2):1566–1579. DOI:10.3390/cancers3021566
   PubMedGoogle Scholar
• Takebe N, Miele L, Harris PJ, et al., Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015. 12(8): 445–464. DOI:10.1038/nrclinonc.2015.61.
   PubMed Web of Science ®Google Scholar
• Boisset JC, Robin C. On the basis of hematopoietic stem cells: progress and controversy. Stem Cell Res. 2012;8(1):1–13. DOI:10.1016/j.scr.2011.07.002
   PubMed Web of Science ®Google Scholar
• Naka K, Hirao A. Maintenance of genomic integrity in hematopoietic stem cells. Int J Hematol. 2011;93(4):434–439. DOI:10.1007/s12185-011-0793-z
   PubMed Web of Science ®Google Scholar
• Satoh C, Ogata K. Hypothesis: myeloid-restricted hematopoietic stem cells with self-renewal capacity may be the transformation site in acute myeloid leukemia. Leuk Res. 2006;30(4):491–495. DOI:10.1016/j.leukres.2005.08.017
   PubMed Web of Science ®Google Scholar
• Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5(7):738–743. DOI:10.1038/ni1080
   PubMed Web of Science ®Google Scholar
• Dührsen U, Hossfeld DK. Stromal abnormalities in neoplastic bone marrow diseases. Ann Hematol. 1996;73(2):53–70. DOI:10.1007/s002770050203
   PubMed Web of Science ®Google Scholar
• Raaijmakers MH, Mukherjee S, Guo S, et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 2010;464(7290):852–857. DOI:10.1038/nature08940
   PubMed Web of Science ®Google Scholar
• Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309–322. DOI:10.1016/j.ccr.2012.02.022
   PubMed Web of Science ®Google Scholar
• Chen Y, Peng C, Sullivan C, et al. Novel therapeutic agents against cancer stem cells of chronic myeloid leukemia. Anticancer Agents Med Chem. 2010;10(2):111–115.
   PubMed Web of Science ®Google Scholar
• Milner LA, Bigas A. Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation. Blood. 1999;93(8):2431–2448.
   PubMed Web of Science ®Google Scholar
• Aster JC, Pear WS, Blacklow SC. Notch signaling in leukemia. Annu Rev Pathol. 2008;3:587–613. DOI:10.1146/annurev.pathmechdis.3.121806.154300
   PubMed Web of Science ®Google Scholar
• Takebe N, Nguyen D, Yang SX. Targeting Notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther. 2014;141(2):140–149. DOI:10.1016/j.pharmthera.2013.09.005 .
   PubMed Web of Science ®Google Scholar
• Fre S, Huyghe M, Mourikis P, et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature. 2005;435:964–968. DOI:10.1038/nature03589
   PubMed Web of Science ®Google Scholar
• Nakamura T, Tsuchiya K, Watanabe M. Crosstalk between Wnt and Notch signaling in intestinal epithelial cell fate decision. J Gastroenterol. 2007;42:705–710. DOI:10.1007/s00535-007-2087-z
   PubMed Web of Science ®Google Scholar
• Ellisen LW, Bird J, West DC, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocation in T lymphoblatic neoplasms. Cell. 1991;66(4):649–661.
   PubMed Web of Science ®Google Scholar
• Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–271. DOI:10.1126/science.1102160
   PubMed Web of Science ®Google Scholar
• Gordon WR, Roy M, Vardar-Ulu D, et al. Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL. Blood. 2009;113(18):4381–4390. DOI:10.1182/blood-2008-08-174748
   PubMed Web of Science ®Google Scholar
• Haydu JE, De Keersmaecker K, Duff MK, et al. An activating intragenic deletion in NOTCH1 in human T-ALL. Blood. 2012;119(22):5211–5214. DOI:10.1182/blood-2011-10-388504
   PubMed Web of Science ®Google Scholar
• Grieselhuber NR, Klco JM, Verdoni AM, et al. Notch signaling in acute promyelocytic leukemia. Leukemia. 2013;27(7):1548–1557. DOI:10.1038/leu.2013.68
   PubMed Web of Science ®Google Scholar
• Aljedai A, Buckle A, Hiwarkar P, et al. Potential role of Notch signalling in CD34+ chronic myeloid leukaemia cells: cross-talk between Notch and BCR-ABL. PLos One. 2015;10(4):e0123016. DOI:10.1371/journal.pone.0123016
   Web of Science ®Google Scholar
• Tse MT. Cancer: activating Notch ameliorates AML. Nat Rev Drug Discov. 2013;12(4):263. DOI:10.1038/nrd3982
   PubMed Web of Science ®Google Scholar
• Tohda S. NOTCH signaling roles in acute myeloid leukemia cell growth and interaction with other stemness-related signals. Anticancer Res. 2014;34(11):6259–6264.
   PubMed Web of Science ®Google Scholar
• Nguyen D, Rubinstein L, Takebe N, et al. Notch1 phenotype and clinical stage progression in non-small cell lung cancer. J Hematol Oncol. 2015;8:9. DOI:10.1186/s13045-014-0104-2 .
   PubMed Web of Science ®Google Scholar
• Lobry C, Ntziachristos P, Ndiaye-Lobry D, et al. Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med. 2013;210(2):301–319. DOI:10.1084/jem.20121484
   PubMed Web of Science ®Google Scholar
• Kannan S, Sutphin RM, Hall MG, et al. Notch activation inhibits AML growth and survival: a potential therapeutic approach. J Exp Med. 2013;210(2):321–337. DOI:10.1084/jem.20121527
   PubMed Web of Science ®Google Scholar
• Kamga PT, Giulio B, Cassaro A, et al. Role of stromal cell-mediated Notch signaling in AML resistance to chemotherapy. Blood. 2014;124(21):1044.
   Google Scholar
• Olsauskas-Kuprys R, Zlobin A, Osipo C. Gamma secretase inhibitors of Notch signaling. Onco Targets Ther. 2013;6:943–955. DOI:10.2147/OTT.S33766
   PubMed Web of Science ®Google Scholar
• Nickoloff BJ, Osborne BA, Miele L. Notch signaling as a therapeutic target in câncer: a new approach to the development of cell fate modifying agentes. Oncogene. 2003;22(42):6598–6608. DOI:10.1038/sj.onc.1206758
   PubMed Web of Science ®Google Scholar
• Kopan R, IIagan MX. Gamma-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol. 2004;5(6):499–504. DOI:10.1038/nrm1406
   PubMed Web of Science ®Google Scholar
• Maetzel D, Denzel S, Mack B, et al. Nuclear signaling by tumour-associated antigen EpCAM. Nat Cell Biol. 2009;11(2):162–171. DOI:10.1038/ncb1824
   PubMed Web of Science ®Google Scholar
• Messersmith WA, Shapiro GI, Cleary JM, et al. A phase I, dose-finding study in patients with advanced solid malignancies of the oral y-secretase inhibitor PF-03084014. Clin Cancer Res. 2015;21(1):60–67. DOI:10.1158/1078-0432.CCR-14-0607
   PubMed Web of Science ®Google Scholar
• Gavai AV, Zhao Y, O’Malley D, et al. BMS-983970, an oral pan-Notch inhibitor for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR. Cancer Res. 2014;74(19Suppl): Abstractnr 1643.
   Google Scholar
• Gavai AV, Quesnelle C, Norris D, et al. Discovery of clinical candidate BMS-906024: a potent Pan-Notch inhibitor for the treatment of leukemia and solid tumors. ACS Med Chem Lett. 2015;6(5):523–527. DOI:10.1021/acsmedchemlett.5b00001
   PubMed Web of Science ®Google Scholar
• Zweidler-McKay PA, DeAngelo DJ, Douer D, et al. The safety and activity of BMS-906024, a gamma secretase inhibitor (GSI) with anti-Notch activity, in patients with relapsed T-cell acute lymphoblastic leukemia (T-ALL): initial results of a phase 1 trial. ASH. 2014; 124(21 Suppl): Abstract nr 968.
   Google Scholar
• Herranz D, Ambesi-Impiombato A, Palomero T, et al. A NOTCH-1 driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat Med. 2014;20(10):1130–1137. DOI:10.1038/nm.3665
   PubMed Web of Science ®Google Scholar
• Massard C, Azaro A, Le Tourneau C, et al. First-human study of LY3039478, a Notch signaling inhibitor in advance or metastatic cancer. J Clin Oncol. 2015;33(suppl; abstr 2533).
   Google Scholar
• Takebe N, Hunsberger S, Yang SX. Expression of Gli1 in the hedgehog signaling pathway and breast cancer recurrence. Chin J Cancer Res. 2012;24(4):257–258. DOI:10.3978/j.issn.1000-9604.2012.09.07
   PubMed Web of Science ®Google Scholar
• Takebe N, Yang SX. Sonic hedgehog signaling pathway and gallbladder cancer: targeting with precision medicine approach. Chin Clin Oncol. 2016;55:1.
   Google Scholar
• Marigo V, Tabin CJ. Regulation of patched by sonic hedgehog in the developing neural tube. Proc Natl Acad Sci. 1996;93(18):9346–9351.
   PubMed Web of Science ®Google Scholar
• Lee J, Platt KA, Censullo P, et al. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development. 1997;124(13):2537–2552.
   PubMed Web of Science ®Google Scholar
• Duman-Scheel M, Weng L, Xin S, et al. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature. 2002;417(6886):299–304. DOI:10.1038/417299a
   PubMed Web of Science ®Google Scholar
• Singh RR, Cho-Vega JH, Davuluri Y, et al. Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma. Cancer Res. 2009;69(6):2550–2558. DOI:10.1158/0008-5472.CAN-08-1808
   PubMed Web of Science ®Google Scholar
• Dierks C, Grbic J, Zirlik K, et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med. 2007;13(8):944–951. DOI:10.1038/nm1614
   PubMed Web of Science ®Google Scholar
• Decker S, Zirlik K, Djebatchie L, et al. Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL. Blood. 2012;119(4):997–1007. DOI:10.1182/blood-2011-06-359075
   PubMed Web of Science ®Google Scholar
• Singh RR, Kim JE, Davuluri Y, et al. Hedgehog signaling pathway is activated in diffuse B-cell lymphoma and contributes to tumor cell survival and proliferation. Leukemia. 2010;24(5):1025–1036. DOI:10.1038/leu.2010.35
   PubMed Web of Science ®Google Scholar
• Lin TL, Wang QH, Brown P, et al. Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926. PLoS One. 2010;5(12):e15262. DOI:10.1371/journal.pone.0015262
   PubMedGoogle Scholar
• Wellbrock J, Latuske E, Köhler J. Expression of Hedgehog pathway mediator GLI represents a negative prognostic marker in human acute myeloid leukemia and its inhibition exerts antileukemic effects. Clin Cancer Res. 2015;21(10):2388–2398. DOI:10.1158/1078-0432.CCR-14-1059
   PubMed Web of Science ®Google Scholar
• Fukushima N, Minami Y, Hayakawa F, et al. Treatment with Hedgehog inhibitor, PF-04449913, attenuates leukemia-initiation potential in acute myeloid leukemia cells. Blood. 2013;122(21):1649. DOI:10.1182/blood-2012-12-471029
   PubMed Web of Science ®Google Scholar
• Houot R, Soussain C, Tilly H, et al. Inhibition of Hedgehog signaling treatment of Lymphoma and CLL: a phase II study from the Lysa. ASH. 2015; 126: abstract nr 3970.
   Google Scholar
• Alonso-Dominguez JM, Grinfeld J, Alikian M, et al. PTCH1 expression at diagnosis predicts imatinib failure in chronic myeloid leukaemia patients in chronic phase. Am J Hematol. 2015;90(1):20–26. DOI:10.1002/ajh.23857
   PubMed Web of Science ®Google Scholar
• Dierks C, Beigi R, Guo GR, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008;14(3):238–249. DOI:10.1016/j.ccr.2008.08.003
   PubMed Web of Science ®Google Scholar
• Long B, Zhu H, Zhu C, et al. Activation of the Hedgehog pathway in chronic myelogenous leukemia patients. J Exp Clin Res. 2011;30:8. DOI:10.1186/1756-9966-30-8
   PubMed Web of Science ®Google Scholar
• Shah NP, Cortes J, Martinelli G, et al. Dasatinib plus Smoothened (SMO) inhibitor BMS-833923 in chronic myeloid leukemia (CLL) with resistance or suboptimal response to a prior tyrosine kinase inhibitor (TKI): phase I study CA180323. ASH. 2014; 124: Abstract nr 4539.
   Google Scholar
• Martinelli G, Oehler VG, Papayannidis C, et al. Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study. Lancet Haematol. 2015;2(8):e339–46. DOI:10.1016/S2352-3026(15)00096-4
   PubMed Web of Science ®Google Scholar
• Jamieson C, Cortes JE, Oehler V, et al. Phase 1 dose-escalation study of PF-04449913, an oral Hedgehog (Hh) inhibitor, in patients with select hematologic malignancies. ASH. 2011; 118: Abstract nr 424.
   Google Scholar
• Irvine DA, Zhang B, Kinstrie R, et al. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Sci Rep. 2016;6:25476. DOI:10.1038/srep25476
   PubMed Web of Science ®Google Scholar
• Reya T, Duncan AW, Ailles L, et al. A role for Wnt signaling in self-renewal of haematopoietic stem cells. Nature. 2003;423(6938):409–414. DOI:10.1038/nature01593
   PubMed Web of Science ®Google Scholar
• Kim Y, Thanendrarajan S, Schmidt-Wolf IGH. Wnt/ß-Catenin: a new therapeutic approach to acute myeloid leukemia. Leuk Res Treatment. 2011;2011:428960.
   PubMedGoogle Scholar
• Mikesch J, Steffen B, Berdel WE, et al. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia. 2007;21(8):1638–1647. DOI:10.1038/sj.leu.2404732
   PubMed Web of Science ®Google Scholar
• Baba Y, Yokota T, Spits H, et al. Constitutively active beta-catenin promotes expansion of multipotent hematopoietic progenitor in culture. J Immunol. 2006;177(4):2294–2303.
   PubMed Web of Science ®Google Scholar
• Khan NI, Bradstock KF, Bendall LJ. Activation of Wnt/beta-catenin pathway mediates growth and survival in B-cell progenitor acute lymphoblastic leukaemia. Br J Haematol. 2007;138(3):338–348. DOI:10.1111/j.1365-2141.2007.06667.x
   PubMed Web of Science ®Google Scholar
• Simon M, Grandage VL, Linch DC, et al. Constitutive activation of the Wnt/beta-catenin signaling pathway in acute myeloid leukaemia. Oncogene. 2005;24(14):2410–2420. DOI:10.1038/sj.onc.1208431
   PubMed Web of Science ®Google Scholar
• Tickenbrock L, Hehn S, Sargin B, et al. Activation of Wnt signalling in acute myeloid leukemia by induction of Frizzled-4. Int J Oncol. 2008;33(6):1215–1221.
   PubMed Web of Science ®Google Scholar
• Valencia A, Román-Gómez J, Cervera J, et al. Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia. Leukemia. 2009;23(9):1658–1666. DOI:10.1038/leu.2009.86
   PubMed Web of Science ®Google Scholar
• Park JW, Park JM, Green JE, et al. Longterm effect of Wnt/β-catenin small molecule inhibitor CWP232291 on intestinal carcinogenesis in novel GEM model deficient in Smad4 and p53. J Clin Oncol. 2016;34(suppl4S; abstr 594).
   Google Scholar
• Cortes JE, Faderl S, Pagel J, et al. Phase 1 study of CWP232291 in relapse/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). J Clin Oncol. 2015;33(suppl;abstr 7044).
   Google Scholar
• Lenz HJ, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci. 2014;105(9):1087–1092. DOI:10.1111/cas.12471
   PubMed Web of Science ®Google Scholar
• Kern D, Regl G, Hofbauer SW, et al. Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia. Oncogene. 2015;34(42):5341–5351. DOI:10.1038/onc.2014.450
   PubMed Web of Science ®Google Scholar