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Harnessing Death Receptor Signaling for Cancer Treatment

Chapter
Part of the Cell Death in Biology and Diseases book series (CELLDEATH)

Abstract

Apoptosis, the cell’s intrinsic cell death program, is a key regulator of tissue homeostasis. Accordingly, tilting the balance between cell death on one side and cell proliferation on the other side toward survival promotes tumor formation. The death receptor (extrinsic) pathway represents one of the major apoptosis signaling cascades, which links exogenous stimuli via transmembrane surface receptors to the intracellular signaling machinery that mediates and executes the death signal. Since defects in death receptor signaling can confer resistance to apoptosis, a better understanding of the regulation of the signaling events and their perturbation in human cancers may lead to the identification of new molecular targets that can be exploited for therapeutic purposes. This strategy is expected to open new perspectives to target the death receptor pathway for cancer therapy.

Keywords

Death Receptor Decoy Receptor Trail Receptor Death Receptor Pathway Tumor Necrosis Factor Superfamily 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Work in the author’s laboratory is supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, the Bundesministerium für Forschung und Technologie (01GM0871, 01GM1104C), Wilhelm-Sander-Stiftung, Else Kröner-Fresenius-Stiftung, Novartis Stiftung für therapeutische Forschung, the European Community (ApopTrain, APO-SYS), and IAP6/18.

References

  1. 1.
    Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241PubMedGoogle Scholar
  2. 2.
    Evan GI, Vousden KH (2001) Proliferation, cell cycle and apoptosis in cancer. Nature 411:342–348PubMedGoogle Scholar
  3. 3.
    Fulda S (2009) Tumor resistance to apoptosis. Int J Cancer 124:511–515PubMedGoogle Scholar
  4. 4.
    Fulda S, Debatin KM (2006) Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25:4798–4811PubMedGoogle Scholar
  5. 5.
    Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108:153–164PubMedGoogle Scholar
  6. 6.
    Makin G, Dive C (2001) Apoptosis and cancer chemotherapy. Trends Cell Biol 11:22–26Google Scholar
  7. 7.
    Ashkenazi A (2008) Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev 19:325–331PubMedGoogle Scholar
  8. 8.
    Lavrik IN, Krammer PH (2012) Regulation of CD95/Fas signaling at the DISC. Cell Death Differ 19:36–41PubMedPubMedCentralGoogle Scholar
  9. 9.
    Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163PubMedGoogle Scholar
  10. 10.
    Fulda S, Galluzzi L, Kroemer G (2010) Targeting mitochondria for cancer therapy. Nat Rev Drug Discov 9:447–464PubMedGoogle Scholar
  11. 11.
    Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11:109–124PubMedGoogle Scholar
  12. 12.
    Logue SE, Martin SJ (2008) Caspase activation cascades in apoptosis. Biochem Soc Trans 36:1–9PubMedGoogle Scholar
  13. 13.
    Friesen C, Fulda S, Debatin KM (1997) Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells. Leukemia 11:1833–1841PubMedGoogle Scholar
  14. 14.
    Fulda S, Scaffidi C, Susin SA et al (1998) Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J Biol Chem 273:33942–33948PubMedGoogle Scholar
  15. 15.
    Fulda S (2009) Inhibitor of apoptosis proteins in hematological malignancies. Leukemia 23:467–476PubMedGoogle Scholar
  16. 16.
    Petak I, Danam RP, Tillman DM et al (2003) Hypermethylation of the gene promoter and enhancer region can regulate Fas expression and sensitivity in colon carcinoma. Cell Death Differ 10:211–217PubMedGoogle Scholar
  17. 17.
    Van Noesel MM, Van Bezouw S, Salomons GS et al (2002) Tumor-specific down-regulation of the tumor necrosis factor-related apoptosis-inducing ligand decoy receptors DcR1 and DcR2 is associated with dense promoter hypermethylation. Cancer Res 62:2157–2161PubMedGoogle Scholar
  18. 18.
    Maecker HL, Yun Z, Maecker HT et al (2002) Epigenetic changes in tumor Fas levels determine immune escape and response to therapy. Cancer Cell 2:139–148PubMedGoogle Scholar
  19. 19.
    Ashkenazi A (2008) Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat Rev Drug Discov 7:1001–1012PubMedGoogle Scholar
  20. 20.
    Dechant MJ, Fellenberg J, Scheuerpflug CG et al (2004) Mutation analysis of the apoptotic “death-receptors” and the adaptors TRADD and FADD/MORT-1 in osteosarcoma tumor samples and osteosarcoma cell lines. Int J Cancer 109:661–667PubMedGoogle Scholar
  21. 21.
    Pai SI, Wu GS, Ozoren N et al (1998) Rare loss-of-function mutation of a death receptor gene in head and neck cancer. Cancer Res 58:3513–3518PubMedGoogle Scholar
  22. 22.
    Jin Z, Mcdonald ER 3rd, Dicker DT et al (2004) Deficient tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor transport to the cell surface in human colon cancer cells selected for resistance to TRAIL-induced apoptosis. J Biol Chem 279:35829–35839PubMedGoogle Scholar
  23. 23.
    Pitti RM, Marsters SA, Lawrence DA et al (1998) Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396:699–703PubMedGoogle Scholar
  24. 24.
    Roth W, Isenmann S, Nakamura M et al (2001) Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Res 61:2759–2765PubMedGoogle Scholar
  25. 25.
    Merino D, Lalaoui N, Morizot A et al (2006) Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2. Mol Cell Biol 26:7046–7055PubMedPubMedCentralGoogle Scholar
  26. 26.
    Chamuleau ME, Ossenkoppele GJ, Van Rhenen A et al (2011) High TRAIL-R3TRAIL-R3 expression on leukemic blasts is associated with poor outcome and induces apoptosis-resistance which can be overcome by targeting TRAIL-R2TRAIL-R2. Leuk Res 35:741–749PubMedGoogle Scholar
  27. 27.
    Granci V, Bibeau F, Kramar A et al (2008) Prognostic significance of TRAIL-R1 and TRAIL-R3 expression in metastatic colorectal carcinomas. Eur J Cancer 44:2312–2318PubMedGoogle Scholar
  28. 28.
    Sheikh MS, Huang Y, Fernandez-Salas EA et al (1999) The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. Oncogene 18:4153–4159PubMedGoogle Scholar
  29. 29.
    Ruiz De Almodovar C, Ruiz-Ruiz C, Rodriguez A et al (2004) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) decoy receptor TRAIL-R3 is up-regulated by p53 in breast tumor cells through a mechanism involving an intronic p53-binding site. J Biol Chem 279:4093–4101PubMedGoogle Scholar
  30. 30.
    Meng RD, Mcdonald ER 3rd, Sheikh MS et al (2000) The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis. Mol Ther 1:130–144PubMedGoogle Scholar
  31. 31.
    Sheikh MS, Burns TF, Huang Y et al (1998) P53-dependent and -independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha. Cancer Res 58:1593–1598PubMedGoogle Scholar
  32. 32.
    Lalaoui N, Morle A, Merino D et al (2011) TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT. PLoS One 6:19679Google Scholar
  33. 33.
    Hao C, Beguinot F, Condorelli G et al (2001) Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis in human malignant glioma cells. Cancer Res 61:1162–1170PubMedGoogle Scholar
  34. 34.
    Krueger A, Baumann S, Krammer PH et al (2001) FLICE-inhibitory proteins: regulators of death receptor-mediated apoptosis. Mol Cell Biol 21:8247–8254PubMedPubMedCentralGoogle Scholar
  35. 35.
    Fulda S, Meyer E, Debatin KM (2000) Metabolic inhibitors sensitize for CD95 (APO-1/Fas)-induced apoptosis by down-regulating Fas-associated death domain-like interleukin 1-converting enzyme inhibitory protein expression. Cancer Res 60:3947–3956PubMedGoogle Scholar
  36. 36.
    Longley DB, Wilson TR, Mcewan M et al (2006) c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene 25:838–848PubMedGoogle Scholar
  37. 37.
    Haag C, Stadel D, Zhou S et al (2011) Identification of c-FLIP(L) and c-FLIP(S) as critical regulators of death receptor-induced apoptosis in pancreatic cancer cells. Gut 60:225–237PubMedGoogle Scholar
  38. 38.
    Krelin Y, Zhang L, Kang TB et al (2008) Caspase-8 deficiency facilitates cellular transformation in vitro. Cell Death Differ 15:1350–1355PubMedGoogle Scholar
  39. 39.
    Fulda S, Kufer MU, Meyer E et al (2001) Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene 20:5865–5877PubMedGoogle Scholar
  40. 40.
    Harada K, Toyooka S, Shivapurkar N et al (2002) Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res 62:5897–5901PubMedGoogle Scholar
  41. 41.
    Hopkins-Donaldson S, Ziegler A, Kurtz S et al (2003) Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ 10:356–364PubMedGoogle Scholar
  42. 42.
    Pingoud-Meier C, Lang D, Janss AJ et al (2003) Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma. Clin Cancer Res 9:6401–6409PubMedGoogle Scholar
  43. 43.
    Teitz T, Wei T, Valentine MB et al (2000) Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 6:529–535PubMedGoogle Scholar
  44. 44.
    Finlay D, Howes A, Vuori K (2009) Critical role for caspase-8 in epidermal growth factor signaling. Cancer Res 69:5023–5029PubMedPubMedCentralGoogle Scholar
  45. 45.
    Fulda S, Debatin KM (2006) 5-Aza-2′-deoxycytidine and IFN-gamma cooperate to sensitize for TRAIL-induced apoptosis by upregulating caspase-8caspase-8. Oncogene 25:5125–5133PubMedGoogle Scholar
  46. 46.
    Fulda S, Poremba C, Berwanger B et al (2006) Loss of caspase-8 expression does not correlate with MYCN amplification, aggressive disease, or prognosis in neuroblastoma. Cancer Res 66:10016–10023PubMedGoogle Scholar
  47. 47.
    Fulda S, Wick W, Weller M et al (2002) Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8:808–815PubMedGoogle Scholar
  48. 48.
    Grau E, Martinez F, Orellana C et al (2011) Hypermethylation of apoptotic genes as independent prognostic factor in neuroblastoma disease. Mol Carcinog 50:153–162PubMedGoogle Scholar
  49. 49.
    Himeji D, Horiuchi T, Tsukamoto H et al (2002) Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood 99:4070–4078PubMedGoogle Scholar
  50. 50.
    Horiuchi T, Himeji D, Tsukamoto H et al (2000) Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes. Biochem Biophys Res Commun 272:877–881PubMedGoogle Scholar
  51. 51.
    Miller MA, Karacay B, Zhu X et al (2006) Caspase 8L, a novel inhibitory isoform of caspase 8, is associated with undifferentiated neuroblastoma. Apoptosis 11:15–24PubMedGoogle Scholar
  52. 52.
    Mohr A, Zwacka RM, Jarmy G et al (2005) Caspase-8L expression protects CD34+ hematopoietic progenitor cells and leukemic cells from CD95-mediated apoptosis. Oncogene 24:2421–2429PubMedGoogle Scholar
  53. 53.
    Cursi S, Rufini A, Stagni V et al (2006) Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression. EMBO J 25:1895–1905PubMedPubMedCentralGoogle Scholar
  54. 54.
    Barbero S, Barila D, Mielgo A et al (2008) Identification of a critical tyrosine residue in caspase 8 that promotes cell migration. J Biol Chem 283:13031–13034PubMedPubMedCentralGoogle Scholar
  55. 55.
    Senft J, Helfer B, Frisch SM (2007) Caspase-8 interacts with the p85 subunit of phosphatidylinositol 3-kinase to regulate cell adhesion and motility. Cancer Res 67:11505–11509PubMedGoogle Scholar
  56. 56.
    Barbero S, Mielgo A, Torres V et al (2009) Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis. Cancer Res 69:3755–3763PubMedPubMedCentralGoogle Scholar
  57. 57.
    Torres VA, Mielgo A, Barbero S et al (2010) Rab5 mediates caspase-8-promoted cell motility and metastasis. Mol Biol Cell 21:369–376PubMedPubMedCentralGoogle Scholar
  58. 58.
    Chuntharapai A, Dodge K, Grimmer K et al (2001) Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. J Immunol 166:4891–4898PubMedGoogle Scholar
  59. 59.
    Ichikawa K, Liu W, Zhao L et al (2001) Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med 7:954–960PubMedGoogle Scholar
  60. 60.
    Takeda K, Yamaguchi N, Akiba H et al (2004) Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J Exp Med 199:437–448PubMedPubMedCentralGoogle Scholar
  61. 61.
    Lin T, Huang X, Gu J et al (2002) Long-term tumor-free survival from treatment with the GFP-TRAIL fusion gene expressed from the hTERT promoter in breast cancer cells. Oncogene 21:8020–8028PubMedGoogle Scholar
  62. 62.
    Mohr A, Albarenque SM, Deedigan L et al (2010) Targeting of XIAP combined with systemic mesenchymal stem cell-mediated delivery of sTRAIL ligand inhibits metastatic growth of pancreatic carcinoma cells. Stem Cells 28:2109–2120PubMedGoogle Scholar
  63. 63.
    Mohr A, Lyons M, Deedigan L et al (2008) Mesenchymal stem cells expressing TRAIL lead to tumour growth inhibition in an experimental lung cancer model. J Cell Mol Med 12:2628–2643PubMedGoogle Scholar
  64. 64.
    Belka C, Schmid B, Marini P et al (2001) Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL. Oncogene 20:2190–2196PubMedGoogle Scholar
  65. 65.
    Chinnaiyan AM, Prasad U, Shankar S et al (2000) Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. Proc Natl Acad Sci USA 97:1754–1759PubMedPubMedCentralGoogle Scholar
  66. 66.
    Gliniak B, Le T (1999) Tumor necrosis factor-related apoptosis-inducing ligand’s antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. Cancer Res 59:6153–6158PubMedGoogle Scholar
  67. 67.
    Keane MM, Rubinstein Y, Cuello M et al (2000) Inhibition of NF-kappaB activity enhances TRAIL mediated apoptosis in breast cancer cell lines. Breast Cancer Res Treat 64:211–219PubMedGoogle Scholar
  68. 68.
    Nagane M, Pan G, Weddle JJ et al (2000) Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 60:847–853PubMedGoogle Scholar
  69. 69.
    Ray S, Almasan A (2003) Apoptosis induction in prostate cancer cells and xenografts by combined treatment with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand and CPT-11. Cancer Res 63:4713–4723PubMedGoogle Scholar
  70. 70.
    Rohn TA, Wagenknecht B, Roth W et al (2001) CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. Oncogene 20:4128–4137PubMedGoogle Scholar
  71. 71.
    Singh TR, Shankar S, Chen X et al (2003) Synergistic interactions of chemotherapeutic drugs and tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand on apoptosis and on regression of breast carcinoma in vivo. Cancer Res 63:5390–5400PubMedGoogle Scholar
  72. 72.
    Meng RD, El-Deiry WS (2001) p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. Exp Cell Res 262:154–169PubMedGoogle Scholar
  73. 73.
    Takimoto R, El-Deiry WS (2000) Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene 19:1735–1743PubMedGoogle Scholar
  74. 74.
    Wang S, El-Deiry WS (2003) Requirement of p53 targets in chemosensitization of colonic carcinoma to death ligand therapy. Proc Natl Acad Sci USA 100:15095–15100PubMedPubMedCentralGoogle Scholar
  75. 75.
    Lacour S, Micheau O, Hammann A et al (2003) Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells. Oncogene 22:1807–1816PubMedGoogle Scholar
  76. 76.
    Morizot A, Merino D, Lalaoui N et al (2011) Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level. Cell Death Differ 18:700–711PubMedPubMedCentralGoogle Scholar
  77. 77.
    Baritaki S, Suzuki E, Umezawa K et al (2008) Inhibition of Yin Yang 1-dependent repressor activity of DR5 transcription and expression by the novel proteasome inhibitor NPI-0052 contributes to its TRAIL-enhanced apoptosis in cancer cells. J Immunol 180:6199–6210PubMedPubMedCentralGoogle Scholar
  78. 78.
    Brooks AD, Jacobsen KM, Li W et al (2010) Bortezomib sensitizes human renal cell carcinomas to TRAIL apoptosis through increased activation of caspase-8caspase-8 in the death-inducing signaling complex. Mol Cancer Res 8:729–738PubMedPubMedCentralGoogle Scholar
  79. 79.
    Concannon CG, Koehler BF, Reimertz C et al (2007) Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway. Oncogene 26:1681–1692PubMedGoogle Scholar
  80. 80.
    Conticello C, Adamo L, Giuffrida R et al (2007) Proteasome inhibitors synergize with tumor necrosis factor-related apoptosis-induced ligand to induce anaplastic thyroid carcinoma cell death. J Clin Endocrinol Metab 92:1938–1942PubMedGoogle Scholar
  81. 81.
    Ding WX, Ni HM, Chen X et al (2007) A coordinated action of Bax, PUMA, and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells. Mol Cancer Ther 6:1062–1069PubMedGoogle Scholar
  82. 82.
    Ganten TM, Koschny R, Haas TL et al (2005) Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL. Hepatology 42:588–597PubMedGoogle Scholar
  83. 83.
    He Q, Huang Y, Sheikh MS (2004) Proteasome inhibitor MG132 upregulates death receptor 5 and cooperates with Apo2L/TRAIL to induce apoptosis in Bax-proficient and -deficient cells. Oncogene 23:2554–2558PubMedGoogle Scholar
  84. 84.
    Hetschko H, Voss V, Seifert V et al (2008) Upregulation of DR5 by proteasome inhibitors potently sensitizes glioma cells to TRAIL-induced apoptosis. FEBS J 275:1925–1936PubMedGoogle Scholar
  85. 85.
    Inoue T, Shiraki K, Fuke H et al (2006) Proteasome inhibition sensitizes hepatocellular carcinoma cells to TRAIL by suppressing caspase inhibitors and AKT pathway. Anticancer Drugs 17:261–268PubMedGoogle Scholar
  86. 86.
    Johnson TR, Stone K, Nikrad M et al (2003) The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. Oncogene 22:4953–4963PubMedGoogle Scholar
  87. 87.
    Kandasamy K, Kraft AS (2008) Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3′-untranslated region. Mol Cancer Ther 7:1091–1100PubMedPubMedCentralGoogle Scholar
  88. 88.
    Kashkar H, Deggerich A, Seeger JM et al (2007) NF-kappaB-independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs. Blood 109:3982–3988PubMedGoogle Scholar
  89. 89.
    Khanbolooki S, Nawrocki ST, Arumugam T et al (2006) Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Mol Cancer Ther 5:2251–2260PubMedGoogle Scholar
  90. 90.
    Koschny R, Ganten TM, Sykora J et al (2007) TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window. Hepatology 45:649–658PubMedGoogle Scholar
  91. 91.
    Koschny R, Holland H, Sykora J et al (2007) Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Clin Cancer Res 13:3403–3412PubMedGoogle Scholar
  92. 92.
    Lashinger LM, Zhu K, Williams SA et al (2005) Bortezomib abolishes tumor necrosis factor-related apoptosis-inducing ligand resistance via a p21-dependent mechanism in human bladder and prostate cancer cells. Cancer Res 65:4902–4908PubMedGoogle Scholar
  93. 93.
    Leverkus M, Sprick MR, Wachter T et al (2003) Proteasome inhibition results in TRAIL sensitization of primary keratinocytes by removing the resistance-mediating block of effector caspase maturation. Mol Cell Biol 23:777–790PubMedPubMedCentralGoogle Scholar
  94. 94.
    Liu FT, Agrawal SG, Gribben JG et al (2008) Bortezomib blocks Bax degradation in malignant B cells during treatment with TRAIL. Blood 111:2797–2805PubMedGoogle Scholar
  95. 95.
    Liu X, Yue P, Chen S et al (2007) The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and surviving expression in human NSCLC cells. Cancer Res 67:4981–4988PubMedGoogle Scholar
  96. 96.
    Nagy K, Szekely-Szuts K, Izeradjene K et al (2006) Proteasome inhibitors sensitize colon carcinoma cells to TRAIL-induced apoptosis via enhanced release of Smac/DIABLO from the mitochondria. Pathol Oncol Res 12:133–142PubMedGoogle Scholar
  97. 97.
    Naumann I, Kappler R, Von Schweinitz D et al (2011) Bortezomib primes neuroblastoma cells for TRAIL-induced apoptosis by linking the death receptor to the mitochondrial pathway. Clin Cancer Res 17:3204–3218PubMedGoogle Scholar
  98. 98.
    Nikrad M, Johnson T, Puthalalath H et al (2005) The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Mol Cancer Ther 4:443–449PubMedGoogle Scholar
  99. 99.
    Sayers TJ, Brooks AD, Koh CY et al (2003) The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 102:303–310PubMedGoogle Scholar
  100. 100.
    Shanker A, Brooks AD, Tristan CA et al (2008) Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody. J Natl Cancer Inst 100:649–662PubMedPubMedCentralGoogle Scholar
  101. 101.
    Tan TT, Degenhardt K, Nelson DA et al (2005) Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell 7:227–238PubMedGoogle Scholar
  102. 102.
    Thorpe JA, Christian PA, Schwarze SR (2008) Proteasome inhibition blocks caspase-8 degradation and sensitizes prostate cancer cells to death receptor-mediated apoptosis. Prostate 68:200–209PubMedGoogle Scholar
  103. 103.
    Unterkircher T, Cristofanon S, Vellanki SH et al (2011) Bortezomib primes glioblastoma, including glioblastoma stem cells, for TRAIL by increasing tBid stability and mitochondrial apoptosis. Clin Cancer Res 17:4019–4030PubMedGoogle Scholar
  104. 104.
    Voortman J, Resende TP, Abou El Hassan MA et al (2007) TRAIL therapy in non-small cell lung cancer cells: sensitization to death receptor-mediated apoptosis by proteasome inhibitor bortezomib. Mol Cancer Ther 6:2103–2112PubMedGoogle Scholar
  105. 105.
    Yoshida T, Shiraishi T, Nakata S et al (2005) Proteasome inhibitor MG132 induces death receptor 5 through CCAAT/enhancer-binding protein homologous protein. Cancer Res 65:5662–5667PubMedGoogle Scholar
  106. 106.
    Zhao X, Qiu W, Kung J et al (2008) Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res 32:275–285PubMedGoogle Scholar
  107. 107.
    Zhu H, Guo W, Zhang L et al (2005) Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. Cancer Biol Ther 4:781–786PubMedPubMedCentralGoogle Scholar
  108. 108.
    Fulda S (2012) Histone deacetylase (HDAC) inhibitors and regulation of TRAIL-induced apoptosis. Exp Cell Res 318:1208–1212Google Scholar
  109. 109.
    Butler LM, Liapis V, Bouralexis S et al (2006) The histone deacetylase inhibitor, suberoylanilide hydroxamic acid, overcomes resistance of human breast cancer cells to Apo2L/TRAIL. Int J Cancer 119:944–954PubMedGoogle Scholar
  110. 110.
    Chopin V, Slomianny C, Hondermarck H et al (2004) Synergistic induction of apoptosis in breast cancer cells by cotreatment with butyrate and TNF-alpha, TRAIL, or anti-FasFas agonist antibody involves enhancement of death receptor’s signaling and requires P21(waf1). Exp Cell Res 298:560–573PubMedGoogle Scholar
  111. 111.
    Earel JK Jr, Vanoosten RL, Griffith TS (2006) Histone deacetylase inhibitors modulate the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand-resistant bladder tumor cells. Cancer Res 66:499–507PubMedGoogle Scholar
  112. 112.
    Guo F, Sigua C, Tao J et al (2004) Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. Cancer Res 64:2580–2589PubMedGoogle Scholar
  113. 113.
    Inoue S, Macfarlane M, Harper N et al (2004) Histone deacetylase inhibitors potentiate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in lymphoid malignancies. Cell Death Differ 11(Suppl 2):193–206Google Scholar
  114. 114.
    Kim YH, Park JW, Lee JY et al (2004) Sodium butyrate sensitizes TRAIL-mediated apoptosis by induction of transcription from the DR5 gene promoter through Sp1 sites in colon cancer cells. Carcinogenesis 25:1813–1820PubMedGoogle Scholar
  115. 115.
    Nakata S, Yoshida T, Horinaka M et al (2004) Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. Oncogene 23:6261–6271PubMedGoogle Scholar
  116. 116.
    Singh TR, Shankar S, Srivastava RK (2005) HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 24:4609–4623PubMedGoogle Scholar
  117. 117.
    Vanoosten RL, Moore JM, Karacay B et al (2005) Histone deacetylase inhibitors modulate renal cell carcinoma sensitivity to TRAIL/Apo-2L-induced apoptosis by enhancing TRAIL-R2 expression. Cancer Biol Ther 4:1104–1112PubMedGoogle Scholar
  118. 118.
    Vanoosten RL, Moore JM, Ludwig AT et al (2005) Depsipeptide (FR901228) enhances the cytotoxic activity of TRAIL by redistributing TRAIL receptor to membrane lipid rafts. Mol Ther 11:542–552PubMedGoogle Scholar
  119. 119.
    Hacker S, Dittrich A, Mohr A et al (2009) Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8. Oncogene 28:3097–3110PubMedGoogle Scholar
  120. 120.
    Aron JL, Parthun MR, Marcucci G et al (2003) Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIPc-FLIP protein. Blood 102:652–658PubMedGoogle Scholar
  121. 121.
    Hernandez A, Thomas R, Smith F et al (2001) Butyrate sensitizes human colon cancer cells to TRAIL-mediated apoptosis. Surgery 130:265–272PubMedGoogle Scholar
  122. 122.
    Pathil A, Armeanu S, Venturelli S et al (2006) HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology 43:425–434PubMedGoogle Scholar
  123. 123.
    Schuchmann M, Schulze-Bergkamen H, Fleischer B et al (2006) Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy. Oncol Rep 15:227–230PubMedGoogle Scholar
  124. 124.
    Watanabe K, Okamoto K, Yonehara S (2005) Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP. Cell Death Differ 12:10–18PubMedGoogle Scholar
  125. 125.
    Reddy RM, Yeow WS, Chua A et al (2007) Rapid and profound potentiation of Apo2L/TRAIL-mediated cytotoxicity and apoptosis in thoracic cancer cells by the histone deacetylase inhibitor Trichostatin A: the essential role of the mitochondria-mediated caspase activation cascade. Apoptosis 12:55–71PubMedGoogle Scholar
  126. 126.
    El-Zawahry A, Lu P, White SJ et al (2006) In vitro efficacy of AdTRAIL gene therapy of bladder cancer is enhanced by trichostatin A-mediated restoration of CAR expression and downregulation of cFLIP and Bcl-XLBcl-XL. Cancer Gene Ther 13:281–289PubMedGoogle Scholar
  127. 127.
    Gillespie S, Borrow J, Zhang XD et al (2006) Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. Apoptosis 11:2251–2265PubMedGoogle Scholar
  128. 128.
    Muhlethaler-Mottet A, Flahaut M, Bourloud KB et al (2006) Histone deacetylase inhibitors strongly sensitise neuroblastoma cells to TRAIL-induced apoptosis by a caspases-dependent increase of the pro- to anti-apoptotic proteins ratio. BMC Cancer 6:214PubMedPubMedCentralGoogle Scholar
  129. 129.
    Neuzil J, Swettenham E, Gellert N (2004) Sensitization of mesothelioma to TRAIL apoptosis by inhibition of histone deacetylase: role of Bcl-xL down-regulation. Biochem Biophys Res Commun 314:186–191PubMedGoogle Scholar
  130. 130.
    Zhang XD, Gillespie SK, Borrow JM et al (2004) The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells. Mol Cancer Ther 3:425–435PubMedGoogle Scholar
  131. 131.
    Abhari BA, Cristofanon S, Kappler R et al (2012) RIP1 is required for IAP inhibitor-mediated sensitization for TRAIL-induced apoptosis via a RIP/FADD/caspase-8 cell death complex. Oncogene: Aug 13 [E-pub ahead of print]Google Scholar
  132. 132.
    Fakler M, Loeder S, Vogler M et al (2009) Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance. Blood 113:1710–1722PubMedGoogle Scholar
  133. 133.
    Hiscutt EL, Hill DS, Martin S et al (2010) Targeting X-linked inhibitor of apoptosis protein to increase the efficacy of endoplasmic reticulum stress-induced apoptosis for melanoma therapy. J Invest Dermatol 130:2250–2258PubMedGoogle Scholar
  134. 134.
    Loeder S, Drensek A, Jeremias I et al (2010) Small molecule XIAP inhibitors sensitize childhood acute leukemia cells for CD95-induced apoptosis. Int J Cancer 126:2216–2228PubMedGoogle Scholar
  135. 135.
    Loeder S, Zenz T, Schnaiter A et al (2009) A novel paradigm to trigger apoptosis in chronic lymphocytic leukemia. Cancer Res 69:8977–8986PubMedGoogle Scholar
  136. 136.
    Stadel D, Mohr A, Ref C et al (2010) TRAIL-induced apoptosis is preferentially mediated via TRAIL receptor 1 in pancreatic carcinoma cells and profoundly enhanced by XIAP inhibitors. Clin Cancer Res 16:5734–5749PubMedGoogle Scholar
  137. 137.
    Varfolomeev E, Alicke B, Elliott JM et al (2009) X chromosome-linked inhibitor of apoptosis regulates cell death induction by proapoptotic receptor agonists. J Biol Chem 284:34553–34560PubMedPubMedCentralGoogle Scholar
  138. 138.
    Vogler M, Durr K, Jovanovic M et al (2007) Regulation of TRAIL-induced apoptosis by XIAP in pancreatic carcinoma cells. Oncogene 26:248–257PubMedGoogle Scholar
  139. 139.
    Vogler M, Walczak H, Stadel D et al (2009) Small molecule XIAP inhibitors enhance TRAIL-induced apoptosis and antitumor activity in preclinical models of pancreatic carcinoma. Cancer Res 69:2425–2434PubMedGoogle Scholar
  140. 140.
    Vogler M, Walczak H, Stadel D et al (2008) Targeting XIAP bypasses Bcl-2-mediated resistance to TRAIL and cooperates with TRAIL to suppress pancreatic cancer growth in vitro and in vivo. Cancer Res 68:7956–7965PubMedGoogle Scholar
  141. 141.
    Eggert A, Grotzer MA, Zuzak TJ et al (2001) Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Cancer Res 61:1314–1319PubMedGoogle Scholar
  142. 142.
    Grotzer MA, Eggert A, Zuzak TJ et al (2000) Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 19:4604–4610PubMedGoogle Scholar
  143. 143.
    Hopkins-Donaldson S, Bodmer JL, Bourloud KB et al (2000) Loss of caspase-8 expression in highly malignant human neuroblastoma cells correlates with resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 60:4315–4319PubMedGoogle Scholar
  144. 144.
    Casciano I, De Ambrosis A, Croce M et al (2004) Expression of the caspase-8caspase-8 gene in neuroblastoma cells is regulated through an essential interferon-sensitive response element (ISRE). Cell Death Differ 11:131–134PubMedGoogle Scholar
  145. 145.
    Ruiz-Ruiz C, Ruiz De Almodovar C, Rodriguez A et al (2004) The up-regulation of human caspase-8 by interferon-gamma in breast tumor cells requires the induction and action of the transcription factor interferon regulatory factor-1. J Biol Chem 279:19712–19720PubMedGoogle Scholar
  146. 146.
    Yang X, Merchant MS, Romero ME et al (2003) Induction of caspase 8 by interferon gamma renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB. Cancer Res 63:1122–1129PubMedGoogle Scholar
  147. 147.
    Casciano I, Banelli B, Croce M et al (2004) Caspase-8 gene expression in neuroblastoma. Ann N Y Acad Sci 1028:157–167PubMedGoogle Scholar
  148. 148.
    Das A, Banik NL, Ray SK (2009) Molecular mechanisms of the combination of retinoid and interferon-gamma for inducing differentiation and increasing apoptosis in human glioblastoma T98G and U87MG cells. Neurochem Res 34:87–101PubMedGoogle Scholar
  149. 149.
    De Ambrosis A, Casciano I, Croce M et al (2007) An interferon-sensitive response element is involved in constitutive caspase-8caspase-8 gene expression in neuroblastoma cells. Int J Cancer 120:39–47PubMedGoogle Scholar
  150. 150.
    Fulda S, Debatin KM (2002) IFN gamma sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway. Oncogene 21:2295–2308PubMedGoogle Scholar
  151. 151.
    Johnsen JI, Pettersen I, Ponthan F et al (2004) Synergistic induction of apoptosis in neuroblastoma cells using a combination of cytostatic drugs with interferon-gamma and TRAIL. Int J Oncol 25:1849–1857PubMedGoogle Scholar
  152. 152.
    Kim KB, Choi YH, Kim IK et al (2002) Potentiation of Fas- and TRAIL-mediated apoptosis by IFN-gamma in A549 lung epithelial cells: enhancement of caspase-8 expression through IFN-response element. Cytokine 20:283–288PubMedGoogle Scholar
  153. 153.
    Kontny HU, Hammerle K, Klein R et al (2001) Sensitivity of Ewing’s sarcoma to TRAIL-induced apoptosis. Cell Death Differ 8:506–514PubMedGoogle Scholar
  154. 154.
    Lissat A, Vraetz T, Tsokos M et al (2007) Interferon-gamma sensitizes resistant Ewing’s sarcoma cells to tumor necrosis factor apoptosis-inducing ligand-induced apoptosis by up-regulation of caspase-8 without altering chemosensitivity. Am J Pathol 170:1917–1930PubMedPubMedCentralGoogle Scholar
  155. 155.
    Meister N, Shalaby T, Von Bueren AO et al (2007) Interferon-gamma mediated up-regulation of caspase-8 sensitizes medulloblastoma cells to radio- and chemotherapy. Eur J Cancer 43:1833–1841PubMedGoogle Scholar
  156. 156.
    Merchant MS, Yang X, Melchionda F et al (2004) Interferon gamma enhances the effectiveness of tumor necrosis factor-related apoptosis-inducing ligand receptor agonists in a xenograft model of Ewing’s sarcoma. Cancer Res 64:8349–8356PubMedGoogle Scholar
  157. 157.
    Ruiz-Ruiz C, Munoz-Pinedo C, Lopez-Rivas A (2000) Interferon-gamma treatment elevates caspase-8 expression and sensitizes human breast tumor cells to a death receptor-induced mitochondria-operated apoptotic program. Cancer Res 60:5673–5680PubMedGoogle Scholar
  158. 158.
    Tekautz TM, Zhu K, Grenet J et al (2006) Evaluation of IFN-gamma effects on apoptosis and gene expression in neuroblastoma–preclinical studies. Biochim Biophys Acta 1763:1000–1010PubMedGoogle Scholar
  159. 159.
    Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662PubMedGoogle Scholar
  160. 160.
    Wexler L, Thiele CJ, Mcclure L et al (1992) Adoptive immunotherapy of refractory neuroblastoma with tumor-infiltrating lymphocytes, interferon-{gamma}, and interleukin-2. Proc Ann Meet Am Soc Clin Oncol 11:368Google Scholar
  161. 161.
    Liedtke C, Groger N, Manns MP et al (2006) Interferon-alpha enhances TRAIL-mediated apoptosis by up-regulating caspase-8 transcription in human hepatoma cells. J Hepatol 44:342–349PubMedGoogle Scholar
  162. 162.
    Ehrhardt H, Hacker S, Wittmann S et al (2008) Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells. Oncogene 27:783–793PubMedGoogle Scholar
  163. 163.
    Jiang M, Zhu K, Grenet J et al (2008) Retinoic acid induces caspase-8 transcription via phospho-CREB and increases apoptotic responses to death stimuli in neuroblastoma cells. Biochim Biophys Acta 1783:1055–1067PubMedPubMedCentralGoogle Scholar
  164. 164.
    Belada D, Smolej L, Stepankova P et al (2010) Diffuse large B-cell lymphoma in a patient with hyper-IgE syndrome: Successful treatment with risk-adapted rituximab-based immunochemotherapy. Leuk Res 34:232–234Google Scholar
  165. 165.
    Fanale MA, Younes A (2008) Nodular lymphocyte predominant Hodgkin’s lymphoma. Cancer Treat Res 142:367–381PubMedGoogle Scholar
  166. 166.
    Herbst RS, Eckhardt SG, Kurzrock R et al (2010) Phase I Dose-Escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. J Clin Oncol 28:2839–2846Google Scholar
  167. 167.
    Soria JC, Mark Z, Zatloukal P et al (2011) Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. J Clin Oncol 29:4442–4451PubMedGoogle Scholar
  168. 168.
    Soria JC, Smit E, Khayat D et al (2010) Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and bevacizumab in patients with advanced non-squamous non-small-cell lung cancer. J Clin Oncol 28:1527–1533PubMedGoogle Scholar
  169. 169.
    Yee YK, Tan VP, Chan P et al (2009) Epidemiology of colorectal cancer in Asia. J Gastroenterol Hepatol 24:1810–1816PubMedGoogle Scholar
  170. 170.
    Greco FA, Bonomi P, Crawford J et al (2008) Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung Cancer 61:82–90PubMedGoogle Scholar
  171. 171.
    Hotte SJ, Hirte HW, Chen EX et al (2008) A Phase 1 Study of Mapatumumab (Fully Human Monoclonal Antibody to TRAIL-R1) in Patients with Advanced Solid Malignancies. Clin Cancer Res 14:3450–3455PubMedGoogle Scholar
  172. 172.
    Leong S, Cohen RB, Gustafson DL et al (2009) Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study. J Clin Oncol 27:4413–4421PubMedGoogle Scholar
  173. 173.
    Mom CH, Verweij J, Oldenhuis CN et al (2009) Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a phase I study. Clin Cancer Res 15:5584–5590PubMedGoogle Scholar
  174. 174.
    Pawel JV, Harvey JH, Spigel DR et al (2010) A randomized phase II trial of mapatumumab, a TRAIL-R1 agonist monoclonal antibody, in combination with carboplatin and paclitaxel in patients with advanced NSCLC. J Clin Oncol 28 supplGoogle Scholar
  175. 175.
    Sun W, Sohal D, Haller DG et al (2011) Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer 117:3187–3192PubMedGoogle Scholar
  176. 176.
    Tolcher AW, Mita M, Meropol NJ et al (2007) Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol 25:1390–1395PubMedGoogle Scholar
  177. 177.
    Trarbach T, Moehler M, Heinemann V et al (2010) Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer 102:506–512PubMedPubMedCentralGoogle Scholar
  178. 178.
    Younes A, Vose JM, Zelenetz AD et al (2010) A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin’s lymphoma. Br J Cancer 103:1783–1787PubMedPubMedCentralGoogle Scholar
  179. 179.
    Merchant MS, Chou AJ, Price A et al (2010) Lexatumumab: Results of a phase I trial in pediatric patients with advanced solid tumors. J Clin Oncol 28:9500 (Meeting Abstracts)Google Scholar
  180. 180.
    Plummer R, Attard G, Pacey S et al (2007) Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res 13:6187–6194PubMedGoogle Scholar
  181. 181.
    Sikic BI, Wakelee HA, Mehren MV et al (2007) A phase 1b study to assess the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2, in 32 combination with gemcitabine, pemetrexed, doxorubicin or FOLFIRI. J Clin Oncol 25:14006 (Meeting Abstracts)Google Scholar
  182. 182.
    Wakelee HA, Patnaik A, Sikic BI et al (2010) Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors. Ann Oncol 21:376–381PubMedPubMedCentralGoogle Scholar
  183. 183.
    Chawla SP, Tabernero J, Kindler HL et al (2010) Phase I evaluation of the safety of conatumumab (AMG 655) in combination with AMG 479 in patients (pts) with advanced, refractory solid tumors. J Clin Oncol 28:3102 (Meeting Abstracts)Google Scholar
  184. 184.
    Doi T, Murakami H, Ohtsu A et al (2011) Phase 1 study of conatumumab, a pro-apoptotic death receptor 5 agonist antibody, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 68:733–741Google Scholar
  185. 185.
    Kindler HL, Garbo L, Stephenson J et al (2009) A phase 1b study to evaluate the safety and efficacy of AMG 655 in combination with gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (PC). J Clin Oncol 27:4501 (Meeting Abstracts)Google Scholar
  186. 186.
    Kindler HL, Richards DA, Stephenson J et al (2010) A placebo-controlled, randomized phase 34 II study of conatumumab (C) or AMG 479 (A) or placebo (P) plus gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (mPC). Clin Oncol 28:4035 (Meeting Abstracts)Google Scholar
  187. 187.
    Paz-Ares L, Torres JMS, Diaz-Padilla I et al (2009) Safety and efficacy of AMG 655 in 33 combination with paclitaxel and carboplatin (PC) in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 27:19048 (Meeting Abstracts)Google Scholar
  188. 188.
    Peeters M, Infante P, PLR J et al (2010) Phase Ib/II trial of conatumumab and panitumumab (pmab) for the treatment (tx) of metastatic colorectal cancer (mCRC): Safety and efficacy, ASCO Gastrointestinal Cancers Symposium, abstract 443Google Scholar
  189. 189.
    Saltz L, Infante J, Schwartzberg L et al (2009) Safety and efficacy of AMG 655 plus modified FOLFOX6 (mFOLFOX6) and bevacizumab (B) for the first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol 27:4079 (Meeting Abstracts)Google Scholar
  190. 190.
    Baron AD, O’bryant CL, Choi Y et al (2011) Phase 1b study of drozitumab combined with cetuximab (CET) plus irinotecan (IRI) or with FOLFIRI±bevacizumab (BV) in previously treated patients (pts) with metastatic colorectal cancer (mCRC). Clin Oncol 29:3581 (Meeting Abstracts)Google Scholar
  191. 191.
    Camidge DR, Herbst RS, Gordon MS et al (2010) A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies. Clin Cancer Res 16:1256–1263PubMedGoogle Scholar
  192. 192.
    Karapetis CS, Clingan PR, Leighl NB et al (2010) Phase II study of PRO95780 plus paclitaxel, carboplatin, and bevacizumab (PCB) in non-small cell lung cancer (NSCLC). J Clin Oncol 28:7535 (Meeting Abstracts)Google Scholar
  193. 193.
    Rocha CSL, Baranda JC, Wallmark J et al (2011) Phase 1b study of drozitumab combined with first-line FOLFOX plus bevacizumab (BV) in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol 29:546 (Meeting Abstracts)Google Scholar
  194. 194.
    Wittebol S, Ferrant A, Wickham NW et al (2010) Phase II study of PRO95780 plus rituximab in patients with relapsed follicular non-Hodgkin’s lymphoma (NHL). J Clin Oncol 28:18511 (Meeting Abstracts)Google Scholar
  195. 195.
    Forero-Torres A, Shah J, Wood T et al (2010) Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5). Cancer biother radiopharm 25:13–19PubMedPubMedCentralGoogle Scholar
  196. 196.
    Sharma S, Vries EGD, Infante JR et al (2008) Phase I trial of LBY135, a monoclonal antibody agonist to DR5, alone and in combination with capecitabine in advanced solid tumors. J Clin Oncol 26:3538 (Meeting Abstracts)Google Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Institute for Experimental Cancer Research in Pediatrics, Goethe-University FrankfurtFrankfurtGermany

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