Emerging pathways and future targets for the molecular therapy of pancreatic cancer

Expert Opinion on Therapeutic Targets

Volumn 15, Issue 10, 2011, Pages 1183-1196

  Vaccaro, Vanja ^a   Melisi, Davide ^b   Bria, Emilio ^a,c   Cuppone, Federica ^a   Ciuffreda, Ludovica ^a   Pino, Maria Simona ^a   Gelibter, Alain ^a   Tortora, Giampaolo ^c   Cognetti, Francesco ^a   Milella, Michele ^a  

^a REGINA ELENA NATIONAL CANCER INSTITUTE   (Italy)

^b NATIONAL CANCER INSTITUTE   (Italy)

^c UNIVERSITY OF VERONA   (Italy)

Author keywords

molecular pathways; pancreatic cancer; targeted therapy

Indexed keywords

ERLOTINIB; FOCAL ADHESION KINASE; GEMCITABINE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LIPOPOLYSACCHARIDE; PROTEIN P21; RHO KINASE; SMAD PROTEIN; SOMATOMEDIN; TRANSFORMING GROWTH FACTOR BETA;

B LYMPHOCYTE; DNA BINDING; GENE TARGETING; HEDGEHOG; HUMAN; IMMUNE RESPONSE; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; PANCREAS CANCER; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION;

HEDGEHOG PROTEINS; HUMANS; NF-KAPPA B; PANCREATIC NEOPLASMS; RECEPTORS, NOTCH; SIGNAL TRANSDUCTION; SOMATOMEDINS; TRANSFORMING GROWTH FACTOR BETA;

EID: 80052886108     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2011.607438     Document Type: Review

References (123)

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300
2. Petrelli NJ, Winer EP, Brahmer J, et al. Clinical Cancer Advances 2009: major research advances in cancer treatment, prevention, and screening - a report from the American Society of Clinical Oncology. J Clin Oncol 2009;27:6052-69
3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25
4. Garber K. Stromal depletion goes on trial in pancreatic cancer. J Natl Cancer Inst 2010;102:448-50
5. Milella M, Bria E, Cuppone F, et al. Current status of targeted agents (TA) in advanced pancreatic cancer (APC): Meta-analysis of randomized clinical trials (RCT). J Clin Oncol 2008;26:4637
6. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801-6
7. Massague J. TGFbeta in cancer. Cell 2008;134:215-30
8. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577-84 (Pubitemid 37280136)
9. Moustakas A, Heldin CH. Non-Smad TGF-beta signals. J Cell Sci 2005;118:3573-84
10. Feng XH, Derynck R. Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol 2005;21:659-93 (Pubitemid 41740650)
11. Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005;19:2783-810 (Pubitemid 41739965)
12. He W, Dorn DC, Erdjument-Bromage H, et al. Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. Cell 2006;125:929-41 (Pubitemid 43795187)
13. Descargues P, Sil AK, Sano Y, et al. IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2/ 3 signaling pathway that controls keratinocyte differentiation. Proc Natl Acad Sci USA 2008;105:2487-92 (Pubitemid 351520540)
14. Ozdamar B, Bose R, Barrios-Rodiles M, et al. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 2005;307:1603-9 (Pubitemid 40354739)
15. Bhowmick NA, Ghiassi M, Bakin A, et al. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 2001;12:27-36 (Pubitemid 32060576)
16. Suzuki K, Wilkes MC, Garamszegi N, et al. Transforming growth factor beta signaling via Ras in mesenchymal cells requires p21-activated kinase 2 for extracellular signal-regulated kinase-dependent transcriptional responses. Cancer Res 2007;67:3673-82 (Pubitemid 46762152)
17. Delaney JR, Mlodzik M. TGF-beta activated kinase-1: new insights into the diverse roles of TAK1 in development and immunity. Cell Cycle 2006;5:2852-5 (Pubitemid 44953934)
18. Yamaguchi K, Shirakabe K, Shibuya H, et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 1995;270:2008-11 (Pubitemid 26097194)
19. Adhikari A, Xu M, Chen ZJ. Ubiquitin-mediated activation of TAK1 and IKK. Oncogene 2007;26:3214-26 (Pubitemid 46763016)
20. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, et al. The kinase TAK1 can activate the NIK-IkappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 1999;398:252-6
21. Thiefes A, Wolter S, Mushinski JF, et al. Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor target genes. J Biol Chem 2005;280:27728-41 (Pubitemid 41076887)
22. Omori E, Matsumoto K, Sanjo H, et al. TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis. J Biol Chem 2006;281:19610-17 (Pubitemid 44035464)
23. Levy L, Hill CS. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 2006;17:41-58 (Pubitemid 43117515)
24. Culhaci N, Sagol O, Karademir S, et al. Expression of transforming growth factor-beta-1 and p27Kip1 in pancreatic adenocarcinomas: relation with cell-cycle-associated proteins and clinicopathologic characteristics. BMC Cancer 2005;5:98
25. Teraoka H, Sawada T, Yamashita Y, et al. TGF-beta1 promotes liver metastasis of pancreatic cancer by modulating the capacity of cellular invasion. Int J Oncol 2001;19:709-15
26. Friess H, Yamanaka Y, Buchler M, et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993;105:1846-56 (Pubitemid 24002804)
27. Wagner M, Kleeff J, Friess H, et al. Enhanced expression of the type II transforming growth factor-beta receptor is associated with decreased survival in human pancreatic cancer. Pancreas 1999;19:370-6 (Pubitemid 29501433)
28. Bierie B, Moses HL. TGF-beta and cancer. Cytokine Growth Factor Rev 2006;17:29-40
29. Yen TW, Aardal NP, Bronner MP, et al. Myofibroblasts are responsible for the desmoplastic reaction surrounding human pancreatic carcinomas. Surgery 2002;131:129-34 (Pubitemid 34169536)
30. Teicher BA. Transforming growth factor-beta and the immune response to malignant disease. Clin Cancer Res 2007;13:6247-51 (Pubitemid 350075011)
31. Bellone G, Carbone A, Smirne C, et al. Cooperative induction of a tolerogenic dendritic cell phenotype by cytokines secreted by pancreatic carcinoma cells. J Immunol 2006;177:3448-60 (Pubitemid 44277866)
32. Korpal M, Kang Y. Targeting the transforming growth factor-beta signalling pathway in metastatic cancer. Eur J Cancer 2010;46:1232-40
33. Furukawa T, Sunamura M, Horii A. Molecular mechanisms of pancreatic carcinogenesis. Cancer Sci 2006;97:1-7 (Pubitemid 43257020)
34. Truty MJ, Urrutia R. Basics of TGF-beta and pancreatic cancer. Pancreatology 2007;7:423-35
35. Biankin AV, Morey AL, Lee CS, et al. DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma. J Clin Oncol 2002;20:4531-42 (Pubitemid 35402956)
36. Pasche B, Kolachana P, Nafa K, et al. TbetaR-I(6A) is a candidate tumor susceptibility allele. Cancer Res 1999;59:5678-82
37. Yingling JM, Blanchard KL, Sawyer JS. Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004;3:1011-22 (Pubitemid 39642364)
38. Melisi D, Ishiyama S, Sclabas GM, et al. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 2008;7:829-40 (Pubitemid 351551036)
39. Sorrentino A, Thakur N, Grimsby S, et al. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol 2008;10:1199-207
40. Melisi D, Xia Q, Paradiso G, et al. Modulation of pancreatic cancer chemoresistance by inhibition of TAK1. J Natl Cancer Inst 2011;103:published online: 8 July 2011; doi: 10.1093/jnci/djr243 (in press)
41. Nagaraj NS, Datta PK. Targeting the transforming growth factor-beta signaling pathway in human cancer. Expert Opin Investig Drugs 2010;19:77-91
42. Oettle H, Hilbig A, Seufferlein T, et al. Phase I/II study with trabedersen (AP 12009) monotherapy for the treatment of patients with advanced pancreatic cancer, malignant melanoma, and colorectal carcinoma. ASCO Meeting Abstracts 2011;29:2513
43. Garber K. Companies waver in efforts to target transforming growth factor beta in cancer. J Natl Cancer Inst 2009;101:1664-7
44. Inman GJ. Switching TGFbeta from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev 2011;21:93-9
45. Adorno M, Cordenonsi M, Montagner M, et al. A mutant-p53/ Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 2009;137:87-98
46. Zhang B, Halder SK, Kashikar ND, et al. Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology 2010;138:969-80; e961-e963
47. Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 2000;92:1472-89
48. Stoeltzing O, Liu W, Reinmuth N, et al. Regulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer. Am J Pathol 2003;163:1001-11 (Pubitemid 37040136)
49. Foulstone E, Prince S, Zaccheo O, et al. Insulin-like growth factor ligands, receptors, and binding proteins in cancer. J Pathol 2005;205:145-53 (Pubitemid 40227987)
50. Momose I, Kunimoto S, Osono M, Ikeda D. Inhibitors of insulin-like growth factor-1 receptor tyrosine kinase are preferentially cytotoxic to nutrient-deprived pancreatic cancer cells. Biochem Biophys Res Commun 2009;380:171-6
51. Piao W, Wang Y, Adachi Y, et al. Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Mol Cancer Ther 2008;7:1483-93
52. Wong HH, Lemoine NR. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat Rev Gastroenterol Hepatol 2009;6:412-22
53. Hakam A, Fang Q, Karl R, Coppola D. Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. Dig Dis Sci 2003;48:1972-8 (Pubitemid 37410086)
54. Min Y, Adachi Y, Yamamoto H, et al. Genetic blockade of the insulin-like growth factor-I receptor: a promising strategy for human pancreatic cancer. Cancer Res 2003;63:6432-41 (Pubitemid 37255193)
55. Bergmann U, Funatomi H, Yokoyama M, et al. Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res 1995;55:2007-11
56. Lin Y, Tamakoshi A, Kikuchi S, et al. Serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, and the risk of pancreatic cancer death. Int J Cancer 2004;110:584-8 (Pubitemid 38658024)
57. Moser C, Schachtschneider P, Lang SA, et al. Inhibition of insulin-like growth factor-I receptor (IGF-IR) using NVP-AEW541, a small molecule kinase inhibitor, reduces orthotopic pancreatic cancer growth and angiogenesis. Eur J Cancer 2008;44:1577-86
58. Dimou AT, Syrigos KN, Saif MW. Novel agents for the treatment of pancreatic adenocarcinoma: any light at the end of the tunnel? Highlights from the "2010 ASCO Annual Meeting". Chicago, IL, USA. June 4-8, 2010; JOP 11: 324-327
59. Javle MM, Varadhachary GR, Shroff RT, et al. Phase I/II study of MK-0646, the humanized monoclonal IGF-1R antibody in combination with gemcitabine or gemcitabine plus erlotinib (E) for advanced pancreatic cancer. J Clin Oncol 2010;28:4039
60. Kindler HL, Richards DA, Stephenson J, et al. A placebo-controlled, randomized phase II study of conatumumab (C) or AMG 479 (A) or placebo (P) plus gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (mPC). J Clin Oncol 2010;28:4035
61. Jassem J, Langer CJ, Karp DD, et al. Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2010;28:7500
62. Zheng D, Golubovskaya V, Kurenova E, et al. A novel strategy to inhibit FAK and IGF-1R decreases growth of pancreatic cancer xenografts. Mol Carcinog 2009;49:200-9
63. Liu W, Bloom DA, Cance WG, et al. FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells. Carcinogenesis 2008;29:1096-107 (Pubitemid 351958687)
64. Bailey JM, Mohr AM, Hollingsworth MA. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene 2009;28:3513-25
65. Hidalgo M, Maitra A. The hedgehog pathway and pancreatic cancer. N Engl J Med 2009;361:2094-6
66. Hezel AF, Kimmelman AC, Stanger BZ, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006;20:1218-49 (Pubitemid 43727584)
67. Xu FG, Ma QY, Wang Z. Blockade of hedgehog signaling pathway as a therapeutic strategy for pancreatic cancer. Cancer Lett 2009;283:119-24
68. Nakamura K, Sasajima J, Mizukami Y, et al. Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells. PLoS One 2010;5:e8824
69. Lauth M, Bergstrom A, Shimokawa T, et al. DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nat Struct Mol Biol 2010;17:718-25
70. Morton JP, Lewis BC. Shh signaling and pancreatic cancer: implications for therapy? Cell Cycle 2007;6:1553-7 (Pubitemid 47327939)
71. Ghaneh P, Costello E, Neoptolemos JP. Biology and management of pancreatic cancer. Postgrad Med J 2008;84:478-97
72. Peukert S, Miller-Moslin K. Small-molecule inhibitors of the hedgehog signaling pathway as cancer therapeutics. ChemMedChem 2010;5:500-12
73. Theunissen JW, de Sauvage FJ. Paracrine Hedgehog signaling in cancer. Cancer Res 2009;69:6007-10
74. Nolan-Stevaux O, Lau J, Truitt ML, et al. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 2009;23:24-36
75. Tian H, Callahan CA, DuPree KJ, et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA 2009;106:4254-9
76. Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008;455:406-10
77. Bailey JM, Swanson BJ, Hamada T, et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res 2008;14:5995-6004
78. Pola R, Ling LE, Silver M, et al. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 2001;7:706-11 (Pubitemid 32588027)
79. Corcoran RB, Bachar Raveh T, Barakat MT, et al. Insulin-like growth factor 2 is required for progression to advanced medulloblastoma in patched1 heterozygous mice. Cancer Res 2008;68:8788-95
80. Yang SH, Andl T, Grachtchouk V, et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/beta3- catenin signaling. Nat Genet 2008;40:1130-5
81. Feldmann G, Dhara S, Fendrich V, et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 2007;67:2187-96 (Pubitemid 46424238)
82. Feldmann G, Habbe N, Dhara S, et al. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 2008;57:1420-30
83. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324:1457-61
84. Mullendore ME, Koorstra JB, Li YM, et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin Cancer Res 2009;15:2291-301
85. Mysliwiec P, Boucher MJ. Targeting Notch signaling in pancreatic cancer patients - rationale for new therapy. Adv Med Sci 2009;54:136-42
86. Dontu G, Jackson KW, McNicholas E, et al. Role of Notch signaling in cell-fate determination of human mammary stem/ progenitor cells. Breast Cancer Res 2004;6:R605-15
87. Siveke JT, Lubeseder-Martellato C, Lee M, et al. Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology 2008;134:544-55
88. Wang Z, Li Y, Kong D, et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res 2009;69:2400-7
89. Wang Z, Banerjee S, Li Y, et al. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res 2006;66:2778-84
90. Wang Z, Sengupta R, Banerjee S, et al. Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer. Cancer Res 2006;66:7653-60 (Pubitemid 44289223)
91. Kong D, Li Y, Wang Z, et al. Inhibition of angiogenesis and invasion by 3,3'-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res 2007;67:3310-19 (Pubitemid 46724870)
92. Imbimbo BP, Panza F, Frisardi V, et al. Therapeutic intervention for Alzheimer's disease with gamma-secretase inhibitors: still a viable option? Expert Opin Investig Drugs 2011;20:325-41
93. Panza F, Frisardi V, Imbimbo BP, et al. Review: gamma-Secretase inhibitors for the treatment of Alzheimer's disease: the current state. CNS Neurosci Ther 2010;16:272-84
94. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002;109(Suppl):S81-96
95. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002;2:301-10 (Pubitemid 37328783)
96. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002;2:725-34
97. Melisi D, Chiao PJ. NF-kappaB as a target for cancer therapy. Expert OpinTher Targets 2007;11:133-44
98. Niu J, Li Z, Peng B, Chiao PJ. Identification of an autoregulatory feedback pathway involving interleukin-1alpha in induction of constitutive NF-kappaB activation in pancreatic cancer cells. J Biol Chem 2004;279:16452-62 (Pubitemid 38509343)
99. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-kappaB activity. Annu Rev Immunol 2000;18:621-63 (Pubitemid 30365393)
100. Schmidt C, Peng B, Li Z, et al. Mechanisms of proinflammatory cytokine-induced biphasic NF-kappaB activation. Mol Cell 2003;12:1287-300 (Pubitemid 37487935)
101. Ben-Neriah Y. Regulatory functions of ubiquitination in the immune system. Nat Immunol 2002;3:20-6 (Pubitemid 34065613)
102. Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol 2002;3:221-7
103. Senftleben U, Cao Y, Xiao G, et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappaB signaling pathway. Science 2001;293:1495-9 (Pubitemid 32801552)
104. Fujioka S, Sclabas GM, Schmidt C, et al. Function of nuclear factor kappaB in pancreatic cancer metastasis. Clin Cancer Res 2003;9:346-54 (Pubitemid 36109751)
105. Fujioka S, Sclabas GM, Schmidt C, et al. Inhibition of constitutive NF-kappaB activity by IkappaBalphaM suppresses tumorigenesis. Oncogene 2003;22:1365-70 (Pubitemid 36384598)
106. Melisi D, Niu J, Chang Z, et al. Secreted interleukin-1alpha induces a metastatic phenotype in pancreatic cancer by sustaining a constitutive activation of nuclear factor-kappaB. Mol Cancer Res 2009;7:624-33
107. Joyce D, Albanese C, Steer J, et al. NF-kappaB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev 2001;12:73-90 (Pubitemid 32294588)
108. Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 2001;107:241-6 (Pubitemid 32157954)
109. Almoguera C, Shibata D, Forrester K, et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988;53:549-54
110. Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 2008;9:517-31 (Pubitemid 351881844)
111. Barbie DA, Tamayo P, Boehm JS, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 2009;462:108-12
112. Kim HJ, Hawke N, Baldwin AS. NF-kappaB and IKK as therapeutic targets in cancer. Cell Death Differ 2006;13:738-47
113. Pikarsky E, Ben-Neriah Y. NF-kappaB inhibition: a double-edged sword in cancer? Eur J Cancer 2006;42:779-84
114. Greten FR, Karin M. The IKK/ NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett 2004;206:193-9 (Pubitemid 38317289)
115. Olivier S, Robe P, Bours V. Can NF-kappaB be a target for novel and efficient anti-cancer agents? Biochem Pharmacol 2006;72:1054-68 (Pubitemid 44465845)
116. Gilmore TD, Herscovitch M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 2006;25:6887-99 (Pubitemid 44657858)
117. Egberts JH, Schniewind B, Sipos B, et al. Superiority of extended neoadjuvant chemotherapy with gemcitabine in pancreatic cancer: a comparative analysis in a clinically adapted orthotopic xenotransplantation model in SCID beige mice. Cancer Biol Ther 2007;6:1227-32 (Pubitemid 351590376)
118. Tepel J, Kruse ML, Kapischke M, et al. Adjuvant treatment of pancreatic carcinoma in a clinically adapted mouse resection model. Pancreatology 2006;6:240-7 (Pubitemid 44114494)
119. Woodcock J, Griffin JP, Behrman RE. Development of novel combination therapies. N Engl J Med 2011;364:985-7
120. Bria E, Milella M, Gelibter A, et al. Gemcitabine-based combinations for inoperable pancreatic cancer: have we made real progress? A meta-analysis of 20 Phase 3 trials. Cancer 2007;110:525-33 (Pubitemid 47106140)
121. Appels NM, Beijnen JH, Schellens JH. Development of farnesyl transferase inhibitors: a review. Oncologist 2005;10:565-78 (Pubitemid 41429120)
122. Bria E, Di Maio M, Carlini P, et al. Targeting targeted agents: open issues for clinical trial design. J Exp Clin Cancer Res 2009;28:66
123. Milella M, Ciuffreda L, Bria E, et al. In: Reddy LH, Couvreur P, editors.Macromolecular anticancer therapeutics. Humana Press; New York: 2010. p. 37-83.