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Reviews

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

, MD, , MD, PhD, , MD, , MD, , PhD, , MD, PhD, , MD, , MD, PhD, , MD & , MD show all
Pages 1183-1196 | Published online: 07 Aug 2011

Bibliography

  • Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300
  • Petrelli NJ, Winer EP, Brahmer J, 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
  • Conroy T, Desseigne F, Ychou M, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25
  • Garber K. Stromal depletion goes on trial in pancreatic cancer. J Natl Cancer Inst 2010;102:448-50
  • Milella M, Bria E, Cuppone F, Current status of targeted agents (TA) in advanced pancreatic cancer (APC): Meta-analysis of randomized clinical trials (RCT). J Clin Oncol 2008;26:4637
  • Jones S, Zhang X, Parsons DW, Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801-6
  • Massague J. TGFbeta in cancer. Cell 2008;134:215-30
  • Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577-84
  • Moustakas A, Heldin CH. Non-Smad TGF-beta signals. J Cell Sci 2005;118:3573-84
  • Feng XH, Derynck R. Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol 2005;21:659-93
  • Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005;19:2783-810
  • He W, Dorn DC, Erdjument-Bromage H, Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. Cell 2006;125:929-41
  • Descargues P, Sil AK, Sano Y, 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
  • Ozdamar B, Bose R, Barrios-Rodiles M, Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 2005;307:1603-9
  • Bhowmick NA, Ghiassi M, Bakin A, Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 2001;12:27-36
  • Suzuki K, Wilkes MC, Garamszegi N, 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
  • 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
  • Yamaguchi K, Shirakabe K, Shibuya H, Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 1995;270:2008-11
  • Adhikari A, Xu M, Chen ZJ. Ubiquitin-mediated activation of TAK1 and IKK. Oncogene 2007;26:3214-26
  • Ninomiya-Tsuji J, Kishimoto K, Hiyama A, 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
  • Thiefes A, Wolter S, Mushinski JF, 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
  • Omori E, Matsumoto K, Sanjo H, TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis. J Biol Chem 2006;281:19610-17
  • 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
  • Culhaci N, Sagol O, Karademir S, 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
  • Teraoka H, Sawada T, Yamashita Y, TGF-beta1 promotes liver metastasis of pancreatic cancer by modulating the capacity of cellular invasion. Int J Oncol 2001;19:709-15
  • Friess H, Yamanaka Y, Buchler M, Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993;105:1846-56
  • Wagner M, Kleeff J, Friess H, 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
  • Bierie B, Moses HL. TGF-beta and cancer. Cytokine Growth Factor Rev 2006;17:29-40
  • Yen TW, Aardal NP, Bronner MP, Myofibroblasts are responsible for the desmoplastic reaction surrounding human pancreatic carcinomas. Surgery 2002;131:129-34
  • Teicher BA. Transforming growth factor-beta and the immune response to malignant disease. Clin Cancer Res 2007;13:6247-51
  • Bellone G, Carbone A, Smirne C, Cooperative induction of a tolerogenic dendritic cell phenotype by cytokines secreted by pancreatic carcinoma cells. J Immunol 2006;177:3448-60
  • Korpal M, Kang Y. Targeting the transforming growth factor-beta signalling pathway in metastatic cancer. Eur J Cancer 2010;46:1232-40
  • Furukawa T, Sunamura M, Horii A. Molecular mechanisms of pancreatic carcinogenesis. Cancer Sci 2006;97:1-7
  • Truty MJ, Urrutia R. Basics of TGF-beta and pancreatic cancer. Pancreatology 2007;7:423-35
  • Biankin AV, Morey AL, Lee CS, DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma. J Clin Oncol 2002;20:4531-42
  • Pasche B, Kolachana P, Nafa K, TbetaR-I(6A) is a candidate tumor susceptibility allele. Cancer Res 1999;59:5678-82
  • Yingling JM, Blanchard KL, Sawyer JS. Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004;3:1011-22
  • Melisi D, Ishiyama S, Sclabas GM, 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
  • Sorrentino A, Thakur N, Grimsby S, The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol 2008;10:1199-207
  • Melisi D, Xia Q, Paradiso G, 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)
  • Nagaraj NS, Datta PK. Targeting the transforming growth factor-beta signaling pathway in human cancer. Expert Opin Investig Drugs 2010;19:77-91
  • Oettle H, Hilbig A, Seufferlein T, 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 Abstracts2011;29:2513
  • Garber K. Companies waver in efforts to target transforming growth factor beta in cancer. J Natl Cancer Inst 2009;101:1664-7
  • Inman GJ. Switching TGFbeta from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev 2011;21:93-9
  • Adorno M, Cordenonsi M, Montagner M, A mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 2009;137:87-98
  • Zhang B, Halder SK, Kashikar ND, Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology 2010;138:969-80; e961–e963
  • 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
  • Stoeltzing O, Liu W, Reinmuth N, 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
  • Foulstone E, Prince S, Zaccheo O, Insulin-like growth factor ligands, receptors, and binding proteins in cancer. J Pathol 2005;205:145-53
  • 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
  • Piao W, Wang Y, Adachi Y, Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Mol Cancer Ther 2008;7:1483-93
  • Wong HH, Lemoine NR. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat Rev Gastroenterol Hepatol 2009;6:412-22
  • 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
  • Min Y, Adachi Y, Yamamoto H, Genetic blockade of the insulin-like growth factor-I receptor: a promising strategy for human pancreatic cancer. Cancer Res 2003;63:6432-41
  • Bergmann U, Funatomi H, Yokoyama M, Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res 1995;55:2007-11
  • Lin Y, Tamakoshi A, Kikuchi S, 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
  • Moser C, Schachtschneider P, Lang SA, 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
  • 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
  • Javle MM, Varadhachary GR, Shroff RT, 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
  • Kindler HL, Richards DA, Stephenson J, 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
  • Jassem J, Langer CJ, Karp DD, 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
  • Zheng D, Golubovskaya V, Kurenova E, A novel strategy to inhibit FAK and IGF-1R decreases growth of pancreatic cancer xenografts. Mol Carcinog 2009;49:200-9
  • Liu W, Bloom DA, Cance WG, FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells. Carcinogenesis 2008;29:1096-107
  • Bailey JM, Mohr AM, Hollingsworth MA. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene 2009;28:3513-25
  • Hidalgo M, Maitra A. The hedgehog pathway and pancreatic cancer. N Engl J Med 2009;361:2094-6
  • Hezel AF, Kimmelman AC, Stanger BZ, Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006;20:1218-49
  • Xu FG, Ma QY, Wang Z. Blockade of hedgehog signaling pathway as a therapeutic strategy for pancreatic cancer. Cancer Lett 2009;283:119-24
  • Nakamura K, Sasajima J, Mizukami Y, 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
  • Lauth M, Bergstrom A, Shimokawa T, DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nat Struct Mol Biol 2010;17:718-25
  • Morton JP, Lewis BC. Shh signaling and pancreatic cancer: implications for therapy? Cell Cycle 2007;6:1553-7
  • Ghaneh P, Costello E, Neoptolemos JP. Biology and management of pancreatic cancer. Postgrad Med J 2008;84:478-97
  • Peukert S, Miller-Moslin K. Small-molecule inhibitors of the hedgehog signaling pathway as cancer therapeutics. ChemMedChem 2010;5:500-12
  • Theunissen JW, de Sauvage FJ. Paracrine Hedgehog signaling in cancer. Cancer Res 2009;69:6007-10
  • Nolan-Stevaux O, Lau J, Truitt ML, GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 2009;23:24-36
  • Tian H, Callahan CA, DuPree KJ, Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA 2009;106:4254-9
  • Yauch RL, Gould SE, Scales SJ, A paracrine requirement for hedgehog signalling in cancer. Nature 2008;455:406-10
  • Bailey JM, Swanson BJ, Hamada T, Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res 2008;14:5995-6004
  • Pola R, Ling LE, Silver M, The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 2001;7:706-11
  • Corcoran RB, Bachar Raveh T, Barakat MT, Insulin-like growth factor 2 is required for progression to advanced medulloblastoma in patched1 heterozygous mice. Cancer Res 2008;68:8788-95
  • Yang SH, Andl T, Grachtchouk V, Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/beta3-catenin signaling. Nat Genet 2008;40:1130-5
  • Feldmann G, Dhara S, Fendrich V, 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
  • Feldmann G, Habbe N, Dhara S, Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 2008;57:1420-30
  • Olive KP, Jacobetz MA, Davidson CJ, Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324:1457-61
  • Mullendore ME, Koorstra JB, Li YM, Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin Cancer Res 2009;15:2291-301
  • Mysliwiec P, Boucher MJ. Targeting Notch signaling in pancreatic cancer patients – rationale for new therapy. Adv Med Sci 2009;54:136-42
  • Dontu G, Jackson KW, McNicholas E, Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 2004;6:R605-15
  • Siveke JT, Lubeseder-Martellato C, Lee M, Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology 2008;134:544-55
  • Wang Z, Li Y, Kong D, 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
  • Wang Z, Banerjee S, Li Y, 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
  • Wang Z, Sengupta R, Banerjee S, Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer. Cancer Res 2006;66:7653-60
  • Kong D, Li Y, Wang Z, 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
  • Imbimbo BP, Panza F, Frisardi V, Therapeutic intervention for Alzheimer's disease with gamma-secretase inhibitors: still a viable option? Expert Opin Investig Drugs 2011;20:325-41
  • Panza F, Frisardi V, Imbimbo BP, Review: gamma-Secretase inhibitors for the treatment of Alzheimer's disease: the current state. CNS Neurosci Ther 2010;16:272-84
  • Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002;109(Suppl):S81-96
  • 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
  • Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002;2:725-34
  • Melisi D, Chiao PJ. NF-kappaB as a target for cancer therapy. Expert Opin Ther Targets 2007;11:133-44
  • 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
  • Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-kappaB activity. Annu Rev Immunol 2000;18:621-63
  • Schmidt C, Peng B, Li Z, Mechanisms of proinflammatory cytokine-induced biphasic NF-kappaB activation. Mol Cell 2003;12:1287-300
  • Ben-Neriah Y. Regulatory functions of ubiquitination in the immune system. Nat Immunol 2002;3:20-6
  • Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol 2002;3:221-7
  • Senftleben U, Cao Y, Xiao G, Activation by IKKalpha of a second, evolutionary conserved, NF-kappaB signaling pathway. Science 2001;293:1495-9
  • Fujioka S, Sclabas GM, Schmidt C, Function of nuclear factor kappaB in pancreatic cancer metastasis. Clin Cancer Res 2003;9:346-54
  • Fujioka S, Sclabas GM, Schmidt C, Inhibition of constitutive NF-kappaB activity by IkappaBalphaM suppresses tumorigenesis. Oncogene 2003;22:1365-70
  • Melisi D, Niu J, Chang Z, 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
  • Joyce D, Albanese C, Steer J, NF-kappaB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev 2001;12:73-90
  • Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 2001;107:241-6
  • Almoguera C, Shibata D, Forrester K, Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988;53:549-54
  • Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 2008;9:517-31
  • Barbie DA, Tamayo P, Boehm JS, Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 2009;462:108-12
  • Kim HJ, Hawke N, Baldwin AS. NF-kappaB and IKK as therapeutic targets in cancer. Cell Death Differ 2006;13:738-47
  • Pikarsky E, Ben-Neriah Y. NF-kappaB inhibition: a double-edged sword in cancer? Eur J Cancer 2006;42:779-84
  • Greten FR, Karin M. The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett 2004;206:193-9
  • 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
  • Gilmore TD, Herscovitch M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 2006;25:6887-99
  • Egberts JH, Schniewind B, Sipos B, 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
  • Tepel J, Kruse ML, Kapischke M, Adjuvant treatment of pancreatic carcinoma in a clinically adapted mouse resection model. Pancreatology 2006;6:240-7
  • Woodcock J, Griffin JP, Behrman RE. Development of novel combination therapies. N Engl J Med 2011;364:985-7
  • Bria E, Milella M, Gelibter A, 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
  • Appels NM, Beijnen JH, Schellens JH. Development of farnesyl transferase inhibitors: a review. Oncologist 2005;10:565-78
  • Bria E, Di Maio M, Carlini P, Targeting targeted agents: open issues for clinical trial design. J Exp Clin Cancer Res 2009;28:66
  • Milella M, Ciuffreda L, Bria E, In: Reddy LH, Couvreur P, editors. Macromolecular anticancer therapeutics. Humana Press; New York: 2010. p. 37-83

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