Targets, trials, and travails in pancreas cancer.

Pancreas cancer is a highly aggressive and rapidly fatal disease. The current standard of care for advanced disease improves survival modestly at best and provides palliation for a minority of patients. The need for new therapies is undisputed. This article describes new therapeutic strategies currently under investigation and discusses possible reasons that others have failed. New potential targets in the treatment of this formidable disease are suggested based on recent findings.

[1]  D. Tuveson,et al.  Dynamics of the immune reaction to pancreatic cancer from inception to invasion. , 2007, Cancer research.

[2]  H. Reber,et al.  Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor. , 2007, Cancer research.

[3]  D. Tuveson,et al.  The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression. , 2007, Cancer research.

[4]  B. Chue Interim results of a weekly, metronomic dosing of paclitaxel, oxaliplatin, leucovorin, 5-FU (POLF) in the treatment of metastatic pancreatic cancer (PC) , 2007 .

[5]  P. Philip,et al.  Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study , 2007 .

[6]  R. Hruban,et al.  Molecular genetics of pancreatic intraepithelial neoplasia. , 2007, Journal of hepato-biliary-pancreatic surgery.

[7]  P. Murawa,et al.  Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  C. Croce,et al.  MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. , 2007, JAMA.

[9]  Jen Jen Yeh,et al.  Targeting signal transduction in pancreatic cancer treatment , 2007, Expert opinion on therapeutic targets.

[10]  T. Seufferlein,et al.  Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay , 2007, Journal of Cell Science.

[11]  Thomas D. Schmittgen,et al.  Expression profiling identifies microRNA signature in pancreatic cancer , 2006, International journal of cancer.

[12]  M. Berger,et al.  Lapatinib plus capecitabine for HER2-positive advanced breast cancer. , 2006, The New England journal of medicine.

[13]  M. Collins,et al.  Mammary-specific Ron receptor overexpression induces highly metastatic mammary tumors associated with beta-catenin activation. , 2006, Cancer research.

[14]  A. Griffioen,et al.  Monocyte/macrophage infiltration in tumors: modulators of angiogenesis , 2006, Journal of leukocyte biology.

[15]  Christopher Chiu,et al.  Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis , 2006, Proceedings of the National Academy of Sciences.

[16]  N. Lemoine,et al.  Gene therapy developments for pancreatic cancer. , 2006, Best practice & research. Clinical gastroenterology.

[17]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[18]  M. Philips,et al.  Compartmentalized Ras/MAPK signaling. , 2006, Annual review of immunology.

[19]  M. Saif Anti-angiogenesis therapy in pancreatic carcinoma. , 2006, JOP : Journal of the pancreas.

[20]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[21]  Zhong Wen-zhao,et al.  Erlotinib in Lung Cancer - Molecular and Clinical Predictors of Outcome , 2006 .

[22]  Ma Dong,et al.  Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer , 2006 .

[23]  E. Furth,et al.  Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. , 2006, Cancer research.

[24]  P. Philip,et al.  A Phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer , 2005, Investigational New Drugs.

[25]  A. Adjei,et al.  K-ras as a target for cancer therapy. , 2005, Biochimica et biophysica acta.

[26]  A. Dachman,et al.  Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  Oriol Casanovas,et al.  Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. , 2005, Cancer cell.

[28]  J. Abbruzzese,et al.  A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: A Southwest oncology group (SWOG 9924) study , 2005, Investigational New Drugs.

[29]  C. Lewis,et al.  Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. , 2005, The American journal of pathology.

[30]  B. Nielsen,et al.  Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation. , 2005, Genes & development.

[31]  S. Tsutsui,et al.  Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. , 2005, Oncology reports.

[32]  C. Croce,et al.  miRNAs, Cancer, and Stem Cell Division , 2005, Cell.

[33]  C. Verbeke,et al.  Cyclooxygenase-2 Expression Associated with Severity of PanIN Lesions: A Possible Link between Chronic Pancreatitis and Pancreatic Cancer , 2005, Pancreatology.

[34]  E. Jaffee,et al.  Immunotherapy for pancreatic cancer — science driving clinical progress , 2005, Nature Reviews Cancer.

[35]  R. Hruban,et al.  Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. , 2005, Cancer cell.

[36]  R. Shiekhattar,et al.  MicroRNA biogenesis and cancer. , 2005, Cancer research.

[37]  J. Baselga,et al.  Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  A. Buck,et al.  Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. , 2005, Gastroenterology.

[39]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[40]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[41]  B. Burtness,et al.  Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody. , 2005, Drugs of today.

[42]  R. Wolff,et al.  A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer , 2005, Cancer Chemotherapy and Pharmacology.

[43]  D. Agus,et al.  CVS‐3983, a selective matriptase inhibitor, suppresses the growth of androgen independent prostate tumor xenografts , 2004, The Prostate.

[44]  J S Wilson,et al.  Desmoplastic Reaction in Pancreatic Cancer: Role of Pancreatic Stellate Cells , 2004, Pancreas.

[45]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[46]  R. Wolff,et al.  Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  Hidetaka Mochizuki,et al.  The Correlation Between Cytoplasmic Overexpression of Epidermal Growth Factor Receptor and Tumor Aggressiveness: Poor Prognosis in Patients With Pancreatic Ductal Adenocarcinoma , 2004, Pancreas.

[48]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[49]  Robert S. Kerbel,et al.  The anti-angiogenic basis of metronomic chemotherapy , 2004, Nature Reviews Cancer.

[50]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[51]  E. Van Cutsem,et al.  Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  S. Rosenberg,et al.  clinical implications of basic research Shedding Light on Immunotherapy for Cancer , 2004 .

[53]  J. Abbruzzese,et al.  Celecoxib Inhibits Vascular Endothelial Growth Factor Expression in and Reduces Angiogenesis and Metastasis of Human Pancreatic Cancer via Suppression of Sp1 Transcription Factor Activity , 2004, Cancer Research.

[54]  D. Iannitti,et al.  Herceptin and Gemcitabine for Metastatic Pancreatic Cancers That Overexpress HER-2/neu , 2004 .

[55]  Xiaoen Wang,et al.  Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor , 1997, Clinical & Experimental Metastasis.

[56]  R. Dickson,et al.  Deregulated activation of matriptase in breast cancer cells , 2004, Clinical & Experimental Metastasis.

[57]  R. Hruban,et al.  Molecular pathogenesis of pancreatic cancer. , 2006, Annual review of genomics and human genetics.

[58]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[59]  Gregory Y. Lauwers,et al.  Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis , 2003, Nature.

[60]  J. Dancey,et al.  Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  Bin Yu,et al.  All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. , 2003, Cancer research.

[62]  R. Hruban,et al.  Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. , 2003, Cancer cell.

[63]  D. Tuveson,et al.  Ras redux: rethinking how and where Ras acts. , 2003, Current opinion in genetics & development.

[64]  G. Pruneri,et al.  Circulating endothelial cells as a novel marker of angiogenesis. , 2003, Advances in experimental medicine and biology.

[65]  Alicia Samuels,et al.  Cancer Statistics, 2003 , 2003, CA: a cancer journal for clinicians.

[66]  Douglas B. Evans,et al.  Restoring apoptosis in pancreatic cancer cells by targeting the nuclear factor-κb signaling pathway with the anti-epidermal growth factor antibody IMC-C225 , 2003, Journal of Gastrointestinal Surgery.

[67]  M. Korc,et al.  Pathways for aberrant angiogenesis in pancreatic cancer , 2003, Molecular Cancer.

[68]  Toru Watanabe,et al.  Clinical effects of tumor-associated macrophages and dendritic cells on renal cell carcinoma. , 2002, Anticancer research.

[69]  R. Saxton,et al.  Selective cyclooxygenase-2 inhibitor rofecoxib (vioxx) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer , 2002, Journal of Gastrointestinal Surgery.

[70]  L. Fu,et al.  Multiple pulmonary adenomas in the lung of transgenic mice overexpressing the RON receptor tyrosine kinase. Recepteur d'origine nantais. , 2002, Carcinogenesis.

[71]  K. Campbell,et al.  Pancreaticoduodenectomy With or Without Distal Gastrectomy and Extended Retroperitoneal Lymphadenectomy for Periampullary Adenocarcinoma, Part 2: Randomized Controlled Trial Evaluating Survival, Morbidity, and Mortality , 2002, Annals of surgery.

[72]  R. Bernards,et al.  Stable suppression of tumorigenicity by virus-mediated RNA interference. , 2002, Cancer cell.

[73]  S. Post,et al.  High Expression of Vascular Endothelial Growth Factor Predicts Early Recurrence and Poor Prognosis after Curative Resection for Ductal Adenocarcinoma of the Pancreas , 2002, Pancreas.

[74]  J. Cameron,et al.  Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. , 2002, American journal of clinical pathology.

[75]  L. Trusolino,et al.  Scatter-factor and semaphorin receptors: cell signalling for invasive growth , 2002, Nature Reviews Cancer.

[76]  B. Fingleton,et al.  Matrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations , 2002, Science.

[77]  D. Hanahan,et al.  VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. , 2002, Cancer cell.

[78]  Z. Werb,et al.  New functions for the matrix metalloproteinases in cancer progression , 2002, Nature Reviews Cancer.

[79]  A. Goldhirsch,et al.  Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[80]  J. Cameron,et al.  Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[81]  A. Frey,et al.  Tumor-Infiltrating Macrophages Induce Apoptosis in Activated CD8+ T Cells by a Mechanism Requiring Cell Contact and Mediated by Both the Cell-Associated Form of TNF and Nitric Oxide1 , 2001, The Journal of Immunology.

[82]  V. Bronte,et al.  Tumor-induced immune dysfunctions caused by myeloid suppressor cells. , 2001, Journal of immunotherapy.

[83]  L. Ellis,et al.  Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. , 2001, Cancer biotherapy & radiopharmaceuticals.

[84]  A. Rosemurgy,et al.  Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[85]  S. Post,et al.  Correlation of postoperative survival and angiogenic growth factors in pancreatic carcinoma. , 2001, Hepato-gastroenterology.

[86]  A. Nakao,et al.  Molecular diagnosis of pancreatic cancer. , 2001, Hepato-gastroenterology.

[87]  A. Ullrich,et al.  The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. , 2001, Endocrine-related cancer.

[88]  H. Friess,et al.  Therapy for pancreatic cancer with a recombinant humanized anti-HER2 antibody (herceptin) , 2001, Journal of Gastrointestinal Surgery.

[89]  S. K. Kim,et al.  Intercellular signals regulating pancreas development and function. , 2001, Genes & development.

[90]  Nicholas R. English,et al.  Increased Production of Immature Myeloid Cells in Cancer Patients: A Mechanism of Immunosuppression in Cancer1 , 2001, The Journal of Immunology.

[91]  R. Hruban,et al.  Molecular pathology of pancreatic cancer. , 2001, Cancer journal.

[92]  H. Friess,et al.  Growth factors and their receptors in pancreatic cancer. , 2001, Teratogenesis, carcinogenesis, and mutagenesis.

[93]  C. Bowden,et al.  Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. , 2001, Cancer research.

[94]  R. Ronca,et al.  Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. , 2000, Blood.

[95]  F. Foss,et al.  DAB(389)IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma. , 2000, Clinical lymphoma.

[96]  R H Hruban,et al.  Progression model for pancreatic cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[97]  T. Fukuda,et al.  High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma , 2000, Cancer.

[98]  D B Evans,et al.  Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[99]  H. Hamada,et al.  Induction of potent antitumor response by vaccination with tumor lysate-pulsed macrophages engineered to secrete macrophage colony-stimulating factor and interferon-γ , 2000, Gene Therapy.

[100]  A. Harris,et al.  The macrophage – a novel system to deliver gene therapy to pathological hypoxia , 2000, Gene Therapy.

[101]  D. Hanahan,et al.  Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. , 1999, Science.

[102]  A. Ullrich,et al.  Epidermal growth factor receptors: critical mediators of multiple receptor pathways. , 1999, Current opinion in cell biology.

[103]  M. Adachi,et al.  Prognostic significance of angiogenesis in human pancreatic cancer , 1999, British Journal of Cancer.

[104]  R. Hruban,et al.  Pathology of incipient pancreatic cancer. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[105]  J. Isaacs,et al.  Macrophage role in the anti-prostate cancer response to one class of antiangiogenic agents. , 1998, Journal of the National Cancer Institute.

[106]  R. Hruban,et al.  Development and characterization of a cytokine-secreting pancreatic adenocarcinoma vaccine from primary tumors for use in clinical trials. , 1998, The cancer journal from Scientific American.

[107]  K. Lillemoe,et al.  DNA content and other factors associated with ten‐year survival after resection of pancreatic carcinoma , 1998, Journal of surgical oncology.

[108]  R H Hruban,et al.  Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. , 1998, The American journal of surgical pathology.

[109]  H. Friess,et al.  Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[110]  D. V. Von Hoff,et al.  Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[111]  H. Schreiber,et al.  Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[112]  E. Leonard,et al.  Identification of the ron gene product as the receptor for the human macrophage stimulating protein. , 1994, Science.

[113]  R. McLeod,et al.  Interim results of a phase II multicenter clinical trial evaluating the activity of a therapeutic allogeneic melanoma vaccine (theraccine) in the treatment of disseminated malignant melanoma. , 1993, Seminars in surgical oncology.

[114]  N. Lemoine,et al.  Ki-ras oncogene activation in preinvasive pancreatic cancer. , 1992, Gastroenterology.

[115]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

[116]  G. Fleuren,et al.  KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. , 1988, Nucleic acids research.

[117]  D. Shibata,et al.  Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes , 1988, Cell.

[118]  J. Bos,et al.  The ras gene family and human carcinogenesis. , 1988, Mutation research.

[119]  E. Winter,et al.  The c-K-ras gene and human cancer (review). , 1987, Anticancer research.

[120]  H. Kern,et al.  Distribution of Extracellular Matrix Proteins in Pancreatic Ductal Adenocarcinoma and Its Influence on Tumor Cell Proliferation in Vitro , 1987, Pancreas.

[121]  S. Rosenberg The adoptive immunotherapy of cancer using the transfer of activated lymphoid cells and interleukin-2. , 1986, Seminars in oncology.

[122]  A. Abioye,et al.  Pancreatic carcinoma. , 2020, Journal of the National Medical Association.

[123]  J. Folkman,et al.  Anti‐Angiogenesis: New Concept for Therapy of Solid Tumors , 1972, Annals of surgery.

[124]  K. T. Steigelman Tumors of the pancreas. , 1951, The Journal of the American Osteopathic Association.