title: Emerging pathways and future targets for the molecular therapy of pancreatic cancer.
abstract: BACKGROUND
  Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing.
  
  
  METHODS
  This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-β, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer.
  
  
  CONCLUSIONS
  Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine-targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.
authors.affiliation: Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Vanja
authors.initials: V
authors.lastname: Vaccaro
authors.forename: Davide
authors.initials: D
authors.lastname: Melisi
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.forename: Federica
authors.initials: F
authors.lastname: Cuppone
authors.forename: Ludovica
authors.initials: L
authors.lastname: Ciuffreda
authors.forename: Maria Simona
authors.initials: MS
authors.lastname: Pino
authors.forename: Alain
authors.initials: A
authors.lastname: Gelibter
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
mesh_terms: D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D016328:NF-kappa B; D051880:Receptors, Notch; D013002:Somatomedins; D016212:Transforming Growth Factor beta