title: Pancreatic Cancer: "A Riddle Wrapped in a Mystery inside an Enigma".
abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult-to-treat cancers. With an increasing incidence and inability to make major progress, it represents the very definition of unmet medical need. Progress has been made in understanding the basic biology-systematic genomic sequencing has led to the recognition that PDAC is not typically a heavily mutated tumor, although there are exceptions. The most consistently mutated genes areKRAS, CDKN2A, TP53, andSMAD4/DPC4Study of familial PDAC has led to the recognition that a variety of defects in DNA repair genes can be associated with the emergence of pancreatic cancer. Recent studies suggest that epigenetics may play a larger role than previously recognized. A major new understanding is the recognition that PDAC should be considered a composite of tumor cells, as well as pancreatic stellate cells, immune cells, and extracellular matrix. The individual components contribute to metabolic aberration, immune dysfunction, and chemotherapy resistance, and therapeutic innovations may be needed to address them individually. It has also been recognized that metastatic seeding from PDAC occurs very early in the disease course-in an estimated 73% of cases, once the tumor reaches 2 cm. The implication of this is that therapies directed toward micrometastatic disease and increasing fractional cell kill are most needed. Neoadjuvant approaches have been taken to increase resectability and improve outcome. So much work remains, and most critical is the need to understand how this tumor originates and develops.Clin Cancer Res; 23(7); 1629-37. ©2017 AACRSee all articles in thisCCR Focussection, "Pancreatic Cancer: Challenge and Inspiration."
authors.affiliation: HonorHealth, Scottsdale, Arizona and TGen, Phoenix, Arizona. Erkut.Borazanci@HonorHealth.com.
authors.forename: Erkut
authors.initials: E
authors.lastname: Borazanci
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.affiliation: National Institutes of Health, Bethesda, Maryland.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.affiliation: Columbia University Medical Center, New York, New York.|James J. Peters Bronx VA Medical Center, Bronx, New York.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.affiliation: Columbia University Medical Center, New York, New York.
authors.forename: John A
authors.initials: JA
authors.lastname: Chabot
authors.affiliation: HonorHealth, Scottsdale, Arizona and TGen, Phoenix, Arizona.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D006801:Humans; D009154:Mutation; D020360:Neoadjuvant Therapy; D058954:Pancreatic Stellate Cells / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C117307:KRAS protein, human; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)