title: Antitumor effects and biomarkers of activity of AZD0530, a Src inhibitor, in pancreatic cancer.
abstract: OBJECTIVE
  To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts and to seek biomarkers predictive of activity.
  
  
  METHODS
  Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopkins were treated with AZD0530 (50 mg/kg/day, p.o.) for 28 days. Baseline gene expression profiles of differently expressed genes in 16 tumors by Affymetrix U133 Plus 2.0 gene array were used to predict AZD0530 sensitivity in an independent group of eight tumors using the K-Top Scoring Pairs (K-TSP) method.
  
  
  RESULTS
  Three patient tumors of 16 were found to be sensitive to AZD0530, defined as tumor growth <50% compared with control tumors (100%). Western blot and/or immunohistochemistry results showed that AZD0530 administration resulted in the down-regulation of Src, FAK, p-FAK, p-paxillin, p-STAT-3, and XIAP in sensitive tumor xenografts compared with control tumors. The K-TSP classifier identified one gene pair (LRRC19 and IGFBP2) from the 16 training cases based on a decision rule. The classifier achieved 100% and 83.3% of sensitivity and specificity in an independent test set that consists of eight xenograft cases.
  
  
  CONCLUSIONS
  AZD0530 treatment significantly inhibits the tumor growth in a subset of human pancreatic tumor xenografts. One gene pair (LRRC19 and IGFBP2) identified by the K-TSP classifier has high predictive power for AZD0530 sensitivity, suggesting the potential for this gene pair as biomarker for pancreatic tumor sensitivity to AZD0530.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, Baltimore, Maryland, USA.
authors.forename: N V
authors.initials: NV
authors.lastname: Rajeshkumar
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: De Oliveira
authors.forename: Chris
authors.initials: C
authors.lastname: Womack
authors.forename: Helen
authors.initials: H
authors.lastname: Wombwell
authors.forename: Shethah
authors.initials: S
authors.lastname: Morgan
authors.forename: Madhuri V
authors.initials: MV
authors.lastname: Warren
authors.forename: Jill
authors.initials: J
authors.lastname: Walker
authors.forename: Tim P
authors.initials: TP
authors.lastname: Green
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051419:Paxillin / Q000037:antagonists & inhibitors / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D014408:Biomarkers, Tumor; D051419:Paxillin; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C515233:saracatinib; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src)