Antitumor effects and biomarkers of activity of AZD0530, a Src inhibitor, in pancreatic cancer.
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.
Rajeshkumar
N V
NV
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, Baltimore, Maryland, USA.
Tan
Aik Choon
AC
De Oliveira
Elizabeth
E
Womack
Chris
C
Wombwell
Helen
H
Morgan
Shethah
S
Warren
Madhuri V
MV
Walker
Jill
J
Green
Tim P
TP
Jimeno
Antonio
A
Messersmith
Wells A
WA
Hidalgo
Manuel
M
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
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)