Abstract
Recently, Src tyrosine kinase has emerged as an attractive target for anticancer therapy, and Src is overexpressed in pancreatic cancer. The purpose of the study was to investigate the in vivo efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, using a panel of human pancreatic tumor xenografts. Surgically resected human pancreatic tumors were implanted into female nude mice and randomized to bosutinib versus control. Src and other pathways were analyzed by Western Blot, IHC, and Affymetrix U133 Plus 2.0 gene arrays. Of 15 patient tumors, 3 patient tumors were found to be sensitive to bosutinib, defined as tumor growth of <45% than that of control tumors. There were no definite differences between sensitive and resistant tumors in the baseline Src kinase pathway protein expression assessed by Western Blot. Caveolin-1 expression, as assessed by reverse transcription-PCR and immunohistochemistry, was frequently higher in sensitive cases. In sensitive tumors, bosutinib resulted in increased apoptosis. Phosphorylation of key signaling molecules downstream of Src, signal transducers and activators of transcription 3, and signal transducers and activators of transcription 3, were significantly inhibited by bosutinib. K-Top Scoring Pairs analysis of gene arrays gave a six-gene classifier that predicted resistance versus sensitivity in six validation cases. These results may aid the clinical development of bosutinib and other Src inhibitors in pancreas cancer.
Highlights
Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths annually
The established tumors showed decreased growth compared with control in sensitive cases (Fig. 1B). This is consistent with previously published studies of bosutinib in colorectal xenografts [24] and breast xenografts [25] as well as other Src inhibitors in pancreas cancer mouse models [14]
Studies oriented to determine which tumors are more likely to respond to drug could facilitate patient selection strategies in clinical trials
Summary
Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths annually. The estimated incidence for 2008 was 37,680 new cancers with an estimated mortality of 34,290 [1]. Despite recent improved understanding in pancreatic cancer biology, the 5-year survival remains at 4% despite multimodality therapy [2]. Improvements in therapy have been modest with the addition of erlotinib or capecitabine to gemcitabine in combination, resulting in improved median survival on the order of weeks [4, 5]. The continued poor survival despite the new understanding of pancreatic cancer biology and the incorporation of novel therapies shows an acute need for improvement in therapy. To this end, a patient-derived pancreatic adenocarcinoma explant xenograft model (PancXenoBank) has been produced to help develop novel therapies for pancreatic cancer [6]
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