Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor.

Abstract	Biomarkers that indicate biological activity and/or efficacy are a potentially useful tool in the development of molecularly targeted therapeutics. It is useful, though challenging, to identify biomarkers during preclinical development in order to impact decision-making during early clinical development. SU11248 is an oral, selective multitargeted tyrosine kinase inhibitor currently in Phase II oncology clinical trials. It exhibits direct antitumor and antiangiogenic activity via inhibition of the receptor tyrosine kinases PDGFR, VEGFR, KIT and FLT3. To identify clinically translatable biomarkers of SU11248 activity, expression profiling was performed on Colo205 human xenograft tumors following treatment with SU11248. Over 100 transcripts changed in abundance in SU11248 as compared to vehicle-treated tumors. Nine candidate transcripts, chosen based on putative function, were also analysed and validated by TaqMan. One such potential biomarker, cadherin-11, was further evaluated at the protein level and was found to have increased expression in xenograft tumors after SU11248 treatment. Interestingly, cadherin-11 expression was also detected via immunohistochemical analysis of archived solid tumors, indicating the technical feasibility of translating this putative biomarker to clinical studies. Importantly, SU11248 treatment also resulted in increased expression of cadherin-11 protein in human tumor biopsies in three out of seven patients examined and confirms the feasibility of using transcriptional profiling of preclinical models to identify clinically translatable biomarkers.
Authors	Alyssa M Morimoto, Nguyen Tan, Kristina West, Grant McArthur, Guy C Toner, William C Manning, Beverly D Smolich, Julie M Cherrington
Journal	Oncogene (Oncogene) Vol. 23 Issue 8 Pg. 1618-26 (Feb 26 2004) ISSN: 0950-9232 [Print] England
PMID	14985702 (Publication Type: Journal Article)
Chemical References	Biomarkers Cadherins Enzyme Inhibitors Indoles Pyrroles osteoblast cadherin Receptor Protein-Tyrosine Kinases Sunitinib
Topics	Animals Biomarkers Cadherins (drug effects, metabolism) Cell Line, Tumor Colonic Neoplasms (metabolism) Enzyme Inhibitors (therapeutic use) Feasibility Studies Female Gene Expression Profiling (methods) Humans Immunohistochemistry Indoles (therapeutic use) Mice Mice, Nude Neoplasm Transplantation Pyrroles (therapeutic use) Receptor Protein-Tyrosine Kinases (antagonists & inhibitors) Sunitinib Transplantation, Heterologous

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