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

Oncogene volume 23, pages 1618–1626 (2004)Cite this article

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.

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Abbreviations

HUVEC:

human umbilical vascular endothelial cells

RTK:

receptor tyrosine kinase

IHC:

immunohistochemistry

qRT-PCR:

quantitative reverse-transcription polymerase chain reaction

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Acknowledgements

We thank S DePrimo for invaluable help with Spotfire analysis and S Coberly for expert pathology advice. We also thank Drs Mendel, DePrimo, Laird and O'Farrell for very helpful comments and suggestions on the manuscript, and B Remley and S Paxton for expert graphics help.

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Authors and Affiliations

  1. Department of Preclinical Research and Exploratory Development, SUGEN, Inc., 230 E Grand Ave., South San Francisco, 94080, CA, USA

    Alyssa M Morimoto, Nguyen Tan, Kristina West, William C Manning, Beverly D Smolich & Julie M Cherrington

  2. Medical Oncology, Peter MacCallum Cancer Institute, St Andrew's Place, East Melbourne, VIC 3002, Australia

    Grant McArthur & Guy C Toner

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  1. Alyssa M Morimoto
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  2. Nguyen Tan
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  3. Kristina West
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Correspondence to Alyssa M Morimoto.

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Morimoto, A., Tan, N., West, K. et al. Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor. Oncogene 23, 1618–1626 (2004). https://doi.org/10.1038/sj.onc.1207268

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