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

• Published in: Oncogene Vol. 23; no. 8; pp. 1618 - 1626
• Main Authors: MORIMOTO, Alyssa M, NGUYEN TAN, WEST, Kristina, MCARTHUR, Grant, TONER, Guy C, MANNING, William C, SMOLICH, Beverly D, CHERRINGTON, Julie M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 26.02.2004; Nature Publishing Group
• Subjects: Animals; Biological activity; Biological and medical sciences; Biomarkers; Biopsy; Cadherins; Cadherins - drug effects; Cadherins - metabolism; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Clinical trials; Colonic Neoplasms - metabolism; Decision making; Drug development; Enzyme inhibitors; Enzyme Inhibitors - therapeutic use; Feasibility Studies; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling - methods; Growth factors; Humans; Immunohistochemistry; Indoles - therapeutic use; Kinases; Mice; Mice, Nude; Molecular and cellular biology; Neoplasm Transplantation; Oncology; Pyrroles - therapeutic use; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Solid tumors; Transcription; Transplantation, Heterologous; Tumors; Tyrosine kinase inhibitors; Vascular endothelial growth factor receptors; Xenografts; United States > US; South San Francisco California; Human; Immunohistochemistry; Digestive system; Enzyme; Transferases; Gut; Biological marker; Heterograft; Microarray; biomarker; Carcinogenesis; SU11248; In vivo; Treatment; Tumor; Inhibitor; Colon; Protein-tyrosine kinase
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207268

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.