Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor.
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.
Department of Preclinical Research and Exploratory Development, SUGEN, Inc., 230 E Grand Ave., South San Francisco, CA 94080, USA. morimoto@gene.com
Alyssa M
AM
Morimoto
Nguyen
N
Tan
Kristina
K
West
Grant
G
McArthur
Guy C
GC
Toner
William C
WC
Manning
Beverly D
BD
Smolich
Julie M
JM
Cherrington
D000818:Animals; D015415:Biomarkers; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005240:Feasibility Studies; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011758:Pyrroles / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000077210:Sunitinib; D014183:Transplantation, Heterologous
D015415:Biomarkers; D015820:Cadherins; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; C086960:osteoblast cadherin; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib