Development of an integrated genomic classifier for a novel agent in colorectal cancer: approach to individualized therapy in early development.

Pitts TM, Tan AC, Kulikowski GN, Tentler JJ, Brown AM, Flanigan SA, Leong S, Coldren CD, Hirsch FR, Varella-Garcia M, Korch C, Eckhardt SG
Clin Cancer Res. 2010 16 (12): 3193-204

PMID: 20530704 · PMCID: PMC2889230 · DOI:10.1158/1078-0432.CCR-09-3191

BACKGROUND - A plethora of agents is in early stages of development for colorectal cancer (CRC), including those that target the insulin-like growth factor I receptor (IGFIR) pathway. In the current environment of numerous cancer targets, it is imperative that patient selection strategies be developed with the intent of preliminary testing in the latter stages of phase I trials. The goal of this study was to develop and characterize predictive biomarkers for an IGFIR tyrosine kinase inhibitor, OSI-906, that could be applied in CRC-specific studies of this agent.

METHODS - Twenty-seven CRC cell lines were exposed to OSI-906 and classified according to IC(50) value as sensitive (5 micromol/L). Cell lines were subjected to immunoblotting and immunohistochemistry for effector proteins, IGFIR copy number by fluorescence in situ hybridization, KRAS/BRAF/phosphoinositide 3-kinase mutation status, and baseline gene array analysis. The most sensitive and resistant cell lines were used for gene array and pathway analyses, along with shRNA knockdown of highly ranked genes. The resulting integrated genomic classifier was then tested against eight human CRC explants in vivo.

RESULTS - Baseline gene array data from cell lines and xenografts were used to develop a k-top scoring pair (k-TSP) classifier, which, in combination with IGFIR fluorescence in situ hybridization and KRAS mutational status, was able to predict with 100% accuracy a test set of patient-derived CRC xenografts.

CONCLUSIONS - These results indicate that an integrated approach to the development of individualized therapy is feasible and should be applied early in the development of novel agents, ideally in conjunction with late-stage phase I trials.

(c) 2010 AACR.

MeSH Terms (23)

Animals Biomarkers, Tumor Cell Line, Tumor Drug Delivery Systems Drug Resistance, Neoplasm Drug Screening Assays, Antitumor Feasibility Studies Female Gene Dosage Gene Expression Profiling Gene Knockdown Techniques Genes, ras Humans Imidazoles Mice Mice, Nude Mutation Protein Kinase Inhibitors Proto-Oncogene Proteins B-raf Pyrazines Receptor, IGF Type 1 Reproducibility of Results Xenograft Model Antitumor Assays

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