Development of an integrated genomic classifier for a novel agent in colorectal cancer: approach to individualized therapy in early development.
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 (<or=1.5 micromol/L) or resistant (>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.
Division of Medical Oncology, University of Colorado Denver, Aurora, CO 80045, USA.
Todd M
TM
Pitts
Aik Choon
AC
Tan
Gillian N
GN
Kulikowski
John J
JJ
Tentler
Amy M
AM
Brown
Sara A
SA
Flanigan
Stephen
S
Leong
Christopher D
CD
Coldren
Fred R
FR
Hirsch
Marileila
M
Varella-Garcia
Christopher
C
Korch
S Gail
SG
Eckhardt
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005240:Feasibility Studies; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf; D011719:Pyrazines / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015203:Reproducibility of Results; D023041:Xenograft Model Antitumor Assays
C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D014408:Biomarkers, Tumor; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D017526:Receptor, IGF Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf