Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification.
BACKGROUND
Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity.


METHODS
Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration.


RESULTS
Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion.


CONCLUSIONS
These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.
DePrimo
Samuel E
SE
Preclinical Research and Exploratory Development, SUGEN, Inc, South San Francisco, CA 94080, USA. samuel-deprimo@sugen.com
Wong
Lily M
LM
Khatry
Deepak B
DB
Nicholas
Susan L
SL
Manning
William C
WC
Smolich
Beverly D
BD
O'Farrell
Anne-Marie
AM
Cherrington
Julie M
JM
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D015703:Antigens, CD / Q000097:blood / Q000235:genetics; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D051927:CD24 Antigen; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007781:Lactoferrin / Q000097:blood / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000235:genetics; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011237:Predictive Value of Tests; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497889:CD24 protein, human; D007211:Indoles; D008562:Membrane Glycoproteins; D011758:Pyrroles; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases; D007781:Lactoferrin; D020780:Matrix Metalloproteinase 9