Application of oligonucleotide microarrays to assess the biological effects of neoadjuvant imatinib mesylate treatment for localized prostate cancer.
OBJECTIVE
Neoadjuvant administration of antineoplastic therapies is used to rapidly assess the clinical and biological activity of novel systemic treatments. To assess the feasibility of using microarrays to assess molecular end points following targeted treatment in a heterogeneous tumor, we measured global gene expression in localized prostate cancer before and following neoadjuvant treatment with imatinib mesylate.


METHODS
Patients with intermediate-risk to high-risk prostate cancer were treated for 6 weeks with 200 to 300 mg of oral imatinib mesylate. Frozen tissue was obtained from pretreatment ultrasound-guided biopsies and posttreatment radical prostatectomy specimens. Oligonucleotide microarray analysis following laser capture microdissection (LCM) and RNA amplification was used to assess gene expression changes associated with imatinib mesylate therapy. Immunohistochemistry was used to measure protein expression of MKP1 and CD31 and to assess cellular apoptosis.


RESULTS
Of the 11 patients enrolled, high-quality microarray data was obtained from both biopsies (n = 7) and radical prostatectomy specimens (n = 9). Technically introduced intrasample gene expression variability was found to be significantly less than intertumor biological variability. Large gene expression differences were observed, and the gene with the most consistent differential expression (MKP1) was validated by immunohistochemistry. Gene set enrichment analysis suggests that imatinib mesylate therapy results in apoptosis of microvascular endothelial cells, an observation anecdotally supported by immunohistochemistry.


CONCLUSIONS
This study shows that high-quality microarray data can be generated using LCM and RNA amplification to discover potential mechanisms of targeted therapy in cancer.
Febbo
Phillip G
PG
Duke Institute for Genome Sciences and Policy, Division of Medical Oncology; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. phil.febbo@duke.edu
Thorner
Aaron
A
Rubin
Mark A
MA
Loda
Massimo
M
Kantoff
Philip W
PW
Oh
William K
WK
Golub
Todd
T
George
Daniel
D
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D007834:Lasers; D008297:Male; D042282:Microdissection; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D051057:Proto-Oncogene Proteins c-akt