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Application of Oligonucleotide Microarrays to Assess the Biological Effects of Neoadjuvant Imatinib Mesylate Treatment for Localized Prostate Cancer

Authors' Affiliations: ¹ Duke Institute for Genome Sciences and Policy, Division of Medical Oncology; Departments of ² Medicine, ³ Molecular Genetics and Microbiology, and ⁴ Surgery, Duke University Medical Center, Durham, North Carolina; Departments of ⁵ Medical Oncology, ⁶ Pathology, and ⁷ Pediatric Oncology; ⁸ Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School; Departments of ⁹ Medicine and ¹⁰ Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and ¹¹ Broad Institute, Cambridge, Massachusetts

Requests for reprints: Phillip G. Febbo, Institute for Genome Sciences and Policy, Duke University Medical Center, DUMC Box 3382, 101 Science Drive, Room 2349, CIEMAS Building, Durham, NC 27710. Phone: 919-668-4774; E-mail: phil.febbo{at}duke.edu.

Purpose: 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.

Patients and 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.