Application of oligonucleotide microarrays to assess the biological effects of neoadjuvant imatinib mesylate treatment for localized prostate cancer

被引:20
作者
Febbo, PG
Thorner, A
Rubin, MA
Loda, M
Kantoff, PW
Oh, WK
Golub, T
George, D
机构
[1] Duke Univ, Med Ctr, Inst Genom Sci & Policy, Div Med Oncol, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[3] Duke Univ, Med Ctr, Dept Microbiol & Mol Genet, Durham, NC 27710 USA
[4] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA
[5] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[7] Harvard Univ, Sch Med, Dept Pediat Oncol, Boston, MA 02115 USA
[8] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA
[9] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[10] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[11] Broad Inst, Cambridge, MA USA
关键词
D O I
10.1158/1078-0432.CCR-05-1652
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:152 / 158
页数:7
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