Neoadjuvant Docetaxel Treatment for Locally Advanced Prostate Cancer Affects miRNA Expression: A Pilot Study
Sara M Falzarano, Ming Zhou, Paula Carver, Eric A Klein, Robert Dreicer, Cristina Magi-Galluzzi. Cleveland Clinic, Cleveland, OH
Background: Taxanes are microtubule-stabilizing drugs used investigationally in adjuvant and neoadjuvant settings of prostate cancer (PCA) treatment in attempt to improve systemic control of high risk disease. Understanding mechanism of response to taxanes is essential to develop novel combination therapies. MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression by binding target messenger RNAs and inhibiting their stability and/or translation. In cancer, miRNAs can act as oncogenes and/or tumor suppressor genes. Our objective was to identify miRNAs that are affected by neoadjuvant docetaxel in high-risk PCA.
Design: Whole cell RNA was extracted from formalin-fixed paraffin-embedded radical prostatectomy specimens from 8 patients with high grade PCA treated with neoadjuvant docetaxel, 8 high grade untreated PCA and their corresponding untreated non-neoplastic tissue. Tumors were matched by Gleason score, patient age and year of surgery. Expression of 88 cancer-associated miRNAs was quantified using a PCR-based miRNA microarray assay.
Results: Thirty-eight (43%) miRNAs (including miR-205, miR-222, and miR-1) were significantly downregulated in untreated PCA compared to untreated non-neoplastic tissue, and one (miR-183) was upregulated (p<0.05). In 25 of the downregulated miRNAs, fold regulation was less than 2 (range -2.1 to -8.0). Twenty (23%) miRNAs (including miR-218, miR-124, and let-7b) were significantly upregulated in treated compared to untreated PCA (p<0.05). Four of them (miR-125a-5p, miR-222, miR-1 and miR-133b) showed fold regulation greater than 2 (range 2.4 to 5.1). Sixteen of 38 miRNAs downregulated in untreated tumors (including miR-125a-5p, miR-222, miR-1 and miR-133b) were upregulated in treated PCA. Expression levels of 7 of them (miR133b, miR-27b, miR-29b, miR-34a, miR-140-5p, miR-9 and miR-15b) were reverted to values similar to untreated non-neoplastic tissue as a result of docetaxel treatment.
Conclusions: MicroRNAs may play a potential role in PCA response to taxanes. A subset of miRNAs are downregulated in untreated tumors but upregulated in treated PCA to levels comparable to non-neoplastic tissue, suggesting a miRNA modulation towards a non-neoplastic expression profile with neoadjuvant docetaxel treatment. miR-133b has been reported to be involved in the regulation of apoptosis, by functionally targeting members of the BCL-2. Further studies are underway to evaluate the miRNA-mediated effects of taxanes in PCA.
Category: Genitourinary (including renal tumors)
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 104, Tuesday Afternoon