Abstract 4395: Modulation of circulating microRNAs in serum of clear cell renal cell carcinoma (ccRCC) patients treated with vorinostat and bevacizumab
Authors: Chintala Sreenivasulu , Miles Kiersten M. , Adelaiye Remi , Pili Roberto 
Published: May 2015

There have been several elegant studies showing non coding resident microRNA and circulating extracellular microRNA alterations in ccRCC. MicroRNAs have been reported to be epigenetically regulated. Histone deacetylase (HDAC) inhibitors are currently in clinical development for ccRCC. The objectives of the study were i) to determine the effect of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab on circulating microRNAs in serum of ccRCC patients with either objective response (Responders) or progression (Progressors); ii) To evaluate serum levels of secreted growth factors (VEGF, FGF2, HGF), apoptotic markers (sFAS-L and TRAIL), invasion and metastatic markers (SDF and OPN), and cytokines (IL8). MicroRNAs were isolated from the serum of ccRCC patient treated with vorinostat and bevacizumab and determined their expression by Exiqon's miRCURY LNATM microarray system. ELISA and Luminex analysis methods were used to measure the secreted growth factors, apoptosis markers, metastasis and invasive makers, and cytokines. In silico bioinformatics analysis was performed to determine the target molecules of the altered microRNAs. Additionally, we have evaluated the possible role of altered microRNA on the regulation of secreted factors in the serum to determine if microRNA could serve as a biomarker of the response to treatment. Exiqon microarray analysis revealed the differential regulation of 134 microRNAs in the post-vs pre-treatment of vorinostat and bevacizumab. The analysis of microRNA expression in Responders and Progressors at the baseline, pre, and post treatment revealed the differential expression of 10 microRNAs in the serum. We found downregulation of miR-20a, miR-142-3p, miR-154, miR-199a-5p, and miR-let-7b and up regulation of miR-99a, miR-605, miR-485-3p, miR-365, and miR-451 in the Responders at baseline. MicroRNA miR-20a and miR-let7b were significantly up regulated after treatment. In addition, miR-605, miR-485-3p, and miR-365 were found to be significantly downregulated after treatment. These results suggest the role of vorinostat and bevacizumab in the alteration of microRNAs miR-20a, miR-let7b, miR-605, miR-485-3p, and miR-365. In patients who progressed there was no downregulation of miR-let7b or upregulation of miR-605, miR-485-3p, and miR-365 following treatment, suggesting the potential role of these microRNAs in the observed response. We also observed downregulation of secreted VEGF, FGF2, SDF, OPN, sFAS-L, and IL8 in Responders following treatment. Bioinformatics analysis revealed the role of microRNAs in the regulation of these markers. Our results suggest the regulation of selected circulating microRNAs in serum of ccRCC patients treated with vorinostat and bevacizumab and the potential role of microRNAs as biomarkers for response in ccRCC patients receiving epigenetic therapies in combination with antiangiogenics.

Citation Format: Sreenivasulu Chintala, Kiersten M. Miles, Remi Adelaiye, Roberto Pili. Modulation of circulating microRNAs in serum of clear cell renal cell carcinoma (ccRCC) patients treated with vorinostat and bevacizumab. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4395. doi:10.1158/1538-7445.AM2014-4395