Abstract 2045: High-dose intervention with atorvastatin affects serum micro-RNAs in men with localized prostate cancer - an exploratory sub-analysis of ESTO1 placebo-controlled clinical trial

Abstract Introduction: Prostate cancer (PCa) is associated with increased cholesterol production, and statins, which inhibit the mevalonate pathway, can reduce PCa cell proliferation. This pathway regulates key cellular processes, including inflammation and growth. Previous trials have shown that statins lower PCa growth in men with localized PCa. Thus, further understanding the effect of statin intervention on PCa is crucial. MicroRNAs (miRNAs) are involved in the post-translational regulation of gene expression and have been linked to PCa risk and outcomes. This study aims to assess the impact of atorvastatin on the serum miRNA profile in men with localized PCa. Materials & Methods: The ESTO1 trial enrolled 158 men with localized PCa who were scheduled for radical prostatectomy. Participants were randomly assigned to receive either 80 mg of atorvastatin or a placebo daily for 21 days before surgery. Serum samples were collected at baseline and the day before surgery. This exploratory sub-analysis included samples from 48 men, representing both high-grade (ISUP grade 3 or higher) and low-grade (ISUP 1-2) cases, with both atorvastatin and placebo groups. RNA was extracted from serum samples, pooled by trial arm and ISUP grade, and analyzed using small RNA sequencing on Illumina equipment. Differential expression was analyzed using DESeq2 in R Studio. MiRNAs showing the most significant changes were confirmed via dPCR analysis in individual samples. Results: In pooled samples, the expression of several miRNAs shifted during atorvastatin treatment in comparison to the placebo group. Most of these miRNAs have been previously linked to PCa, including miRNA-205-5p, miRNA-21-3p, and miRNA-210-3p. Individual sample analysis confirmed atorvastatin-induced upregulation of miRNA-205-5p in high-grade cases (p = 0.03). Atorvastatin also altered the expression of certain miRNAs that have not been previously studied in the context of PCa, such as miRNA-10b-3p, miRNA-2355-3p, and miRNA-502-3p. Conclusions: Atorvastatin treatment induced expression changes in several miRNAs, particularly increasing miRNA-205-5p in high-grade cases, which was confirmed through individual sample analysis. This suggests that atorvastatin’s tumor growth-inhibiting effects in PCa may be partially mediated by its influence on miRNA expression and epigenetic regulation. Citation Format: Reetta Nätkin, Tiina Jokela, Aino Siltari, Tia-Marje K. Korhonen, Eija Laakkonen, Teemu J. Murtola. High-dose intervention with atorvastatin affects serum micro-RNAs in men with localized prostate cancer - an exploratory sub-analysis of ESTO1 placebo-controlled clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2045.