Abstract
10548 Background: miRNAs are small non-coding RNAs of 20-25 nucleotides with diverse regulatory functions including proliferation, cell differentiation and apoptosis. Unlike mRNA, miRNAs are stable in circulation, potentially offering valuable insights to pharmacologic modulation of drug targets and cell physiology, overcoming some of the challenges associated with tumor biopsies. We explored circulating miRNAs as a biomarker in the Phase I trial of saracatinib (AZD0530) in combination with standard doses of P and/or C (NCT00496028). Methods: Formalin fixed paraffin embedded (FFPE) tumor (n=29) and serum samples (n=69; 22/69 paired pre- and post-treatment) were profiled using Exiqon LNA based QPCR system (n=730 miRNAs) to analyze miRNA expression. Tumor samples analyzed included colorectal (CRC; n=8), ovary (7), pancreas (3), breast (2), esophagus (3), bladder (2), bone, lung, prostate, stomach (1 each). Results: Pre-analytical quality control revealed 28/29 tumor and 55/69 serum samples suitable for miRNA assessment. Unsupervised clustering of miRNAs derived from FFPE samples revealed discriminatory potential to identify the tissue of origin. Importantly, while distinct miRNA profiles were associated with certain tumor types, only selected miRNAs were concordant in matched tumor-serum samples, eg high miR192 and miR194 in CRC. We further examined specific miRNAs that may function as surrogate markers of Src kinase activity, eg miR194 (Li et al. Oncogene 2009;28:4272–83). Although there was no significant change in miR194 levels in 22 paired serum samples, when we excluded CRC patients which typically have high miR194 levels, significant increase in miR194 was seen post exposure to treatment (n=14, P=0.037). Conclusions: Circulating miRNA profiles can be reliably and reproducibly measured in serum, with some degree of tumor-serum concordance. Validation of miRNAs regulated by drug-targeted pathways should consider tumor-of-origin artifacts; adoption of a ‘miRNA profile’ may circumvent this concern. The role of circulating miRNAs as a biomarker in clinical trials warrants further evaluation.
Published Version
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