P-226 Pharmacodynamic Serum Biomarker Discovery in Pediatric Inflammatory Bowel Diseases. (March 2016)

• Record Type: Journal Article
• Authors: Heier, Christopher; Hathout, Yetrib; Fiorillo, Alyson; Hoffman, Eric; Gordish-Dressman, Heather; Conklin, Laurie
• Is Part Of: Inflammatory bowel diseases. Volume 22(2016:Mar.)Supplement 1
• Publication Date: 2016-03
• Subjects: Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1097/01.MIB.0000480341.69217.f3
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract : Background: Non-invasive pharmacodynamic (PD) biomarkers used in conjunction with patient-reported outcome measures are potential endpoints for Inflammatory Bowel Disease (IBD) trials. PD biomarkers may also be used to predict efficacy and ablate placebo effects, thereby supporting extrapolation in pediatric trials. To identify potential serum-based molecules that change with anti-inflammatory therapies, we used 2 candidate-based approaches: a microRNA and a proteomic discovery platform. Methods: Serum samples were obtained pre- and post-corticosteroid therapy for a median duration of 9 weeks (range: 3–18 weeks) in 10 children with Crohn's Disease (CD) and 2 with ulcerative colitis (UC). Serum samples were obtained pre-infliximab therapy, and at 6 weeks (post 2 doses) in another set of 12 children with CD and 2 with UC. All patients demonstrated clinical response by PCDAI and PUCAI. MicroRNAs were analyzed by candidate-based qPCR in both cohorts. Proteins were analyzed by SomaScan aptamer-based analysis of the corticosteroid treated cohort. A core set of protein candidates, and encoding genes, was assembled. To determine if changes in expression could reflect treatment effects at either inflammation-regulated or steroid-regulated gene elements in DNA, we surveyed the binding of NF-κB and glucocorticoid receptor (GRE) proteins to regulatory promoter regions in each gene using ChIP-seq data. Results: Several microRNAs were consistently reduced by short-term treatment with corticosteroids and infliximab, including miR-146a, miR-146b, miR-486, miR-320a, and miR-762. Some of these miRNAs are regulated by the activity of NF-κB. Several proteins were highly responsive to corticosteroid therapy, including a set associated with inflammation, and another set associated with metabolic activity. Some of these genes were found to have NF-κB binding regulatory promotor regions. Conclusions: Changes in molecules related to inflammatory pathways were identified in both steroidal and biologic-based treatment groups. Changes in metabolic-related molecules were also noted, which may be indicative of steroid-specific effects. Circulating serum NF-κB-dependent microRNAs and proteins are potential non-invasive PD biomarkers of therapeutic response in IBD. These biomarkers warrant further study, including correlation with post-treatment endoscopic evaluation.