1566P - Down-regulation of target gene expression in human white blood cells (hWBCs) by MRX34, a liposomal miR-34 mimic: Next generation sequencing (NGS) r...
Date | 10 October 2016 |
Event | ESMO 2016 Congress |
Session | Poster display |
Topics | Translational Research Basic Principles in the Management and Treatment (of cancer) |
Presenter | Kevin Kelnar |
Citation | Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392 |
Authors |
K. Kelnar, H.J. Peltier, A.G. Bader
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Abstract
Background
Each microRNA (miRNA) modulates the expression of hundreds of genes across distinct cellular pathways, giving miRNA-based therapy the potential to simultaneously repress multiple oncogenic processes in the tumor microenvironment, including growth and proliferation, resistance, cancer stem cells, metastasis, and immune evasion. The naturally occurring tumor suppressor miR-34a has been shown to down-regulate the expression of >30 oncogenes (eg, MET, MEK1, MYC, PDGFR-α, CDK4/6, BCL2, WNT 1/3, NOTCH1, CD44), as well as genes involved in tumor immune evasion (eg, PD-L1, DGK&zgr;). MRX34, a liposome-encapsulated miR-34a mimic, is a potential first-in-class miRNA therapy for cancer.
Methods
In the MRX34-101 phase I trial (NCT01829971), patients with advanced malignancies under dexamethasone premedication received IV infusions of MRX34 daily for 5 d in week 1 with 2 weeks off in 21d cycles (QDx5 schedule). Whole blood was collected pretreatment and at multiple time points during and post-infusion. Total RNA from hWBCs (LeukoLOCK method) was isolated (mirVana kit) and assessed for quality (Agilent 2100 Bioanalyzer). Whole transcriptome RNA sequencing (RNASeq) was then used to compare the relative expression levels of 99 experimentally confirmed and 443 predicted direct miR-34a target genes in pre- and postdose samples.
Results
Expression of the majority of established and predicted miR-34a target genes was repressed in hWBCs 24 hrs after the start of MRX34 dosing. The effect was dose dependent such that the number of down-regulated genes increased at higher MRX34 doses corresponding to increased exposure to and uptake of miR-34a in hWBCs.
Conclusions
This NGS analysis of hWBC samples from patients treated with MRX34 in a first-in-human clinical trial of miRNA cancer therapy showed dosedependent modulation of expression for validated and predicted miR-34a target genes, including key oncogenes. Our work suggests that MRX34 effectively delivers active miR-34a mimics to hWBCs in patients with cancer, and provides a potentially useful method to evaluate biomarkers of response to MRX34 therapy.
Clinical trial identification
NCT01829971
Legal entity responsible for the study
Mirna Therapeutics Inc
Funding
Mirna Therapeutics Inc
Disclosure
K. Kelnar, H.J. Peltier: Employment, Mirna Therapeutics. A.G. Bader: Employment, Stock Ownership, Mirna Therapeutics Inc.