1534P - Effects of MRX34, a liposomal miR-34 mimic, on target gene expression in human white blood cells (hWBCs): qRT-PCR results from a first-in-human tri...

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Presenter Heidi Peltier
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors H.J. Peltier, K. Kelnar, A.G. Bader
  • Translational Research, Mirna Therapeutics Inc, 78744 - Austin/US

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 rest in 21d cycles (QDx5 schedule). Whole blood was collected pretreatment and at multiple times after the first and during subsequent infusions. Total RNA from hWBCs (LeukoLOCK method) was isolated (mirVana kit) and assessed for quality (Agilent 2100 Bioanalyzer). qRT-PCR was used to measure and compare the relative expression levels of selected direct miR-34a target genes in the RNA from pre- and post-dose samples.

Results

Expression of miR-34a target genes was repressed in hWBCs 24 hrs after the start of MRX34 dosing. The effect was dose-dependent such that the depth of repression increased at higher MRX34 doses corresponding to increased exposure to and uptake of miR-34a in hWBCs. In contrast, expression of p21 (CDKN1A), a tumor-suppressor gene specifically induced by miR-34a, was increased.

Conclusions

This qRT-PCR analysis of hWBC samples obtained from patients treated with MRX34 in a first-in-human clinical trial of miRNA cancer therapy showed dose-dependent modulation of expression in target genes directly regulated by miR-34a. Our work suggests that MRX34 effectively delivers active miR-34a mimics to hWBCs in pts 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

H.J. Peltier, K. Kelnar: Employment, Mirna Therapeutics Inc. A.G. Bader: Employment, Stock Ownership, Mirna Therapeutics, Inc.