Abstract 974: Targeting the tumor microenvironment with antimiRs that exploit oncomiR addiction in lymphoma
Authors: Christopher J. Cheng, Don M. Engelman, Mark Saltzman, Frank J. Slack
Journal: Cancer Research (2014)

Abstract The purpose of this study was to develop a tumor-targeted therapeutic to antagonize aberrantly expressed microRNAs in lymphoma. MicroRNA dysfunction has been linked to the onset cancer. For example, in lymphoma miR-155 can affect carcinogenesis by acting as a hyperexpressed microRNA oncogene, or oncomiR. As ubiquitous regulators of gene expression, microRNAs are promising therapeutic targets. As such, numerous recent preclinical and clinical studies have utilized therapeutic oligonucleotides, known as antimiRs, to bind to and inhibit disease-associated microRNAs. However, the efficacy of systemically administered antimiRs is hindered by non-specific tissue targeting, which typically results in substantial liver uptake. We have developed an antimiR-peptide conjugate which preferentially targets the acidic tumor microenvironment. Intravital imaging and confocal tissue analysis show that this conjugate accumulates in tumors, while avoiding the liver, and has no observable systemic or cellular toxicity. The antimiR component of this conjugate comprises charge-neutral peptide nucleic acids (PNA). Due to their stability and high binding affinity, PNAs are effective antimiRs; however, they do not efficiently enter cells without a delivery vector. In addition to its tumor targeting benefits, we have previously shown that this peptide can deliver cargo into cells by translocating tethered molecules directly across lipid membranes. Via this non-endocytic mechanism, this peptide also promotes the effective delivery of PNA antimiRs into cultured B lymphocytes. Therefore, this conjugate both targets tumors and delivers antimiRs into cells via non-canonical pathways. Here we will detail the design and characterization of this conjugate, with specific emphasis on its ability to deliver antimiRs into cells via a non-endocytic route. In cultured cells we will demonstrate the efficacy of miR-155 inhibition using reporter and cell viability assays. For in vivo studies, we developed a metastatic mouse model of inducible diffuse large B cell lymphoma that is addicted to miR-155, such that lymphomagenesis is dependent on overexpression of the oncomiR, and withdrawal of miR-155 leads to cancer regression. Using this spontaneous miR-155-addicted lymphoma tumor model, we will discuss the biodistribution of the conjugate, as well as the effects of antimiR-155 therapy on lymphoid tumor growth and metastasis. In addition, we will outline how antagonizing miR-155 affects novel gene targets and biological pathways involved in oncomiR addiction, which were uncovered via RNA-seq differential gene expression analysis. OncomiRs have recently established a new paradigm for anti-cancer gene therapy. This work introduces a versatile and non-toxic tumor microenvironment-targeted system that exploits these lynchpin molecules as therapeutic tools. Citation Format: Christopher J. Cheng, Don M. Engelman, Mark Saltzman, Frank J. Slack. Targeting the tumor microenvironment with antimiRs that exploit oncomiR addiction in lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 974. doi:10.1158/1538-7445.AM2014-974