Systemic Delivery of a miR34a Mimic as a Potential Therapeutic for Liver Cancer

Abstract

miR34a is a tumor-suppressor miRNA that functions within the p53 pathway to regulate cell-cycle progression and apoptosis. With apparent roles in metastasis and cancer stem cell development, miR34a provides an interesting opportunity for therapeutic development. A mimic of miR34a was complexed with an amphoteric liposomal formulation and tested in two different orthotopic models of liver cancer. Systemic dosing of the formulated miR34a mimic increased the levels of miR34a in tumors by approximately 1,000-fold and caused statistically significant decreases in the mRNA levels of several miR34a targets. The administration of the formulated miR34a mimic caused significant tumor growth inhibition in both models of liver cancer, and tumor regression was observed in more than one third of the animals. The antitumor activity was observed in the absence of any immunostimulatory effects or dose-limiting toxicities. Accumulation of the formulated miR34a mimic was also noted in the spleen, lung, and kidney, suggesting the potential for therapeutic use in other cancers. Mol Cancer Ther; 13(10); 2352-60. Ó2014 AACR.

Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model

“…Unfortunately, all five phase III human clinical trials of small-molecule drugs for hepatocellular carcinoma (HCC) treatment failed within the past four years in part because debilitating, late-stage liver dysfunction amplifies drug toxicity (11,12). MicroRNAs (miRNAs) present a promising alternative cancer treatment strategy because they can function as tumor suppressors by concurrently targeting multiple pathways involved in cell differentiation, proliferation, and survival (13)(14)(15)(16)(17)(18)(19). In this study, we used a highly aggressive, inducible MYC-driven transgenic liver cancer model where the chance for successful therapy is very limited, in equal part due to the rapidly growing cancer and the compromised function of the overtaken liver.…”

Dysregulation of microRNA biogenesis and gene silencing in cancer

“…Thus, miR34a/b/c is not critical to the p53 response (36). Clinical trials are in progress to assess whether replacement therapy with miR-34a mimics will suppress tumors (37). Besides miR-34, a few other miRNAs modulate gene expression in the DDR (38).…”

MicroRNA-34 dysregulation in gastric cancer and gastric cancer stem cell

“…In this study, a critical role for the miRNA-34a-MYCN-survivin pathway was proposed in cell death induced by CDK1 inhibition in neuroblastoma cells. 151 He et al 78 and Tazawa et al 97 Cyclin D1 (CCND1) Regulator of cell cycle G1/S transition, involved in cell proliferation and invasion 131,132 Non-small cell lung cancer A549 cell line 3′-UTR luciferase reporter assay, qRT-PCR Sun et al 84 Cyclin E2 (CCNE2) Regulator of cell cycle G1/S transition, involved in cell proliferation He et al, 78 Li et al, 88 Yan et al, 101 Peng et al 112 and Daige et al 133 PDGFRα/β Cell growth, proliferation, tumour angiogenesis, invasion, metastasis, apoptosis inhibition Gastric cancer AGS and MKN-45 cell lines 3′-UTR luciferase reporter assay, BCL2: B-cell CLL/lymphoma 2; SIRT1: silent information regulator 1; CDK: cyclin-dependent kinase; MET: hepatocyte growth factor receptor; PDGFR: platelet-derived growth factor receptor; mTORC2: mammalian target of rapamycin complex 2; LRP: low-density lipoprotein (LDL) receptor-related protein; TCF/LEF: T-cell factor/lymphocyte enhancer factor; DLL1: Delta-like 1; Tgif2: transforming growth factor-beta-induced factor 2; 3′-UTR: 3′-untranslated region; qRT-PCR: quantitative real-time polymerase chain reaction; TGF-β: transforming growth factor β;…”