MicroRNA silencing for cancer therapy targeted to the tumor microenvironment
By Christopher J. Cheng, R. Bahal, I. Babar, Zachary Pincus, Francisco N. Barrera, Connie Liu, Alexander A. Svoronos, D. Braddock, P. Glazer, Donald M. Engelman and 2 more. Nature, 2014
767 citations recorded by the source corpus.
MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes, and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction. Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells. Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.
Subfields: Cancer Research, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/75ff6213c2e303d9835d1fa72c47ff8adbc5e5a7
Citations in the corpus
- OncomiR or Tumor Suppressor? The Duplicity of MicroRNAs in Cancer (2016, unknown): “It possesses an oncogenic role in a large number of solid and hematologic malignancies (6–8), and its overexpression alone in lymphoid tissues is sufficient to produce an aggressive disseminated lymphoma in a miR-155 Cre-loxP tetracycline-controlled knock-in mouse model (6, 7).”
- Non-coding RNAs in disease: from mechanisms to therapeutics (2023, unknown): “Clinical applications related to suppressing miR-155 for cancer therapy targeted to the tumour microenvironment were developed for diffuse large B cell lymphoma 318 using the attachment of nucleic acid anti-miRNAs to a peptide with a low pH-induced transmembrane structure (pHLIP).”