Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future

Our plain-English summary of Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future, by G. Reid, T.G. Johnson, N. van Zandwijk (Frontiers in Oncology, 2020).

The study

• Authors: G. Reid, T.G. Johnson, N. van Zandwijk
• Journal: Frontiers in Oncology
• Published: 2020;10:105
• Type of article: Review
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

microRNAs (miRNAs) are an important class of non-coding RNA that post-transcriptionally regulate the expression of most protein-coding genes. Their aberrant expression in tumors contributes to each of the hallmarks of cancer. In malignant pleural mesothelioma (MPM), in common with other tumor types, changes in miRNA expression are characterized by a global downregulation, although elevated levels of some miRNAs are also found. While an increasing number of miRNAs exhibit altered expression in MPM, relatively few have been functionally characterized. Of a growing number with tumor suppressor activity in vitro, miR-16, miR-193a, and miR-215 were also shown to have tumor suppressor activity in vivo. In the case of miR-16, the significant inhibitory effects on tumor growth following targeted delivery of miR-16-based mimics in a xenograft model was the basis for a successful phase I clinical trial. More recently overexpressed miRNAs with oncogenic activity have been described. Many of these changes in miRNA expression are related to the characteristic loss of tumor suppressor pathways in MPM tumors. In this review we will highlight the studies providing evidence for therapeutic effects of modulating microRNA levels in MPM, and discuss these results in the context of emerging approaches to miRNA-based therapy.

Copyright © 2020 Reid, Johnson and van Zandwijk.

In plain English

This article is a review, not a new study. The authors summarized published laboratory, animal and early clinical research on microRNAs, a class of non-coding RNA that controls the activity of many genes, in malignant pleural mesothelioma (MPM). It does not examine asbestos exposure. The authors reported that most microRNAs are found at lower levels in MPM and that relatively few have been tested for their function. Of the microRNAs shown to suppress tumors, only a handful had been shown to work in clinically relevant animal models. Mimics of miR-16-5p or miR-193a-3p delivered inside bacterial minicells slowed tumor growth. A miR-215-5p mimic given into the chest cavity reduced tumor growth and improved survival of tumor-bearing mice. The phase I MesomiR-1 trial of a miR-16-based mimic included 27 patients. It showed safety, one objective response and stable disease in a further 15 patients. The review also covered overexpressed microRNAs whose blocking reduced MPM cell growth, and new delivery methods. The authors concluded that the evidence supports continued development of microRNA-based therapies. They noted that delivering such drugs remains far from solved.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published studies
• Who was studied: Published laboratory (cell line), animal xenograft and early clinical studies of microRNAs in malignant pleural mesothelioma; no new patients or samples were studied
• Exposure: No asbestos exposure was studied. The review covers experimental approaches that change microRNA levels: mimics to restore tumor suppressor microRNAs lost in MPM, inhibitors of overexpressed oncogenic microRNAs, and ways of delivering them (bacterial minicells, atelocollagen, adenoviral vectors, extracellular vesicles)
• Main results:
  • Across the studies reviewed, microRNA levels in MPM were generally lower overall, though some microRNAs were found at higher levels
  • Of the growing number of microRNAs with tumor suppressor function in MPM, only a handful had been shown to have activity in clinically relevant animal models
  • In two cited xenograft studies, miR-16-5p and miR-193a-3p mimics given systemically in minicells significantly inhibited tumor growth
  • The cited phase I MesomiR-1 trial of a miR-16-based mimic involved 27 patients and showed safety, with one objective response and stable disease in a further 15 patients
  • In a cited mouse study, a miR-215-5p mimic given into the pleural space reduced growth of orthotopic xenografts and improved survival of tumor-bearing mice
  • In cited cell studies, blocking the overexpressed miR-182-5p and miR-183-5p with inhibitors reversed their effects on MPM cell proliferation and invasion
  • The authors proposed that mutations in three commonly altered pathways in MPM (p53, Hippo signaling, BAP1) are likely contributors to the overall loss of microRNAs
• The authors' conclusion: The authors concluded that multiple lines of evidence support continued development of microRNA-based therapies for MPM. They said further clinical investigation and better methods for preparing and loading delivery vesicles will be needed.
• Limitations the authors state:
  • The authors stated that effective delivery of microRNA mimics and similar drugs is far from solved
  • The authors noted that the only clinical experience with microRNA mimics in MPM so far is the MesomiR-1 trial
  • The authors stated that the role of microRNAs in sarcomatoid tumors needs a larger number of samples to confirm

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Clinical Trial.

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