Promising therapeutic potential of tumor suppressor microRNAs for malignant pleural mesothelioma

Our plain-English summary of Promising therapeutic potential of tumor suppressor microRNAs for malignant pleural mesothelioma, by S. Dixit, A.Y. Choi, A. Singh, et al (Journal of Cancer Metastasis and Treatment, 2022).

The study

• Authors: S. Dixit, A.Y. Choi, A. Singh, K. Pittala, N. Pruett, C.D. Hoang
• Journal: Journal of Cancer Metastasis and Treatment
• Published: 2022;8
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive and recalcitrant surface neoplasm that defies current multimodality treatments. MicroRNAs (miRNAs) are small noncoding RNAs that epigenetically regulate multiple gene networks and cellular processes. In cancer, miRNA dysregulation is associated with tumorigenesis, with tumor suppressor miRNAs underexpressed or lost, while oncogenic miRNAs are overexpressed. Consequently, miRNAs have emerged as potential therapeutic candidates. Because loss of tumor suppressors predominates the pathophysiology of MPM, re-expressing tumor suppressor miRNAs could be an effective therapeutic strategy. This review highlights the most promising MPM-specific tumor suppressor miRNAs that could be developed into novel therapeutics, the supporting data, and what is known about their molecular mechanism(s).

In plain English

This article was a review, not a new study. The authors, from the Thoracic Surgery Branch of the US National Cancer Institute, looked at published laboratory, animal and early clinical research on microRNAs (small RNA molecules that help control genes) as possible treatments for malignant pleural mesothelioma (MPM). A PubMed search from 2008 to June 2022 found 204 articles. To choose microRNAs, the authors applied several criteria: low levels in human MPM specimens, low levels linked to poor outcomes, and high levels linked to good outcomes. In the studies reviewed, restoring several of these microRNAs held back the growth or spread of mesothelioma cells in the laboratory, and some shrank tumors or improved survival in mice. One cited first-in-man phase 1 trial of a miR-16-5p treatment reported a 5% objective response rate (n = 22) and a 68% disease control rate. One cited study linked high miR-29c-5p levels to better survival irrespective of asbestos exposure. The review itself did not study asbestos exposure. Other microRNAs gave inconsistent results. The authors concluded that the list of well-established tumor suppressor microRNAs in MPM was surprisingly short. They said microRNAs already reported but incompletely characterized still needed verification, and that there should be great optimism for microRNA-based therapies.

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 research on tumor suppressor microRNAs in malignant pleural mesothelioma
• Who was studied: Published articles on microRNA and mesothelioma: a PubMed search from 2008 to June 2022 found 204 articles. The authors selected microRNAs using their criteria. The reviewed studies used MPM tumor samples, MPM cell lines, mouse xenograft models and one phase 1 trial in patients.
• Exposure: The review did not study an asbestos or other environmental exposure. It concerns re-expressing tumor suppressor microRNAs as a possible treatment for MPM.
• Main results:
  • The authors applied several criteria to focus on microRNAs: low levels in human MPM specimens (preferably compared with non-cancerous mesothelium), low tumor expression linked to poor outcomes, and high expression linked to good outcomes. Not every microRNA in their table had a reported prognostic link.
  • In a cited study, high miR-29c-5p expression in MPM was associated with improved survival irrespective of asbestos exposure.
  • In a cited mouse study, a single peri-tumoral injection of miR-215-5p mimic around subcutaneous MPM xenografts in NSG mice shrank tumors.
  • In a cited mouse study, miR-206 delivered locally suppressed the growth of subcutaneous and orthotopic xenografts and increased survival in mice.
  • A cited phase 1, first-in-man trial of systemic miR-16-5p mimic in MPM reported a 5% objective response rate (partial response by CT image, n = 22) and a 68% disease control rate.
  • Several microRNAs proposed as tumor suppressors (miR-31-5p, let-7a, miR-302b-3p, miR-137-3p) were judged ambiguous because the evidence was mainly in vitro or inconsistent.
  • The authors found a short list of tumor suppressor microRNAs in MPM with verified gene targets and consistent in vivo effects.
• The authors' conclusion: The authors concluded that there should be great optimism for microRNA-based therapies for MPM because new approaches have addressed in vivo delivery. They also said microRNAs already reported but incompletely characterized still need to be verified.
• Limitations the authors state:
  • The authors described the PubMed search count as only a rough estimate.
  • Many microRNAs are underexpressed in MPM, but the authors noted that only a few have been functionally well characterized.
  • The authors noted that in some mouse models the cells were treated before implantation. This leaves unclear whether giving the microRNA as a treatment would shrink tumors.
  • The authors noted that the benefit of lowering PD-L1 with microRNAs in MPM remains unclear, given current clinical trial results.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Neoplasm, Carcinogenesis.

Related studies

• MicroRNAs in mesothelioma: from tumour suppressors and biomarkers to therapeutic targets — G. Reid (2015)
• Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma — S.C. Kao, Y.Y. Cheng, et al. (2017)
• MicroRNA expression in lung tissues of asbestos-exposed mice: Upregulation of miR-21 and downregulation of tumor suppressor genes Pdcd4 and Reck — Y. Hiraku, J. Watanabe, et al. (2021)
• Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence — G. Reid, M. Williams, et al. (2025)
• miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma — M. Williams, M.B. Kirschner, et al. (2015)
• Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma — H. Yang, D. Xu, et al. (2020)

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