Novel Therapeutic Targets and Immune Dysfunction in Malignant Pleural Mesothelioma

Our plain-English summary of Novel Therapeutic Targets and Immune Dysfunction in Malignant Pleural Mesothelioma, by M. Lapidot, S.V. Saladi, R. Salgia, et al (Frontiers in Pharmacology, 2021).

The study

• Authors: M. Lapidot, S.V. Saladi, R. Salgia, M. Sattler
• Journal: Frontiers in Pharmacology
• Published: 2021;12:806570
• Type of article: Review
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Advances in the treatment of malignant pleural mesothelioma (MPM) have been disappointing, despite the apparent need for new therapeutic options for this rare and devastating cancer. Drug resistance is common and surgical intervention has brought benefits only to a subset of patients. MPM is a heterogenous disease with a surprisingly low mutation rate and recent sequencing efforts have confirmed alterations in a limited number of tumor suppressors that do not provide apparent insights into the molecular mechanisms that drive this malignancy. There is increasing evidence that epigenetic regulation leads to immune evasion and transformation in MPM. Further, the low efficacy of immune checkpoint inhibitors is consistent with a suppression of genes involved in the anti-tumor immune response. We review three promising emerging therapeutic targets (STAT3, KDM4A, heparanase) and highlight their potential effects on the immune response.

Copyright © 2022 Lapidot, Saladi, Salgia and Sattler.

In plain English

This article was a review, not a new study of patients. The authors wrote about malignant pleural mesothelioma (MPM), a cancer they described as mainly related to breathing in asbestos fibers at work. They surveyed published research on current treatments, the genetic changes found in MPM, and three possible new drug targets: STAT3, KDM4A and heparanase. Much of the work on these targets came from laboratory cells and mice, including the authors' own earlier experiments. The review cited an earlier study that found activated STAT3 in 61.4% (27/44) of archived MPM cases. It also cited earlier mouse studies in which the heparanase-blocking drugs pixatimod and defibrotide appeared more effective than cisplatin at restraining tumor growth. The authors summarized the CheckMate 743 trial, in which nivolumab plus ipilimumab extended median overall survival by 9.3 months in patients with non-epithelioid MPM, or by 4 months for all patients. They noted that there are currently no effective biomarkers that allow easy screening of at-risk patients with a history of asbestos exposure or other inciting events. The authors concluded that the goal should be treatment tailored to each individual patient.

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: Review of published research on new therapeutic targets and immune dysfunction in malignant pleural mesothelioma
• Who was studied: Not applicable: a review of published research on malignant pleural mesothelioma; no new patients were studied
• Exposure: Asbestos exposure was not studied. The authors noted in their introduction that MPM is mainly related to inhaled asbestos fibers from occupational exposure. No fiber type was named.
• Main results:
  • A cited earlier study (Achcar et al., 2007) found tyrosine-phosphorylated (activated) STAT3 in 61.4% (27/44) of archived MPM cases
  • The authors' own earlier work (Lapidot et al., 2020a) showed the STAT3 pathway inhibitors atovaquone and pyrimethamine were effective in laboratory (in vitro) and animal (in vivo) models of MPM
  • The authors' earlier data (Lapidot et al., 2021) showed KDM4A is expressed at high levels in MPM patients. Highly specific KDM4A inhibitors suitable for clinical trials are not yet available.
  • In cited studies, MPM patients with high heparanase staining survived less than those with low levels. In mice, the heparanase inhibitors pixatimod (PG545) and defibrotide appeared more effective than cisplatin at restraining tumor growth.
  • In the cited CheckMate 743 trial (Baas et al., 2021), nivolumab plus ipilimumab extended median overall survival by 9.3 months (18.1 months total) in patients with non-epithelioid MPM, or by 4 months for all patients
  • The authors stated there are currently no effective biomarkers that allow easy screening of at-risk patients with a history of asbestos exposure or other inciting events
• The authors' conclusion: The authors concluded that tailoring the right treatment approach for each individual patient should be the goal of MPM treatment

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, checkpoint inhibitors.

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