The role of BCL-2 family proteins and therapeutic potential of BH3-mimetics in malignant pleural mesothelioma

Our plain-English summary of The role of BCL-2 family proteins and therapeutic potential of BH3-mimetics in malignant pleural mesothelioma, by S. Arulananda, E.F. Lee, W.D. Fairlie, et al (Expert Review of Anticancer Therapy, 2021).

The study

• Authors: S. Arulananda, E.F. Lee, W.D. Fairlie, T. John
• Journal: Expert Review of Anticancer Therapy
• Published: 2021;21(4):413-424
• Type of article: Review
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: With limited recent therapeutic changes, malignant pleural mesothelioma (MPM) is associated with poor survival and death within 12 months, making it one of the most lethal malignancies. Due to unregulated asbestos use in developing countries and home renovation exposures, cases of MPM are likely to present for decades. As MPM is largely driven by dysregulation of tumor suppressor genes, researchers have examined other mechanisms of subverting tumor proliferation and spread. Over-expression of pro-survival BCL-2 family proteins impairs cells from undergoing apoptosis, and BH3-mimetics targeting them are a novel treatment option across various cancers, though have not been widely investigated in MPM.Areas covered: This review provides an overview of MPM and its current treatment landscape. It summarizes the role of BCL-2 family proteins in tumorigenesis and the therapeutic potential of BH3-mimetics . Finally, it discusses the role of BCL-2 proteins in MPM and the pre-clinical rationale for investigating BH3-mimetics as a therapeutic strategy.Expert opinion: As a disease without readily actionable oncogene driver mutations and with modest benefit from immune checkpoint inhibition, novel therapeutic options are urgently needed for MPM. Hence, BH3-mimetics provide a promising treatment option, with evidence supporting dependence on pro-survival BCL-2 proteins for MPM cell survival.

In plain English

This article is a review, not a new study. The authors summarised published research on malignant pleural mesothelioma (MPM). They covered the BCL-2 family of proteins, which help decide whether a cell undergoes programmed cell death, and BH3-mimetics, drugs designed to block the pro-survival members of this family. The review described how these drugs were developed and tested in other cancers. It then examined laboratory, tissue and animal studies in mesothelioma. The authors reported that earlier studies of these proteins in MPM tissue gave contradictory results and had small sample numbers. They also cited their own separate study of samples from 326 patients. In that study, most samples had high levels of the proteins BCL-XL and MCL-1, and fewer than 10% had high BCL-2. In the same study, combining BCL-XL-blocking drugs with the MCL-1-blocking drug S63845 showed strong combined effects against MPM cell lines. The authors concluded that BH3-mimetics are a potential treatment strategy worth exploring in MPM. They added that further laboratory and animal work is needed on how well these drugs work and how safe they are in MPM.

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
• Who was studied: No study population of its own. The review covered published studies of mesothelioma tissue samples, cell lines and mouse models, and studies in other cancers.
• Exposure: Not an asbestos exposure study. Asbestos appears only as background. The review concerns BCL-2 family proteins and BH3-mimetic drugs.
• Main results:
  • A cited earlier study of 35 human MPM tissue samples found 20% positive for BCL-2.
  • A cited later study of 54 cases reported over-expression of BCL-2 in 40%, BCL-XL in 24%, MCL-1 in 92%, BAK in 24% and BAX in 42%. The authors described these results as conflicting with the earlier study.
  • The authors' own separate study of samples from 326 patients found that most samples (50-80%) had high levels of BCL-XL and MCL-1, as well as BAX and BAK. Fewer than 10% had high BCL-2 levels.
  • In that 326-patient study, the authors described a trend towards poorer overall survival in patients with high BCL-XL (11.8 versus 16.8 months). Patients with high BCL-2 had significantly worse overall survival.
  • In the authors' own study, BCL-XL inhibitors combined with the MCL-1 inhibitor S63845 showed strong synergy against MPM cell lines in the laboratory.
  • In the authors' own mouse xenograft experiments, BCL-XL inhibitors controlled tumour growth similarly to cisplatin. When the two were combined, survival times essentially doubled.
• The authors' conclusion: The authors concluded that the data make a case for exploring BH3-mimetics as a potential treatment strategy in MPM.
• Limitations the authors state:
  • The authors noted that the tissue studies they reviewed had small sample numbers.
  • The authors suggested that differences between tissue studies could reflect the different antibodies and scoring criteria used.
  • The authors stated that BH3-mimetics have not yet been widely investigated in MPM.
  • The authors stated that further laboratory and animal work is needed on the efficacy and safety of BH3-mimetics in MPM.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Tumor Suppressor Gene, Apoptosis, Carcinogenesis.

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• Anticancer property of bromelain with therapeutic potential in malignant peritoneal mesothelioma — K. Pillai, J. Akhter, et al. (2013)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)

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