Benefits and Challenges of Inhibiting EZH2 in Malignant Pleural Mesothelioma

Our plain-English summary of Benefits and Challenges of Inhibiting EZH2 in Malignant Pleural Mesothelioma, by M.O. Al Khatib, G. Pinton, L. Moro, et al (Cancers, 2023).

The study

• Authors: M.O. Al Khatib, G. Pinton, L. Moro, C. Porta
• Journal: Cancers
• Published: 2023;15(5)
• Type of article: Review
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer that is mainly associated with prior exposure to asbestos fibers. Despite being a rare cancer, its global rate is increasing and the prognosis remains extremely poor. Over the last two decades, despite the constant research of new therapeutic options, the combination chemotherapy with cisplatin and pemetrexed has remained the only first-line therapy for MPM. The recent approval of immune checkpoint blockade (ICB)-based immunotherapy has opened new promising avenues of research. However, MPM is still a fatal cancer with no effective treatments. Enhancer of zeste homolog 2 (EZH2) is a histone methyl transferase that exerts pro-oncogenic and immunomodulatory activities in a variety of tumors. Accordingly, a growing number of studies indicate that EZH2 is also an oncogenic driver in MPM, but its effects on tumor microenvironments are still largely unexplored. This review describes the state-of-the-art of EZH2 in MPM biology and discusses its potential use both as a diagnostic and therapeutic target. We highlight current gaps of knowledge, the filling of which will likely favor the entry of EZH2 inhibitors within the treatment options for MPM patients.

In plain English

This article was a narrative review, not an original study. The authors summarized published laboratory, animal and clinical research on EZH2, a protein that helps switch off genes, in malignant pleural mesothelioma (MPM). MPM is a cancer of the pleura, the lining around the lungs, which they described as mainly associated with prior asbestos exposure. The review did not itself examine asbestos exposure. In studies it described, EZH2 was reported as overexpressed in 44.4–57% of MPM cases but not in reactive mesothelial hyperplasia, a benign condition. The authors suggested combining BAP1 and EZH2 tests could be highly sensitive (90.0%) and specific (100%) in separating MPM from benign mesothelial growths. A phase II trial of the EZH2-blocking drug tazemetostat in patients with BAP1-inactivated, relapsed or refractory MPM reached its 12-week disease-control goal in about half of patients, and two patients had a partial response. The authors' own earlier laboratory work found that tazemetostat also increased recruitment of tumor-promoting monocytes. The authors concluded that EZH2 inhibitors could be a new potential approach worth testing with immunotherapy. They noted that the drugs' effects on immune cells in MPM remain largely unexplored.

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 preclinical and clinical studies on EZH2 in malignant pleural mesothelioma
• Who was studied: No new population was studied. The review covered published studies of MPM cell lines, tumor biopsies, mouse models and clinical trials, including a phase II tazemetostat trial in patients with BAP1-inactivated relapsed or refractory MPM.
• Exposure: Not an asbestos exposure study. Asbestos is mentioned only as the main cause of MPM. The topic is EZH2 and drugs that inhibit it, such as tazemetostat (EPZ-6438), EPZ011989 and DZNep.
• Main results:
  • The review reports that, in other studies, EZH2 was overexpressed in 44.4–57% of MPM cases but not in reactive mesothelial hyperplasia (RMH) cases.
  • The authors suggested that combined BAP1 and EZH2 immunohistochemistry 'could be' a highly sensitive (90.0%) and specific (100%) approach for MPM diagnosis. This was discussed in the context of distinguishing MPM from benign mesothelial proliferations.
  • According to the authors, high EZH2 can help separate MPM from benign mesothelial proliferations but not from other lung malignancies, because EZH2 is not a tissue-specific marker.
  • The review reports that, in an earlier mouse xenograft study, DZNep was associated with an approximately 50% decrease in MPM tumor mass by the end of treatment.
  • The review reports results from a phase II trial of tazemetostat in BAP1-inactivated relapsed or refractory MPM patients. The 12-week disease-control end-point was reached in about half of patients, with a favorable safety profile. Two patients had a partial response, with a 30-week median duration of response.
  • In the authors' own earlier MPM multicellular spheroid study, tazemetostat raised chemokines that recruit cytotoxic immune cells. It also increased recruitment of tumor-promoting monocytes.
  • In the authors' own earlier cell work, CDKN2A null MPM cells underwent apoptosis when treated with the EZH2 inhibitor EPZ6438.
• The authors' conclusion: The authors concluded that EZH2 has emerged as a diagnostic marker with prognostic potential. They also concluded that EZH2 inhibitors could represent a new potential therapeutic approach that warrants evaluation in combination with immunotherapy.
• Limitations the authors state:
  • The effects of EZH2 on immune cells within MPM tumors have never been fully explored.
  • Earlier systematic reviews failed to define a reliable diagnostic biomarker panel. Results differ across studies, which the authors attribute to differences in sample sizes, antibodies, staining and quantification techniques.
  • The phase II tazemetostat trial enrolled patients with more indolent disease. It also included a substantial share of surgically resected patients, which did not reflect typical patients.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Chemotherapy, Cisplatin, Pemetrexed (Alimta), First-line Therapy, Immunotherapy, Tumor Microenvironment.

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