The Rocky Road from Preclinical Findings to Successful Targeted Therapy in Pleural Mesothelioma

Our plain-English summary of The Rocky Road from Preclinical Findings to Successful Targeted Therapy in Pleural Mesothelioma, by J. Paajanen, R. Bueno, A. De Rienzo (International Journal of Molecular Sciences, 2022).

The study

• Authors: J. Paajanen, R. Bueno, A. De Rienzo
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(21)
• Type of article: Review
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM) is a rare and aggressive disease that arises from the mesothelial cells lining the pleural cavity. Approximately 80% of PM patients have a history of asbestos exposure. The long latency period of 20-40 years from the time of asbestos exposure to diagnosis, suggests that multiple somatic genetic alterations are required for the tumorigenesis of PM. The genomic landscape of PM has been characterized by inter- and intratumor heterogeneity associated with the impairment of tumor suppressor genes such as CDKN2A, NF2, and BAP1. Current systemic therapies have shown only limited efficacy, and none is approved for patients with relapsed PM. Advances in understanding of the molecular landscape of PM has facilitated several biomarker-driven clinical trials but so far, no predictive biomarkers for targeted therapies are in clinical use. Recent advances in the PM genetics have provided optimism for successful molecular strategies in the future. Here, we summarize the molecular mechanism underlying PM pathogenesis and review potential therapeutic targets.

In plain English

This article was a review, not a new study. The authors summarized published research on genetic changes in pleural mesothelioma and drugs targeting them. They noted that about 80% of cases are attributed to previous asbestos exposure. The review described inherited BAP1 mutations; cited studies reported that carriers can develop pleural or peritoneal mesothelioma with no or minimal asbestos exposure, and that their tumors are less aggressive. It also described a mouse study in which mice carrying one abnormal BAP1 copy and given crocidolite asbestos developed mesothelioma significantly more often than normal mice. In single-group trials, disease control at 12 weeks was 58% (95% CI 33 to 77) among 26 patients with BAP1/BRCA1-deficient relapsed mesothelioma given rucaparib, and 54% (95% CI 42 to 67) among 61 patients with BAP1 inactivation given tazemetostat; most, but not all, had pleural mesothelioma. Defactinib, tested in 344 patients, did not significantly improve survival compared with placebo. Vorinostat, tested in 661 patients, did not improve overall survival. The authors concluded that no predictive biomarkers for targeted therapies have yet been adopted for wide clinical use.

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 genetic, laboratory, animal and clinical trial research on targeted therapy in pleural mesothelioma
• Who was studied: No new patients were studied. The review covered published genomic studies, preclinical studies and clinical trials in pleural mesothelioma (PM).
• Exposure: This was not an exposure study. The review stated that previous asbestos exposure is the most common risk factor for pleural mesothelioma, accounting for approximately 80% of cases. It also cited a mouse experiment that used crocidolite asbestos.
• Main results:
  • A cited study of 198 unrelated mesothelioma patients (pleural, peritoneal and tunica vaginalis) found 24 germline mutations in 13 genes in 12% of patients. BAP1 was the most common mutation, found in 3% of tested patients.
  • In a cited mouse study, mice carrying one abnormal copy of BAP1 were treated with a low (0.05 mg weekly) or standard (0.5 mg weekly) dose of crocidolite asbestos. They developed pleural mesothelioma significantly more frequently than wildtype control mice.
  • Cited studies reported that mesotheliomas resulting from inherited BAP1 mutations are less aggressive than sporadic tumors, with a median survival ranging from 5 to 7 years.
  • A cited phase II single-arm trial tested rucaparib in BAP1/BRCA1-deficient relapsed mesothelioma. Of 36 patients screened, 26 were included, and 96% of these had pleural mesothelioma. Disease control was 58% (95% CI 33 to 77) at 12 weeks and 23% (95% CI 9 to 44) at 24 weeks. BAP1/BRCA1 status did not predict treatment response.
  • A cited phase II single-arm trial tested tazemetostat in 61 patients with BAP1 inactivation, 57 (93%) of whom had pleural mesothelioma. Disease control was 54% (95% CI 42 to 67) at 12 weeks and 33% (95% CI 21 to 45) at 24 weeks. The overall response rate was 3%.
  • A cited randomized, placebo-controlled phase II trial tested maintenance defactinib in 344 patients with advanced pleural mesothelioma. Compared with placebo, there were no significant improvements in progression-free survival (median 4.1 versus 4.0 months) or overall survival (median 12.7 versus 13.6 months).
  • A cited phase III placebo-controlled trial tested vorinostat in 661 patients with advanced pleural mesothelioma. Median overall survival was 30.7 weeks with vorinostat and 27.1 weeks with placebo (HR 0.98, 95% CI 0.83 to 1.17). Progression-free survival was significantly longer with vorinostat (HR 0.75, 95% CI 0.63 to 0.88).
• The authors' conclusion: The authors concluded that pleural mesothelioma is characterized by inactivation of tumor suppressor genes, which are difficult to target directly with drugs. Biomarker-driven trials have shown promising development, but no predictive biomarkers for targeted therapies have been adopted for wide clinical use so far. Molecular differences within and between tumors may explain past challenges in drug development.

Topics

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

Medical terms in this study, explained in our Lexicon: Targeted Therapy, Pleural Mesothelioma, Mesothelial Cells, Pleural Cavity, Asbestos Exposure, Latency, Tumorigenesis, Tumor Suppressor Gene.

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