Mesothelioma: Hippo pathway as a target, lessons from COMMAND

Our plain-English summary of Mesothelioma: Hippo pathway as a target, lessons from COMMAND, by D.A. Fennell, E.Y. Baitei (Oncotarget, 2019).

The study

• Authors: D.A. Fennell, E.Y. Baitei
• Journal: Oncotarget
• Published: 2019;10(40):3996-3997
• Type of article: Editorial
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

In plain English

This was a two-page editorial, not a new study, and it reported no data of its own. The authors discussed COMMAND, a double blind randomized phase II trial that tested the drug defactinib against placebo as maintenance therapy in patients with Merlin negative mesothelioma. They described COMMAND as negative. The editorial opened by stating that mesothelioma is an incurable cancer caused by exposure to asbestos, but it did not examine asbestos exposure. Citing genomic data from the Tumour Genome Atlas cohort, the authors reported that 51% of mesotheliomas carried at least one alteration in the Hippo pathway, a tumor suppressor pathway, and 19.5% carried more than one. They suggested that selecting patients by only one component of this pathway may have limited COMMAND's ability to detect a signal. They also cited a separate phase II trial of defactinib given before surgery, which reported 80% disease control and a 13% response rate, with responses not limited to Merlin-negative tumors. They proposed that drugs disrupting the YAP/TEAD complex could be another approach. The authors concluded that targeting the Hippo pathway remained a potentially promising strategy.

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: Editorial (commentary discussing a published trial and other published studies; no original data)
• Who was studied: No study population of its own. The editorial discusses the COMMAND trial, which compared defactinib with placebo as maintenance therapy in patients with Merlin negative mesothelioma, and genomic data from 82 patients in the Tumour Genome Atlas cohort.
• Exposure: Not studied. The editorial concerns drug treatment (defactinib) and tumor genetics. It states only that mesothelioma is caused by asbestos exposure and names no fiber types.
• Main results:
  • The authors describe the COMMAND trial (defactinib versus placebo, double blind randomized phase II) as negative.
  • Citing the Tumour Genome Atlas cohort (82 patients, per Figure 1), the editorial reports that 51% of mesotheliomas had at least one somatic alteration in the Hippo pathway, and 19.5% had more than one.
  • The authors suggest that selecting patients for COMMAND based on only one Hippo pathway component may have limited the trial's ability to detect a signal.
  • The editorial cites a separate phase II trial of defactinib alone given before surgical resection that reported 80% disease control and a 13% response rate.
  • In that separate pre-surgery trial, responses were reported not to be limited to Merlin-negative mesotheliomas.
  • The authors propose that drugs disrupting the YAP/TEAD complex could be a way to target Hippo-defective mesothelioma regardless of which part of the pathway is affected.
• The authors' conclusion: The authors concluded that targeting the Hippo pathway remains a potentially promising strategy for controlling mesothelioma. They suggested that wider biomarkers of Hippo pathway defects, or directly blocking YAP/TEAD transcription, may be next-generation approaches.

Topics

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

Related studies

• TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth — M. Fujii, T. Toyoda, et al. (2012)
• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)
• Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma — Y. Sekido (2018)
• NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma — H. Yang, S.R.R. Hall, et al. (2021)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)
• The hippo pathway provides novel insights into lung cancer and mesothelioma treatment — X.L. Liu, R. Zuo, et al. (2018)

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