Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma

Our plain-English summary of Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma, by D.P. Anobile, P. Bironzo, F. Picca, et al (Cancers, 2021).

The study

• Authors: D.P. Anobile, P. Bironzo, F. Picca, M.F. Lingua, D. Morena, L. Righi, F. Napoli, M.G. Papotti, A. Pittaro, F. Di Nicolantonio, C. Gigliotti, F. Bussolino, V. Comunanza, F. Guerrera, A. Sandri, F. Leo, R. Libener, P. Aviles, S. Novello, R. Taulli, G.V. Scagliotti, C. Riganti
• Journal: Cancers
• Published: 2021;13(10)
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy.

Methods: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation.

Results: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro.

Conclusion: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients.

In plain English

This laboratory study, carried out in Italy, tested the drug lurbinectedin on 12 cell cultures grown from tumor samples of patients with malignant pleural mesothelioma. The cultures covered the epithelioid, sarcomatoid and biphasic subtypes. Six were positive and six negative for the BAP1 protein. Asbestos exposure was not studied. Lurbinectedin reduced cell viability in every culture. The half-maximal inhibitory concentrations (IC50) ranged from 0.073 to 4.54 nanomolar. IC50 was slightly higher in BAP1-negative cultures and in sarcomatoid or biphasic cultures, but these differences were not statistically significant. In longer tests, treatment markedly reduced cell growth and colony formation, with no difference by BAP1 status. The drug caused cells to build up in the S-phase of the cell cycle, produced signs of DNA damage, and caused strong cell death by apoptosis. The authors concluded that lurbinectedin was effective against these cells at nanomolar concentrations and that the results provide a basis for investigating it in mesothelioma treatment. They noted that the number of cultures was small and that freshly established cultures may be more sensitive to such drugs than tumors in patients.

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: laboratory (in vitro) study of a drug on patient-derived mesothelioma cell cultures
• Who was studied: 12 primary malignant pleural mesothelioma cell cultures. They were grown from biopsies or pleurectomy samples taken at hospitals in Torino, Orbassano and Alessandria, Italy. Six cultures were BAP1-positive and six BAP1-negative, representing the epithelioid, sarcomatoid and biphasic subtypes. Seven were put directly into culture and five were first grown as tumors implanted in mice. Dates of sampling are not given.
• Exposure: The drug lurbinectedin (PM01183) at nanomolar concentrations, given for periods from 24 hours to 20 days depending on the test. Asbestos exposure was not studied.
• Main results:
  • Lurbinectedin reduced cell viability in a dose-dependent way in all 12 cultures. IC50 values ranged from 0.073 nM (UPN1) to 4.54 nM (UPN12).
  • IC50 was slightly higher in BAP1-negative than BAP1-positive cultures, and in sarcomatoid/biphasic than epithelioid cultures. Neither difference was statistically significant.
  • The three cultures from patients who later received trabectedin and survived less than 12 months (UPN6, UPN10, UPN12) had the highest IC50 values, all below 5 nM.
  • Long-term treatment reduced cell growth over 10 days and colony formation in soft agar over 20 days, with no differences between BAP1-positive and BAP1-negative cells.
  • After 24 hours of treatment, cells accumulated in the S-phase of the cell cycle, in both BAP1-positive and BAP1-negative cultures.
  • Treatment produced dose-dependent DNA fragmentation and increased markers of the DNA damage response (phosphorylated Chk1, Chk2, p53 and H2AX).
  • Treatment strongly induced apoptosis (cell death), with dose-dependent activation of caspase 3.
• The authors' conclusion: The authors concluded that their work showed lurbinectedin to be effective at nanomolar concentration against primary mesothelioma cells. They judged the results encouraging and a basis for investigating the drug in different treatment settings for mesothelioma.
• Limitations the authors state:
  • The panel was limited in the number of cell lines.
  • Freshly established cultures may be more sensitive to cytotoxic drugs than tumors are in patients.
  • The results still need to be confirmed in mesothelioma patient-derived xenograft (animal) models.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Tumor Microenvironment, Small Cell Lung Cancer, Disease Progression, Chemotherapy, Histological Subtype, Epithelioid.

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