Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?

Cantini, Luca; Hassan, Raffit; Sterman, Daniel H.; Aerts, Joachim

doi:10.3389/fonc.2020.00343

Cited by 49 publications

(45 citation statements)

References 118 publications

(89 reference statements)

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“…New treatment opportunities have also been defined for patients with WT-1 expressing malignant pleural mesothelioma. A WT-1 cancer vaccine made out of molecules similar to those in the WT-1 protein in combination with checkpoint inhibition is being tested in a phase I study [34]. In this context, our findings may contribute to clinical implications not only on prognosis but also on therapeutic strategies in DMPM.…”

Section: Discussionmentioning

confidence: 80%

“…Nevertheless, some molecules have been proposed as targets for personalized therapy, mostly for the pleural variant. In CDKN2A-mutated malignant pleural mesothelioma cell lines and in a mouse model, the inhibition of CDK4/CDK6 was shown to suppress cell viability and tumour growth [34]. This gave rise to a multi-arm stratified therapy based clinical trial for patients with CDKN2A negative relapsed mesothelioma.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic Value of Ki67 Percentage, WT-1 Expression and p16/CDKN2A Deletion in Diffuse Malignant Peritoneal Mesothelioma: A Single-Centre Cohort Study

et al. 2020

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Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignant neoplasm with a poor survival. Although some advances in knowledge have been obtained for the pleural form, much less is known about DMPM. Advantages in terms of prognosis are still limited and strong efforts need to be made. The aim of our study was to correlate several histological and molecular factors with survival in a large cohort of 45 DMPMs. We evaluated histotype, nuclear grade, mitotic count, necrosis, inflammation, desmoplastic reaction, Ki67 percentage, WT-1 expression, p16 protein by immunohistochemistry and CDKN2A deletion by FISH. Our results showed that epithelioid histotype, nuclear grade 2, mitotic count ≤5 x mm2, absence of desmoplasia and p16/CDKN2A deletion, low Ki67 value, and high WT-1 expression were correlated with the most prolonged survival (p = 0.0001). Moreover, p16 loss in immunohistochemistry reflected CDKN2A deletion detected with FISH, and both were correlated with the worst survival (p = 0.0001). At multivariate analysis, Ki67 value, WT-1 expression and p16/CDKN2A deletion emerged as independent prognostic factors (p = 0.01, p = 0.0001 and p = 0.01, respectively). These parameters are easy to analyse at the time of DMPM diagnosis and may support better patient stratification, prediction of treatment effectiveness and therapeutic optimization.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Ki67 Percentage, WT-1 Expression and p16/CDKN2A Deletion in Diffuse Malignant Peritoneal Mesothelioma: A Single-Centre Cohort Study

et al. 2020

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“…Given the significant advances in understanding the biology of mesothelioma and the development of new therapeutics, it is likely more agents could receive regulatory approval in the near future. Several recent reviews have described in detail different agents in clinical trials for treatment of mesothelioma 22,23 . The focus of our current review is primarily on immune checkpoint inhibitors and mesothelin‐targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

Malignant mesothelioma: Advances in immune checkpoint inhibitor and mesothelin‐targeted therapies

Ghafoor

Sengupta

et al. 2021

Cancer

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Malignant mesothelioma is an aggressive cancer with a poor prognosis and limited treatment options. For many years, the only US Food and Drug Administration‐approved first‐line treatment for unresectable mesothelioma was pemetrexed plus cisplatin. However, the recent approval of nivolumab plus ipilimumab as frontline treatment for patients with pleural mesothelioma marks a significant milestone for the treatment of this disease. In this review, the authors describe recent advances in therapeutic strategies for the treatment of patients with advanced, unresectable mesothelioma, highlighting the emerging use of immunotherapy and mesothelin‐targeted therapies for the management of malignant mesothelioma.

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“…Recently, the combination of immune checkpoint inhibitors directed against programmed death-1 (PD-1) and cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) showed its superiority over chemotherapy in previously untreated and unresectable MPM, especially in non-epithelioid tumors [ 12 ]. Conversely, no second-line standard therapy has been approved, despite the pre-clinical and the clinical evaluation of different therapeutic agents [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma

Anobile

Bironzo²,

Picca

et al. 2021

Cancers

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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.

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Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?

Cited by 49 publications

References 118 publications

Prognostic Value of Ki67 Percentage, WT-1 Expression and p16/CDKN2A Deletion in Diffuse Malignant Peritoneal Mesothelioma: A Single-Centre Cohort Study

Prognostic Value of Ki67 Percentage, WT-1 Expression and p16/CDKN2A Deletion in Diffuse Malignant Peritoneal Mesothelioma: A Single-Centre Cohort Study

Malignant mesothelioma: Advances in immune checkpoint inhibitor and mesothelin‐targeted therapies

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma

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