Progress in the Management of Malignant Pleural Mesothelioma in 2017

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment. CA Cancer J Clin 2019;69:402-429.

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“…The trial met its primary endpoint, with a disease control rate of 51% at 12 weeks. Translational work is ongoing to interpret these results …”

Section: Treatmentmentioning

confidence: 99%

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

Carbone

Adusumilli

Alexander

et al. 2019

CA A Cancer J Clinicians

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365

488

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“…Platinum‐based (cisplatin/carboplatin) chemotherapy in combination with antifolate agents (pemetrexed, raltitrexed) is a standard of care for advanced stage disease . Immunotherapy, targeted therapies and tumor microenvironment‐targeting approaches are still under development. All treatments produce only partial responses, because of the strong chemoresistance of MPM …”

Section: Introductionmentioning

confidence: 99%

Wnt/IL‐1β/IL‐8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5

Milosevic

Kopecka

Salaroglio

et al. 2019

Intl Journal of Cancer

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Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM‐initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness‐related pathways determine chemoresistance. Moreover, there are no predictive markers of IC‐associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness‐related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo‐sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5‐knocked‐out (KO) IC clones were resensitized to the drugs in vitro and in patient‐derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3β/β‐catenin/c‐myc axis that also increased IL‐8 and IL‐1β production. IL‐8 and IL‐1β‐KO IC clones reduced the c‐myc‐driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5‐KO clones had lower IL‐8 and IL‐1β secretion, and c‐myc transcriptional activity, suggesting that either Wnt/GSK3β/β‐catenin and IL‐8/IL‐1β signaling drive c‐myc‐mediated transcription of ABCB5. ABCB5 correlated with lower time‐to‐progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first‐line chemotherapy in MPM patients.

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“…It is generally believed that effective therapy for MPM is multimodal, and it comprises preoperative combination chemotherapy, surgery, and radiotherapy. [3][4][5][6][7][8][9][10][11] Radical surgery includes 2 major procedures, an extrapleural pneumonectomy (EPP) and then a pleurectomy and decortication (P/D) with the aim of achieving a complete macroscopic resection. Surgery-based treatment appears to provide a prolonged survival for selected patients with MPM.…”

Section: Introductionmentioning

confidence: 99%