Advances in the systemic therapy of malignant pleural mesothelioma

Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Liburn Road, Belfast BT9 7BL, Northern Ireland, UK.
Nature Clinical Practice Oncology (Impact Factor: 8). 04/2008; 5(3):136-47. DOI: 10.1038/ncponc1039
Source: PubMed


Malignant pleural mesothelioma is an aggressive thoracic malignancy associated with exposure to asbestos, and its incidence is anticipated to increase during the first half of this century. Chemotherapy is the mainstay of treatment, yet sufficiently robust evidence to substantiate the current standard of care has emerged only in the past 5 years. This Review summarizes the evidence supporting the clinical activity of chemotherapy, discusses the use of end points for its assessment and examines the influence of clinical and biochemical prognostic factors on the natural history of malignant pleural mesothelioma. Early-phase clinical trials of second-line and novel agents are emerging from an increased understanding of mesothelioma cell biology. Coupled with high-quality translational research, such developments have real potential to improve the outlook of patients at a time of increasing incidence.

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Available from: Luciano Mutti
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    • "Patient selection is important as the prolonged survival must be weighted against the potential morbidity and mortality associated with aggressive cytoreductive surgery [13]. Systemic chemotherapy in recent years using a combination of cisplatin and permetrexed (antimetabolite) have demonstrated an improved median survival of 12-14 month [14] [15], compared to the older combination of cisplatin and gemcitabine with a median survival of 6-9 months [16]. However, the median survival of about 1 year is dismal and its role has been limited to palliation and should be considered as the standard of care for patients with unresectable malignant mesothelioma or for patients who are not fit for surgery. "
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    ABSTRACT: Malignant mesothelioma is a rare but highly aggressive and fatal tumour arising from the mesothelial cells, which is associated with an involvement of the peritoneum in 30% of cases. We report a 48-year-old man with malignant peritoneal mesothelioma who presented with ascites of unknown origin, and discussed the clinical presentation, investigation and management, as well as the diagnostic difficulties in managing this unusual and unfortunate case.
    Full-text · Article · Jan 2015
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    • "The multimodality treatment for MPM in the clinic often consists of surgery, adjuvant or neoadjuvant chemotherapy, and radiation [2]. Most chemotherapeutic agents are not very effective against MPM, with typical single-agent response rates of ≤20% [5]. The median survival of MPM patients ranges from 9–17 months, and remains unacceptably low [3]. "
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effectively treat and manage this disease in clinic. CARP-1 functional mimetics (CFMs) are a novel class of compounds that inhibit growth of diverse cancer cell types. Here we investigated MPM cell growth suppression by the CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited MPM cell growth, in vitro, in part by stimulating apoptosis. Apoptosis by CFM-4 involved activation of pro-apoptotic stress-activated protein kinases (SAPKs) p38 and JNK, elevated CARP-1 expression, cleavage of PARP1, and loss of the oncogene c-myc as well as mitotic cyclin B1. Treatments of MPM cells with CFM-4 resulted in depletion of NF-κB signaling inhibitor ABIN1 and Inhibitory κB (IκB)α and β, while increasing expression of pro-apoptotic death receptor (DR) 4 protein. CFM-4 enhanced expression of serine-phosphorylated podoplanin and cleavage of vimetin. CFMs also attenuated biological properties of the MPM cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Both podoplanin and vimentin regulate processes of cell motility and invasion, and their expression often correlates with metastatic disease, and poor prognosis. The fact that phosphorylation of serines in the cytoplasmic domain of podoplanin interferes with processes of cellular motility, CFM-4-dependent elevated phosphorylated podoplanin and cleavage of vimentin underscore a metastasis inhibitory property of these compounds, and suggest that CFMs and/or their future analogs have potential as anti-MPM agents.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "Malignant pleural mesothelioma (MPM) is an aggressive cancer caused by exposure to asbestos. It is increasing in incidence worldwide however there is a paucity of effective therapy [1]. Pemetrexed or raltitrexed when combined with cisplatin have been shown to lead to modest improvements in overall survival [2], [3]. "
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    ABSTRACT: Based on promising preclinical efficacy associated with the 20S proteasome inhibitor bortezomib in malignant pleural mesothelioma (MPM), two phase II clinical trials have been initiated (EORTC 08052 and ICORG 05-10). However, the potential mechanisms underlying resistance to this targeted drug in MPM are still unknown. Functional genetic analyses were conducted to determine the key mitochondrial apoptotic regulators required for bortezomib sensitivity and to establish how their dysregulation may confer resistance. The multidomain proapoptotic protein BAK, but not its orthologue BAX, was found to be essential for bortezomib-induced apoptosis in MPM cell lines. Immunohistochemistry was performed on tissues from the ICORG-05 phase II trial and a TMA of archived mesotheliomas. Loss of BAK was found in 39% of specimens and loss of both BAX/BAK in 37% of samples. However, MPM tissues from patients who failed to respond to bortezomib and MPM cell lines selected for resistance to bortezomib conserved BAK expression. In contrast, c-Myc dependent transactivation of NOXA was abrogated in the resistant cell lines. In summary, the block of mitochondrial apoptosis is a limiting factor for achieving efficacy of bortezomib in MPM, and the observed loss of BAK expression or NOXA transactivation may be relevant mechanisms of resistance in the clinic.
    Full-text · Article · Dec 2013 · PLoS ONE
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