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Current chemotherapy strategies in malignant pleural mesothelioma.

ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a 5-year survival rate of ~10%. Since most patients present with irresectable disease, the vast majority is treated with chemotherapy. The only registered therapy for MPM is platinum-pemetrexed doublet therapy, although only up to half of patients have clinical benefit from this palliative treatment. Of the anti-angiogenesis agents, only bevacizumab and nintedanib have shown activity with platinum-pemetrexed doublet therapy. Other anti-angiogenesis agents like thalidomide did not prolong (progression free) survival or response rate. Eventually, all patients will get a recurrence and no active second line therapy has been identified to date. The clinical benefit of (switch) maintenance therapy after first line treatment and combination strategies of different chemotherapies with angiogenesis inhibitors are currently under investigation. The major challenges are finding optimal treatment combinations and to select the adequate treatment for an individual patient. This review focusses on the current standard of chemotherapy and new systemic therapy strategies under investigation.

SUBMITTER: de Gooijer CJ

PROVIDER: S-EPMC6204415 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Current chemotherapy strategies in malignant pleural mesothelioma.

de Gooijer Cornedine Jannette CJ Baas Paul P Burgers Jacobus Adrianus JA

Translational lung cancer research 20181001 5

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a 5-year survival rate of ~10%. Since most patients present with irresectable disease, the vast majority is treated with chemotherapy. The only registered therapy for MPM is platinum-pemetrexed doublet therapy, although only up to half of patients have clinical benefit from this palliative treatment. Of the anti-angiogenesis agents, only bevacizumab and nintedanib have shown activity with platinum-pemetrexed doublet therapy. O ...[more]

PMID: 30450296

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Project description:Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy, which consists of concurrent treatment with pemetrexed and cisplatin. Pemetrexed limits tumor growth by inhibiting critical metabolic enzymes involved in nucleotide synthesis. Cisplatin causes direct DNA damage, such as intra-strand and inter-strand cross-links, which are repaired by the nucleotide excision repair pathway, which depends on relatively high nucleotide levels. We hypothesized that prolonged pretreatment with pemetrexed might deplete nucleotide pools, thereby sensitizing cancer cells to subsequent cisplatin treatment. The MPM cell lines ACC-MESO-1 and NCI-H28 were treated for 72 h with pemetrexed. Three treatment schedules were evaluated by initiating 24 h of cisplatin treatment at 0 h (concomitant), 24 h, and 48 h relative to pemetrexed treatment, resulting in either concomitant administration or pemetrexed pretreatment for 24 h or 48 h, respectively. Multicolor flow cytometry was performed to detect γH2AX (phosphorylation of histone H2AX), a surrogate marker for the activation of the DNA damage response pathway. DAPI staining of DNA was used to analyze cell cycle distribution. Forward and side scatter intensity was used to distinguish subpopulations based on cellular size and granularity, respectively. Our study revealed that prolonged pemetrexed pretreatment for 48 h prior to cisplatin significantly reduced long-term cell growth. Specifically, pretreatment for 48 h with pemetrexed induced a cell cycle arrest, mainly in the G2/M phase, accumulation of persistent DNA damage, and induction of a senescence phenotype. The present study demonstrates that optimizing the treatment schedule by pretreatment with pemetrexed increases the efficacy of the pemetrexed-cisplatin combination therapy in MPM. We show that the observed benefits are associated with the persistence of treatment-induced DNA damage. Our study suggests that an adjustment of the treatment schedule could improve the efficacy of the standard chemotherapy regimen for MPM and might improve patient outcomes.

Project description:Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n=40), normal lung specimens (n=4), normal pleura specimens (n=5), and MPM and SV40-immortalized mesothelial cell lines (n=5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma which correlate loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (i.e. software) to create and explore complex physiological pathways that may be relevant in mesothelioma tumorigenesis, pathobiology, or both. Tissues and cell lines profiled using microarrays. Discarded MPM surgical specimens (n=40), normal pleura specimens (n=5), and normal lung specimens (n=4) were freshly collected (and snap frozen) from patients who underwent surgery at Boston's Brigham and Women's Hospital (BWH) between October 1998 and August 2000. All of these patients underwent extrapleural pneumonectomy with heated intra-pleural cisplatin chemotherapy delivered after the specimens were removed. All normal specimens were obtained from patients who were never diagnosed with MPM. Two human MPM cell lines (MS589 and MS428) were kindly provided by Jonathan A. Fletcher, M.D., Department of Pathology, BWH. The JMN1B MPM cell line19,20 has been described previously. The SV40-immortalized, non-tumorigenic mesothelial cell line (Met-5A)21 and the MPM cell line MSTO-211H22 were purchased from the American Type Culture Collection. Normal tissues were obtained from additional consented patients undergoing treatment for diseases other than MPM. All MPM samples used in these studies contained relatively pure tumor (greater than 50% tumor cells per high power field examined in a section adjacent to the tissue used). The microscopic slides from the patients' resection specimens were reviewed by one of the authors (J.G.), and the diagnosis and histologic subclassification of MPM confirmed in all cases. Linked clinical and pathological data were obtained for all patients who contributed tumor specimens. Specimens and data were rendered anonymous to protect patient confidentiality. Studies utilizing human tissues were approved by and conducted in accordance with the policies of the Institutional Review Board at BWH.

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Current chemotherapy strategies in malignant pleural mesothelioma.

Publications

Current chemotherapy strategies in malignant pleural mesothelioma.

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