The resistance related to targeted therapy in malignant pleural mesothelioma: Why has not the target been hit yet?

Bronte, Giuseppe; Incorvaia, Lorena; Rizzo, Sérgio; Passiglia, Francesco; Galvano, Antonio; Rizzo, F; Rolfo, Christian; Fanale, Daniele; Listì, Angela; Natoli, Clara; Bazan, Viviana

doi:10.1016/j.critrevonc.2016.08.011

Cited by 29 publications

(20 citation statements)

References 111 publications

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“…Besides, targeted therapy is not yet available for this deadly disease, even though several molecular pathways implicated in MPM have been identified to date. Of note, these pathways include cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis [ 15 ]. Unfortunately, the clinical trials targeting these molecular processes have demonstrated limited, if not completely ineffective, efficacy against MPM [ 13 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Of note, these pathways include cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis [ 15 ]. Unfortunately, the clinical trials targeting these molecular processes have demonstrated limited, if not completely ineffective, efficacy against MPM [ 13 , 15 ]. Further studies are therefore needed for a thorough understanding of the biological basis of MPM, especially in the context of genetic, epigenetic, and transcriptomic alterations.…”

Section: Introductionmentioning

confidence: 99%

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Genomics and Functional Genomics of Malignant Pleural Mesothelioma

Çakıroğlu

Şentürk

2020

IJMS

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Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the mesothelial cells lining the pleural surface of the chest wall and lung. The etiology of MPM is strongly associated with prior exposure to asbestos fibers, and the median survival rate of the diagnosed patients is approximately one year. Despite the latest advancements in surgical techniques and systemic therapies, currently available treatment modalities of MPM fail to provide long-term survival. The increasing incidence of MPM highlights the need for finding effective treatments. Targeted therapies offer personalized treatments in many cancers. However, targeted therapy in MPM is not recommended by clinical guidelines mainly because of poor target definition. A better understanding of the molecular and cellular mechanisms and the predictors of poor clinical outcomes of MPM is required to identify novel targets and develop precise and effective treatments. Recent advances in the genomics and functional genomics fields have provided groundbreaking insights into the genomic and molecular profiles of MPM and enabled the functional characterization of the genetic alterations. This review provides a comprehensive overview of the relevant literature and highlights the potential of state-of-the-art genomics and functional genomics research to facilitate the development of novel diagnostics and therapeutic modalities in MPM.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

Çakıroğlu

Şentürk

2020

IJMS

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“…14 In keeping with this, we have recently demonstrated that ErbB re-targeted CAR T-cells achieve significant antitumor activity combined with excellent safety in pre-clinical models of malignant pleural mesothelioma (MPM). 15 The MET receptor tyrosine kinase is also aberrantly expressed in a large proportion of mesotheliomas [16][17][18][19][20][21] and has been proposed as an attractive therapeutic target in this disease. 18,22,23 Disappointingly however, a phase II trial of the selective MET inhibitor tivantinib has recently been terminated (https://clini caltrials.gov/ct2/show/NCT01861301; accessed March 25th, 2017).…”

Section: Introductionmentioning

confidence: 99%

CAR T-cell immunotherapy of MET-expressing malignant mesothelioma

et al. 2017

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Mesothelioma is an incurable cancer for which effective therapies are required. Aberrant MET expression is prevalent in mesothelioma, although targeting using small molecule-based therapeutics has proven disappointing. Chimeric antigen receptors (CARs) couple the HLA-independent binding of a cell surface target to the delivery of a tailored T-cell activating signal. Here, we evaluated the anti-tumor activity of MET re-targeted CAR T-cells against mesothelioma. Using immunohistochemistry, MET was detected in 67% of malignant pleural mesotheliomas, most frequently of epithelioid or biphasic subtype. The presence of MET did not influence patient survival. Candidate MET-specific CARs were engineered in which a CD28+CD3ζ endodomain was fused to one of 3 peptides derived from the N and K1 domains of hepatocyte growth factor (HGF), which represents the minimum MET binding element present in this growth factor. Using an NIH3T3-based artificial antigen-presenting cell system, we found that all 3 candidate CARs demonstrated high specificity for MET. By contrast, these CARs did not mediate T-cell activation upon engagement of other HGF binding partners, namely CD44v6 or heparan sulfate proteoglycans, including Syndecan-1. NK1-targeted CARs demonstrated broadly similar potency, indicated by destruction of MET-expressing mesothelioma cell lines, accompanied by cytokine release. anti-tumor activity was demonstrated following intraperitoneal delivery to mice with an established mesothelioma xenograft. Progressive tumor regression occurred without weight loss or other clinical indicators of toxicity. These data confirm the frequent expression of MET in malignant pleural mesothelioma and demonstrate that this can be targeted effectively and safely using a CAR T-cell immunotherapeutic strategy.

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“…Without treatment, median overall survival is less than 12 months. Although the incidence of MM has been growing worldwide [1], effective treatments are disputed [2] and none of the explored targeted approaches can currently be recommended as routine treatments for this condition [3]. A new therapeutic approach to MM is therefore required.…”

Section: Introductionmentioning

confidence: 99%

A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells

et al. 2018

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Background: Wnt signaling plays an essential role in tumor cell growth, including the development of malignant mesothelioma (MM). Epigenetic silencing of negative Wnt regulators leading to constitutive Wnt signaling has been observed in various cancers and warrants further attention. We have reported that a succinate ether derivative of α-tocotrienol (T3E) has potent cytotoxic effects in MM cells. Thus, in this study, we investigated whether the anti-MM effect of T3E could be mediated via the epigenetic alteration of the Wnt antagonist gene, Dickkopf-1 (DKK1). Methods: WST-1 and cell analyzers were employed to analyze the effects of T3E on cell viability and apoptosis of human MM cell lines (H2452, H28). Real-time PCR and Western blot were performed to evaluate the expression at mRNA and protein levels. Methylation status and epigenetic modifications of DKK1’s promoter regions after T3E treatment in MM cells were studied using methylation-specific PCR and Chromatin immunoprecipitation. Small interfering RNA-mediated knockdown (siRNA), and specific inhibitors, were used to validate DKK1 as a target of T3E. Results: T3E markedly impaired MM cell viability, increased the expression of phosphorylated-JNK and DKK1 and suppressed cyclin D, a downstream target gene of Wnt signaling. Knockdown of DKK1 expression by siRNA or a specific JNK inhibitor confirmed the contribution of DKK1 and JNK to T3E-induced cytotoxicity in MM cells. On the other hand, cytoskeleton-associated protein 4 (CKAP4) expression, which promotes cell proliferation as a Wnt-independent DKK1 receptor was inhibited by T3E. Silencing CKAP4 by siRNA did not appear to directly affect MM cell viability, thereby indicating that expression of both DKK1 and CKAP4 is required. Furthermore, T3E-mediated inhibition of both DNA methyltransferases (DNMT1, 3A, and 3B) and histone deacetylases (HDAC1, 2, 3, and 8) in MM cells leads to increased DKK1 expression, thereby promoting tumor growth inhibition. MM cells treated with Zebularine (a DNMT inhibitor) and sodium butyrate (an HDAC inhibitor) exhibited cytotoxic effects, which may explain the inhibitory action of T3E on MM cells. In addition, an enhanced expression of DKK1 in MM cells following T3E treatment is positively correlated with the methylation status of its promoter; T3E decreased DNA methylation and increased histone acetylation. Moreover, T3E specifically increased histone H3 lysine 4 (H3K4) methylation activity, whereas no effects were observed on histone H3K9 and H3K27. Conclusions: Targeting the epigenetic induction of DKK1 may lead to effective treatment of MM, and T3E has great potential to induce anti-MM activity.

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The resistance related to targeted therapy in malignant pleural mesothelioma: Why has not the target been hit yet?

Cited by 29 publications

References 111 publications

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

CAR T-cell immunotherapy of MET-expressing malignant mesothelioma

A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells

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