scholarly journals LOCAL DELIVERY OF TARGETED NANOPARTICLES AS THERAPEUTIC APPROACH TO OBLITERANS BRONCHIOLITIS AND MALIGNANT PLEURAL MESOTHELIOMA

2017 ◽  
Author(s):  
Federica Meloni ◽  
Emanuela Cova ◽  
Davide Piloni ◽  
Simona Inghilleri ◽  
Giulia Maria Stella ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Therapeutic Approach ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Primary Cultures ◽  
Local Treatment ◽  
Target Cells ◽  
Pleural Mesothelioma ◽  
Small Airways

Our work has the objective to develop and provide a new therapeutic approach to rare respiratory disease with poor prognosis. These diseases are united by the fact of being rare diseases, defined orphan, with a very poor prognosis and limited treatment options. Furthermore, they share the possibility to apply a local treatment with the advantage of decreased unwanted biodistribution and systemic toxicity. Bronchiolitis obliterans (BO) is a disease characterized by fibrotic obliteration of the small airways that occurs in response to inflammatory and immunological insults. Malignant pleural mesothelioma (MPM) is a rare malignant tumor that originates from the pleura, strongly associated with environmental exposure to asbestos. Our approach consists in the creation of nanocarriers (gold nanoparticles, GNPs), which can be loaded with specific anti-proliferative drugs, specifically targeted to the cells responsible of the two pathological processes (fibroblastoid-like mesenchymal cells in BO, malignant mesothelioma cells in MPM) and suitable for administration by local street (inhaled or intrapleural). First, we isolated, cultured and phenotyped primary cells from patients from BO and MPM. Once you have identified some targets (CD44 for the BO and CD146 for MPM) we designed a nanotool loaded with the specific drugs (everolimus or pemetrexed) and decorated with monoclonal antibody on the surface. We performed experiments in vitro on primary cultures of pathological cells and we demonstrated that these nanoparticles were able to penetrate specifically in target cells expressing the specific receptor and not in other types of normal cells tested, except for the alveolar macrophage which presented the tendency to absorb the nanoparticles, also the not functionalized ones. The anti-proliferative, pro-apoptotic and anti-inflammatory action of these nanoparticles was tested in vitro. We have also conducted experiments in animals to prove the lack of both pulmonary and extrapulmonary toxicity following administration of nanoparticles by inhalation.

scholarly journals Oncological Frontiers in the Treatment of Malignant Pleural Mesothelioma

2021 ◽  
Vol 10 (11) ◽  
pp. 2290
Author(s):  
Emanuele Vita ◽  
Alessio Stefani ◽  
Mariantonietta Di Di Salvatore ◽  
Marco Chiappetta ◽  
Filippo Lococo ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Genomic Sequencing ◽  
Pleural Mesothelioma ◽  
Targeted Drugs ◽  
Treatment Algorithms ◽  
Rare Malignancy ◽  
New Generation ◽  
The Way

Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by very poor prognosis and lack of treatment options. Immunotherapy has rapidly emerged as an effective tool for MPM, particularly for tumors of non-epithelioid histology. At the same time, comprehensive genomic sequencing may open the way to new-generation targeted-drugs able to hit specific MPM molecular vulnerabilities. These innovations will possibly enrich, but also dramatically complicate, the elucidation of treatment algorithms. Multidisciplinary integration is urgently needed.

scholarly journals Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Duo Xu ◽  
Shun-Qing Liang ◽  
Zhang Yang ◽  
Haitang Yang ◽  
Rémy Bruggmann ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Integrated Analysis ◽  
Pleural Mesothelioma ◽  
Bh3 Mimetics ◽  
Domain 3

AbstractEscape from programmed cell death is a hallmark of cancer. In this study, we investigated the anti-apoptotic mechanisms and explored the therapeutic potential of BCL-2 homology domain-3 (BH3) mimetics in malignant pleural mesothelioma (MPM), a lethal thoracic malignancy with an extreme dearth of treatment options. By implementing integrated analysis of functional genomic data of MPM cells and quantitative proteomics of patients’ tumors, we identified BCL-XL as an anti-apoptotic driver that is overexpressed and confers an oncogenic dependency in MPM. MPM cells harboring genetic alterations that inactivate the NF2/LATS1/2 signaling are associated with increased sensitivity to A-1155463, a BCL-XL-selective BH3 mimetic. Importantly, BCL-XL inhibition elicits protective autophagy, and concomitant blockade of BCL-XL and autophagic machinery with A-1155463 and hydroxychloroquine (HCQ), the US Food and Drug Administration (FDA)-approved autophagy inhibitor, synergistically enhances anti-MPM effects in vitro and in vivo. Together, our work delineates the molecular basis underlying resistance to apoptosis and uncovers an evasive mechanism that limits response to BH3 mimetics in MPM, suggesting a novel strategy to target this aggressive disease.

scholarly journals Blocking the GITR-GITRL pathway to overcome resistance to therapy in sarcomatoid malignant pleural mesothelioma

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Meilin Chan ◽  
Licun Wu ◽  
Zhihong Yun ◽  
Trevor D. McKee ◽  
Michael Cabanero ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Malignant Pleural Mesothelioma ◽  
Neutralizing Antibodies ◽  
Pleural Mesothelioma ◽  
Spheroid Formation ◽  
Resistance To Therapy ◽  
Sarcomatoid Mesothelioma

AbstractMalignant pleural mesothelioma (MPM) is an aggressive neoplasm originating from the pleura. Non-epithelioid (biphasic and sarcomatoid) MPM are particularly resistant to therapy. We investigated the role of the GITR-GITRL pathway in mediating the resistance to therapy. We found that GITR and GITRL expressions were higher in the sarcomatoid cell line (CRL5946) than in non-sarcomatoid cell lines (CRL5915 and CRL5820), and that cisplatin and Cs-137 irradiation increased GITR and GITRL expressions on tumor cells. Transcriptome analysis demonstrated that the GITR-GITRL pathway was promoting tumor growth and inhibiting cell apoptosis. Furthermore, GITR+ and GITRL+ cells demonstrated increased spheroid formation in vitro and in vivo. Using patient derived xenografts (PDXs), we demonstrated that anti-GITR neutralizing antibodies attenuated tumor growth in sarcomatoid PDX mice. Tumor immunostaining demonstrated higher levels of GITR and GITRL expressions in non-epithelioid compared to epithelioid tumors. Among 73 patients uniformly treated with accelerated radiation therapy followed by surgery, the intensity of GITR expression after radiation negatively correlated with survival in non-epithelioid MPM patients. In conclusion, the GITR-GITRL pathway is an important mechanism of autocrine proliferation in sarcomatoid mesothelioma, associated with tumor stemness and resistance to therapy. Blocking the GITR-GITRL pathway could be a new therapeutic target for non-epithelioid mesothelioma.

scholarly journals Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3932
Author(s):  
Dannel Yeo ◽  
Laura Castelletti ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Treatment Options ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Pleural Mesothelioma ◽  
Normal Tissues ◽  
Drug Conjugates ◽  
Aggressive Cancer ◽  
Immunotherapy Target ◽  
Bull's Eye

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody–drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

scholarly journals Pemetrexed-loaded nanoparticles targeted to malignant pleural mesothelioma cells: In-vitro study

2015 ◽  
Author(s):  
Giulia Stella ◽  
Emanuela Cova ◽  
Simona Inghilleri ◽  
Davide Piloni ◽  
Miriam Colombo ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
In Vitro Study ◽  
Vitro Study ◽  
Pleural Mesothelioma

scholarly journals WT1 Tumor Antigen is Overexpressed in Kaposi Sarcoma and is Regulated by KSHV vFLIP

2021 ◽  
Author(s):  
Ayana Morales ◽  
Caitlyn Genovese ◽  
Matthew Bott ◽  
Julio Alvarez ◽  
Sung Soo Mun ◽  
...  
Keyword(s):  
T Cell ◽  
Therapeutic Approach ◽  
Poor Prognosis ◽  
Wilms Tumor ◽  
Kaposi Sarcoma ◽  
Host Protein ◽  
People Living With Hiv ◽  
Potential Biomarker ◽  
Wilms Tumor 1

AbstractPurposeWilms’ tumor 1 (WT1) is overexpressed in several cancers, and WT1 expression levels are associated with poor prognosis. As a host protein that functions as an oncogene, it represents an important immunotherapeutic target. This study evaluated WT1 expression in Kaposi sarcoma (KS) tumors to assess whether immunotherapy targeting WT1 is a potential therapeutic approach for KS. We also investigated the role of the causal agent of KS, Kaposi sarcoma herpesvirus (KSHV/HHV-8) in regulating WT1 expression.Experimental designImmunohistochemistry for WT1, KSHV, and B and T cells subsets, followed by image analysis, was performed in 363 KS tumor biopsies. Expression of KSHV vFLIP was evaluated by immunofluorescence. Primary endothelial cell cultures and cell lines were infected with KSHV in vitro, or transduced with an inducible vFLIP vector and induced with doxycycline, and then assessed for WT1 expression. Binding of ESK-1, a T cell receptor mimic therapeutic antibody that recognizes WT1 peptides presented on MHC HLA-A0201, was assessed using flow cytometry.ResultsWe report overexpression of WT1 in KS tumors, which was associated with increased with increasing histopathologic stage and the proportion of KSHV-infected cells. Areas with high WT1 expression showed sparse T cell infiltrates. KSHV infection in vitro resulted in WT1 upregulation, mediated by the viral protein vFLIP, which resulted in stronger binding of ESK1.ConclusionsKS lesions express high levels of WT1, a process regulated by the KSHV-encoded vFLIP. These findings suggest that immunotherapy directed against WT1 may represent a therapeutic approach for this cancer.Translational RelevanceKaposi sarcoma (KS) is a vascular neoplasm caused by the Kaposi sarcoma herpesvirus (KSHV/HHV-8). People living with HIV are not only at a significantly higher risk of developing KS, but also often have a more aggressive clinical course. Although antiretroviral therapy may cause regression of HIV-associated KS lesions, advanced cases of KS also require chemotherapy, which is rarely curative. Wilms’ tumor 1 (WT1) has been reported to be overexpressed in various cancers, functioning as an oncogene and associated with a poor prognosis. WT1 is also an important immunotherapeutic target, with several WT1-directed therapies showing promising results in early clinical trials for leukemias and solid tumors. Here we report high expression of WT1 in KS, especially in higher histological stages. Our findings provide pre-clinical evidence that supports conducting anti-WT1 immunotherapy trials in KS, and evaluating WT1 expression as a potential biomarker to identify individuals most likely to benefit.

scholarly journals Aminopeptidase N/CD13 as a potential therapeutic target in malignant pleural mesothelioma

2018 ◽  
Vol 51 (5) ◽  
pp. 1701610 ◽  
Author(s):  
Takahiko Otsuki ◽  
Taku Nakashima ◽  
Hironobu Hamada ◽  
Yusuke Takayama ◽  
Shin Akita ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Malignant Pleural Mesothelioma ◽  
Poor Prognosis ◽  
Tumour Growth ◽  
Tumour Progression ◽  
Molecular Target ◽  
Aminopeptidase N ◽  
Pleural Mesothelioma ◽  
Tumour Angiogenesis ◽  
Potential Therapeutic Target

Angiogenesis is a crucial factor in the progression of malignant pleural mesothelioma (MPM) and antiangiogenic strategies might be effective against MPM. Aminopeptidase N (APN)/CD13 promotes tumour angiogenesis and is associated with poor prognosis; however, its clinical significance in MPM remains unclear.In 37 consecutive patients with surgically resected MPM, we evaluated the association between immunohistochemical APN/CD13 expression in resected tumours and survival. Additionally, the antitumour and antiangiogenic effects of MT95-4, a fully humanised anti-APN/CD13 monoclonal antibody, were evaluated in mice orthotopically implanted with EHMES-10 (abundantly expressing APN/CD13) and MSTO-211H (scarcely expressing APN/CD13) MPM cells.High tumour APN/CD13 expression was associated with poor prognosis in MPM patients (p=0.04), and MT95-4 treatment reduced tumour growth and angiogenesis in mice harbouring EHMES-10 but not MSTO-211H cells. Furthermore, in mice harbouring EHMES-10 cells, MT95-4 combined with cisplatin more effectively suppressed tumour progression than cisplatin alone.Taken together, these results suggest that APN/CD13 is implicated in the aggressiveness of MPM. Here, MT95-4 treatment reduced tumour progression likely by inhibiting angiogenesis, suggesting APN/CD13 as a potential molecular target for MPM treatment. Additionally, combination treatment with MT95-4 and cisplatin could represent a promising approach to treating MPM exhibiting high APN/CD13 expression.

scholarly journals Treatment of malignant pleural mesothelioma: current status and future directions

2016 ◽  
Vol 73 (2) ◽  
Author(s):  
X. Dhalluin ◽  
A. Scherpereel
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
European Society ◽  
Poor Prognosis ◽  
Asbestos Exposure ◽  
Therapeutic Strategies ◽  
Current Status ◽  
Pleural Mesothelioma ◽  
European Respiratory Society ◽  
Future Directions ◽  
Cell Therapies

Previously considered to be rare, malignant pleural mesothelioma (MPM) is a highly aggressive tumour that has become a very important issue over recent years due to its poor prognosis and its increasing incidence mostly linked to previous asbestos exposure. An optimal treatment for MPM is not established yet; new therapies and predictive tools are still needed in the management of this cancer. Thus the aim of this review is to provide clinicians clear and up-to-dated data on the latest therapeutic strategies for MPM patients in 2010. The guidelines recently proposed by the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS) taskforce are summarized here. The authors also briefly reviewed the future directions in MPM treatment including targeted therapies, gene or cell therapies.

scholarly journals Patient-derived malignant pleural mesothelioma cell cultures: a tool to advance biomarker-driven treatments

Thorax ◽  
2020 ◽  
Vol 75 (11) ◽  
pp. 1004-1008 ◽  
Author(s):  
Nikolaos I Kanellakis ◽  
Rachelle Asciak ◽  
Megat Abd Hamid ◽  
Xuan Yao ◽  
Mark McCole ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Malignant Pleural Mesothelioma ◽  
Poor Prognosis ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
Pleural Mesothelioma ◽  
Ex Vivo Model ◽  
High Throughput Drug Screening ◽  
Aggressive Cancer ◽  
Malignant Pleural Mesothelioma Cell

Malignant pleural mesothelioma (MPM) is an aggressive cancer, associated with poor prognosis. We assessed the feasibility of patient-derived cell cultures to serve as an ex vivo model of MPM. Patient-derived MPM cell cultures (n=16) exhibited stemness features and reflected intratumour and interpatient heterogeneity. A subset of the cells were subjected to high-throughput drug screening and coculture assays with cancer-specific cytotoxic T cells and showed diverse responses. Some of the biphasic MPM cells were capable of processing and presenting the neoantigen SSX-2 endogenously. In conclusion, patient-derived MPM cell cultures are a promising and faithful ex vivo model of MPM.

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