-
Trends in Cancer Sep 2016Malignant mesothelioma is an aggressive cancer largely associated with asbestos exposure. In this review, we will discuss the significant advancements in our... (Review)
Review
Malignant mesothelioma is an aggressive cancer largely associated with asbestos exposure. In this review, we will discuss the significant advancements in our understanding of its genetics and molecular biology and their translational relevance. Remarkable findings included the discovery of germline and somatic mutations of BRCA1 associated protein-1 (BAP1) in patients, and the genome-wide characterization of pathways altered in mesothelioma that could be potentially exploited to design novel therapeutic approaches. Nevertheless, the clinical translation of these molecular findings has been slow and insufficient. In order to rapidly move translation from the bench to the bedside, we believe that cooperative research efforts have to be further endorsed and promoted at all levels.
Topics: Animals; Antineoplastic Agents; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Molecular Targeted Therapy; Translational Research, Biomedical
PubMed: 28603777
DOI: 10.1016/j.trecan.2016.07.004 -
Genome Medicine Nov 2022Diffuse pleural mesothelioma (DPM) is an aggressive malignancy that, despite recent treatment advances, has unacceptably poor outcomes. Therapeutic research in DPM is...
BACKGROUND
Diffuse pleural mesothelioma (DPM) is an aggressive malignancy that, despite recent treatment advances, has unacceptably poor outcomes. Therapeutic research in DPM is inhibited by a paucity of preclinical models that faithfully recapitulate the human disease.
METHODS
We established 22 patient-derived xenografts (PDX) from 22 patients with DPM and performed multi-omic analyses to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these PDX models and compared features to those of the matched primary patient tumors. Targeted next-generation sequencing (NGS; MSK-IMPACT), immunohistochemistry, and histologic subtyping were performed on all available samples. RNA sequencing was performed on all available PDX samples. Clinical outcomes and treatment history were annotated for all patients. Platinum-doublet progression-free survival (PFS) was determined from the start of chemotherapy until radiographic/clinical progression and grouped into < or ≥ 6 months.
RESULTS
PDX models were established from both treatment naïve and previously treated samples and were noted to closely resemble the histology, genomic landscape, and proteomic profiles of the parent tumor. After establishing the validity of the models, transcriptomic analyses demonstrated overexpression in WNT/β-catenin, hedgehog, and TGF-β signaling and a consistent suppression of immune-related signaling in PDXs derived from patients with worse clinical outcomes.
CONCLUSIONS
These data demonstrate that DPM PDX models closely resemble the genotype and phenotype of parental tumors, and identify pathways altered in DPM for future exploration in preclinical studies.
Topics: Animals; Humans; Xenograft Model Antitumor Assays; Heterografts; Transcriptome; Proteomics; Mesothelioma; Genomics; Disease Models, Animal
PubMed: 36380343
DOI: 10.1186/s13073-022-01129-4 -
Open Biology Oct 2020RNA editing is a post-transcriptional process increasing transcript diversity, thereby regulating different biological processes. We recently observed that mutations... (Review)
Review
RNA editing is a post-transcriptional process increasing transcript diversity, thereby regulating different biological processes. We recently observed that mutations resulting from RNA editing due to hydrolytic deamination of adenosine increase during the development of mesothelioma, a rare cancer linked to chronic exposure to asbestos. This review gathers information from the published literature and public data mining to explore several aspects of RNA editing and their possible implications for cancer growth and therapy. We address possible links between RNA editing and particular types of mesothelioma genetic and epigenetic alterations and discuss the relevance of an edited substrate in the context of current chemotherapy or immunotherapy.
Topics: Adenosine Deaminase; Animals; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Genomic Instability; Humans; Interferon Type I; Mesothelioma; Protein Binding; RNA Editing; RNA Processing, Post-Transcriptional; RNA-Binding Proteins
PubMed: 33050791
DOI: 10.1098/rsob.200112 -
ESMO Open Mar 2020Malignant pleural mesothelioma is a rare and aggressive malignancy mostly associated with occupational asbestos exposure. Prognosis is poor and only highly selected... (Review)
Review
Malignant pleural mesothelioma is a rare and aggressive malignancy mostly associated with occupational asbestos exposure. Prognosis is poor and only highly selected patients may benefit from aggressive surgical management, also as part of a multimodal approach. In advanced disease, the combination of pemetrexed and platinum remains the only established treatment, while efficacy evidence of second line chemotherapy is lacking. Thus, a deeper knowledge of biology of the disease and more effective treatments are urgently needed. Refer to specialised centres with multidisciplinary expertise is mandatory, as well as inclusion of patients in clinical trials is advisable whenever possible. In all stages of disease focus on symptoms control is paramount.
Topics: Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms
PubMed: 32156681
DOI: 10.1136/esmoopen-2019-000669 -
International Journal of Molecular... May 2018Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly... (Review)
Review
Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly caused by inter- and intra-tumor heterogeneity of mesotheliomas. This diversity can be observed at the morphological and molecular levels. Molecular analyses reveal a high heterogeneity (i) between patients; (ii) within different areas of a given tumor in terms of different clonal compositions; and (iii) during treatment over time. The aim of the present review is to highlight this diversity and its therapeutic implications.
Topics: Antineoplastic Agents; Genetic Heterogeneity; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Neoplastic Stem Cells
PubMed: 29848954
DOI: 10.3390/ijms19061603 -
British Journal of Cancer Oct 2021Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of... (Review)
Review
Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.
Topics: Asbestos; Combined Modality Therapy; Epigenesis, Genetic; Gene Regulatory Networks; Humans; Mesothelioma; Prognosis
PubMed: 34226685
DOI: 10.1038/s41416-021-01462-2 -
Journal of Thoracic Oncology : Official... Mar 2022Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features...
INTRODUCTION
Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features of a prospectively collected MPeM cohort.
METHODS
Next-generation sequencing (NGS) was performed on MPeM tumors. Genomic near-haploidization (GNH) was assessed. WT1, BAP1, mesothelin, VISTA, and programmed death-ligand 1 were evaluated by immunohistochemistry (IHC) when tissue was available. Overall survival was stratified by selected genomic and IHC features.
RESULTS
A total of 50 consented patients with MPeM (45 epithelioid, 5 nonepithelioid) were studied exhibiting common alterations in BAP1 (60%; 30 of 50), NF2 (24%; 12 of 50) SETD2 (22%; 11 of 50), and TP53 (16%; 8 of 50). A total of 76% (38 of 50) of specimens were assessable for allele-specific copy number analysis; 8% (3 of 38) had GNH. IHC positivity rates were 93% (37 of 40) for mesothelin, 96% (46 of 48) for WT1, 50% (19 of 38) for programmed death-ligand 1, and 89% (34 of 38) for VISTA. BAP1 loss by IHC was observed in 76% (29 of 38), including five wild-type on NGS. Combining NGS and IHC for BAP1, overall survival was worse with alteration or loss compared with wild-type or retained in all patients (n = 37 versus 13, 43.8 versus 117.3 mo, p = 0.04) Three of 30 patients had a pathogenic germline variant: POT1 I78T, MUTYH R109Y, and BAP1 E402∗.
CONCLUSIONS
MPeM has distinct biology and genomic composition. CDKN2A/B alterations were rare in MPeM, whereas BAP1, NF2, TP53, SETD2, and LATS2 were common. BAP1 alteration/loss was associated with shorter survival when all patients were included. A notable minority of specimens had GNH associated with NF2, TP53, and SETDB1 mutations. Pathogenic germline mutations were found in 3 of 30 patients.
Topics: Humans; Mesothelioma; Mesothelioma, Malignant; Peritoneal Neoplasms
PubMed: 34648949
DOI: 10.1016/j.jtho.2021.09.012 -
Current Oncology Reports Nov 2022For patients with malignant pleural mesothelioma, prognosis is poor with extremely low 5-year survival rates and limited therapeutic options. Here, we review the current... (Review)
Review
PURPOSE OF REVIEW
For patients with malignant pleural mesothelioma, prognosis is poor with extremely low 5-year survival rates and limited therapeutic options. Here, we review the current treatment landscape for mesothelioma and highlight promising future therapeutic directions.
RECENT FINDINGS
Evolving frontline therapeutic options for mesothelioma include VEGF inhibition in combination with chemotherapy and dual immune checkpoint inhibition, with synergisms between the therapies and response prediction via biomarkers also being explored. Evolving experimental treatments for mesothelioma include PARP and ALK inhibitors, dendritic and CAR T-cell therapies, anti-mesothelin vaccines, and oncolytic viral therapies, representing timely advances in the field. The therapeutic landscape for malignant pleural mesothelioma is evolving and preferred treatment in the frontline and later settings will likely evolve with it. However, this does not preclude the evidence for including multi-modal therapies spanning angiogenesis and immune checkpoint inhibitors, and biomarker utilization, in current clinical trials and management.
Topics: Humans; Mesothelioma, Malignant; Pleural Neoplasms; Immune Checkpoint Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Vascular Endothelial Growth Factor A; Lung Neoplasms; Immunotherapy; Mesothelioma; Receptor Protein-Tyrosine Kinases
PubMed: 35657483
DOI: 10.1007/s11912-022-01302-3 -
Respiratory Medicine Jan 2018Malignant Pleural Mesothelioma (MPM) is currently an incurable cancer with a typical survival of 1 year from the time of diagnosis. The recent genomic and transcriptomic... (Review)
Review
Malignant Pleural Mesothelioma (MPM) is currently an incurable cancer with a typical survival of 1 year from the time of diagnosis. The recent genomic and transcriptomic characterization of MPM presents new opportunities and challenges for MPM researchers. Recent advances in clinical and laboratory diagnostics, and proposals for an updated, data-driven, staging system, also present new challenges for clinicians and hospital services involved in MPM care. The aim of this review is first to introduce the reader to the topic of MPM, a disease that is causally linked to prior, typically occupational, exposure to asbestos fibres. Secondly, we will discuss MPM from the clinical and laboratory perspectives, including reviews of current and evolving therapies and our present understanding of the molecular basis of the disease. Finally, we will attempt to identify critical knowledge gaps that currently prevent more effective treatment, including the challenges involved in early detection and chemoprophylaxis.
Topics: Biomarkers, Tumor; Biopsy; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Mesothelioma; Mesothelioma, Malignant; Mutation; Neoplasm Staging; Positron Emission Tomography Computed Tomography; Translational Research, Biomedical
PubMed: 29413505
DOI: 10.1016/j.rmed.2017.11.015 -
Journal of Thoracic Oncology : Official... Sep 2018Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that arises from the mesothelial surface of the pleural and peritoneal cavities, the pericardium,... (Review)
Review
Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that arises from the mesothelial surface of the pleural and peritoneal cavities, the pericardium, and rarely, the tunica vaginalis. The incidence of MPM is expected to increase worldwide in the next two decades. However, even with the use of multimodality treatment, MPM remains challenging to treat, with a 5-year survival rate of less than 5%. The International Association for the Study of Lung Cancer has gathered experts in different areas of mesothelioma research and management to summarize the most significant scientific advances and new frontiers related to mesothelioma therapeutics.
Topics: Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant
PubMed: 29966799
DOI: 10.1016/j.jtho.2018.06.011