bims-mesote 2023-06-18 papers

Issue of 2023–06–18
nine papers selected by
Laura Mannarino, Humanitas Research

Clin Lung Cancer. 2023 Apr 07. pii: S1525-7304(23)00060-8. [Epub ahead of print]

Short Report of a Phase II Trial of Nintedanib in Recurrent Malignant Pleural Mesothelioma (MPM).

Antoinette J Wozniak, Bryan Schneider, Gregory P Kalemkerian, Bobby Daly, Wei Chen, Jaclyn Ventimiglia, Misako Nagasaka, Marjorie G Zauderer.

Keywords: Angiogenesis; Epithelioid; Sarcomatoid; Tyrosine kinase inhibitor; VEGF

DOI: https://doi.org/10.1016/j.cllc.2023.04.004

Cancers (Basel). 2023 May 27. pii: 2940. [Epub ahead of print]15(11):

Success of Checkpoint Blockade Paves the Way for Novel Immune Therapy in Malignant Pleural Mesothelioma.

Lizbeth Rondon, Roberto Fu, Manish R Patel.

Malignant pleural mesothelioma (MPM) is a malignancy associated with asbestos exposure and is typically categorized as an orphan disease. Recent developments in immunotherapy with anti-PD-1 and anti-CTLA-4 antibodies, specifically with agents nivolumab and ipilimumab, have demonstrated an improvement in overall survival over the previous standard chemotherapy leading to their FDA-approval as first-line therapy for unresectable disease. For quite some time, it has been known that these proteins are not the only ones that function as immune checkpoints in human biology, and the hypothesis that MPM is an immunogenic disease has led to an expanding number of studies investigating alternative checkpoint inhibitors and novel immunotherapy for this malignancy. Early trials are also supporting the notion that therapies that target biological molecules on T cells, cancer cells, or that trigger the antitumor activity of other immune cells may represent the future of MPM treatment. Moreover, mesothelin-targeted therapies are thriving in the field, with forthcoming results from multiple trials signaling an improvement in overall survival when combined with other immunotherapy agents. The following manuscript will review the current state of immune therapy for MPM, explore the knowledge gaps in the field, and discuss ongoing novel immunotherapeutic research in early clinical trials.

Keywords: B7-H3; CAR-T cells; CTLA-4; NK cells; PD-1; PD-L1; immune checkpoint inhibitors; malignant pleural mesothelioma; mesothelin therapy

DOI: https://doi.org/10.3390/cancers15112940

J Cancer Metastasis Treat. 2022 ;pii: 47. [Epub ahead of print]8

Promising therapeutic potential of tumor suppressor microRNAs for malignant pleural mesothelioma.

Shivani Dixit, Agnes Y Choi, Anand Singh, Karthik Pittala, Nathan Pruett, Chuong D Hoang.

Malignant pleural mesothelioma (MPM) is an aggressive and recalcitrant surface neoplasm that defies current multimodality treatments. MicroRNAs (miRNAs) are small noncoding RNAs that epigenetically regulate multiple gene networks and cellular processes. In cancer, miRNA dysregulation is associated with tumorigenesis, with tumor suppressor miRNAs underexpressed or lost, while oncogenic miRNAs are overexpressed. Consequently, miRNAs have emerged as potential therapeutic candidates. Because loss of tumor suppressors predominates the pathophysiology of MPM, re-expressing tumor suppressor miRNAs could be an effective therapeutic strategy. This review highlights the most promising MPM-specific tumor suppressor miRNAs that could be developed into novel therapeutics, the supporting data, and what is known about their molecular mechanism(s).

Keywords: Malignant pleural mesothelioma; microRNA; therapeutic; tumor suppressor

DOI: https://doi.org/10.20517/2394-4722.2022.70

Int J Mol Sci. 2023 May 23. pii: 9165. [Epub ahead of print]24(11):

Target Therapy in Malignant Pleural Mesothelioma: Hope or Mirage?

Federica Borea, Marika A Franczak, Maria Garcia, Matteo Perrino, Nadia Cordua, Ryszard T Smolenski, Godefridus J Peters, Rafal Dziadziuszko, Armando Santoro, Paolo A Zucali, Elisa Giovannetti.

Malignant Pleural Mesothelioma (MPM) is a rare neoplasm that is typically diagnosed in a locally advanced stage, making it not eligible for radical surgery and requiring systemic treatment. Chemotherapy with platinum compounds and pemetrexed has been the only approved standard of care for approximately 20 years, without any relevant therapeutic advance until the introduction of immune checkpoint inhibitors. Nevertheless, the prognosis remains poor, with an average survival of only 18 months. Thanks to a better understanding of the molecular mechanisms underlying tumor biology, targeted therapy has become an essential therapeutic option in several solid malignancies. Unfortunately, most of the clinical trials evaluating potentially targeted drugs for MPM have failed. This review aims to present the main findings of the most promising targeted therapies in MPM, and to explore possible reasons leading to treatments failures. The ultimate goal is to determine whether there is still a place for continued preclinical/clinical research in this area.

Keywords: BAP1; CDKN2A; NF2; anti-angiogenic drugs; growth factors; mTOR; malignant pleural mesothelioma; mesothelin; target therapy

DOI: https://doi.org/10.3390/ijms24119165

Front Oncol. 2023 ;13 1190988

Indolyl-chalcone derivatives trigger apoptosis in cisplatin-resistant mesothelioma cells through aberrant tubulin polymerization and deregulation of microtubule-associated proteins.

Sophia Steinlein, Frank Essmann, Amanda Franceschini Ghilardi, Heike Horn, Julia Schüler, Angelika Hausser, Lijun Sun, German Ott, Claudia Kalla.

Introduction: Malignant pleural mesothelioma (MPM) is a neoplasm with dismal prognosis and notorious resistance to the standard therapeutics cisplatin and pemetrexed. Chalcone derivatives are efficacious anti-cancer agents with minimal toxicity and have, therefore, gained pharmaceutical interest. Here, we investigated the efficacy of CIT-026 and CIT-223, two indolyl-chalcones (CITs), to inhibit growth and viability of MPM cells and defined the mechanism by which the compounds induce cell death.
Methods: The effects of CIT-026 and CIT-223 were analyzed in five MPM cell lines, using viability, immunofluorescence, real-time cell death monitoring, and tubulin polymerization assays, along with siRNA knockdown. Phospho-kinase arrays and immunoblotting were used to identify signaling molecules that contribute to cell death.
Results: CIT-026 and CIT-223 were toxic in all cell lines at sub-micromolar concentrations, in particular in MPM cells resistant to cisplatin and pemetrexed, while normal fibroblasts were only modestly affected. Both CITs targeted tubulin polymerization via (1) direct interaction with tubulin and (2) phosphorylation of microtubule regulators STMN1, CRMP2 and WNK1. Formation of aberrant tubulin fibers caused abnormal spindle morphology, mitotic arrest and apoptosis. CIT activity was not reduced in CRMP2-negative and STMN1-silenced MPM cells, indicating that direct tubulin targeting is sufficient for toxic effects of CITs.
Discussion: CIT-026 and CIT-223 are highly effective inducers of tumor cell apoptosis by disrupting microtubule assembly, with only modest effects on non-malignant cells. CITs are potent anti-tumor agents against MPM cells, in particular cells resistant to standard therapeutics, and thus warrant further evaluation as potential small-molecule therapeutics in MPM.

Keywords: CIT-026; CIT-223; apoptosis; cisplatin resistance; indolyl-chalcone; microtubules; pleural mesothelioma; stathmin

DOI: https://doi.org/10.3389/fonc.2023.1190988

Int J Environ Res Public Health. 2023 May 25. pii: 5957. [Epub ahead of print]20(11):

The Epidemiological Surveillance of Mesothelioma Mortality in Italy as a Tool for the Prevention of Asbestos Exposure.

Lucia Fazzo, Giada Minelli, Marco De Santis, Emiliano Ceccarelli, Ivano Iavarone, Amerigo Zona.

As part of a surveillance plan active since the early 1990s, this study evaluates malignant mesothelioma (MM) mortality for the time-window 2010-2019 in Italy, a country that banned asbestos in 1992. National and regional mortality rates for MM, and municipal standardized mortality ratios (all mesotheliomas, pleural (MPM) and peritoneal (MPeM)), by gender and age group were calculated. A municipal clustering analysis was also performed. There were 15,446 deaths from MM (11,161 males, 3.8 × 100,000; 4285 females, 1.1 × 100,000), of which 12,496 were MPM and 661 were MPeM. In the study period, 266 people ≤50 years died from MM. A slightly decreasing rate among males since 2014 was observed. The areas at major risk hosted asbestos-cement plants, asbestos mines (chrysotile in Balangero), shipyards, petrochemical and chemical plants, and refineries. Female mortality excesses particularly were found in municipalities with a fluoro-edenite-contaminated mine (Biancavilla) and textile facilities. Excesses were also found in a region with the presence of natural asbestos fibres and in males living in two small islands. The Italian National Prevention Plan stated recommendations to eliminate asbestos exposures and to implement health surveillance and healthcare for people exposed to asbestos.

Keywords: asbestos; childhood exposure; environmental exposure; malignant mesothelioma; mortality; occupational exposure

DOI: https://doi.org/10.3390/ijerph20115957

Mod Pathol. 2023 Jun 07. pii: S0893-3952(23)00142-4. [Epub ahead of print] 100237

Recurrent tumor suppressor alterations in primary pericardial mesothelioma.

Inga-Marie Schaefer, Adrian Mariño-Enríquez, Mark M Hammer, Robert F Padera, Lynette M Sholl.

Primary pericardial mesotheliomas are extremely rare, accounting for <1% of all mesotheliomas, and their molecular genetic features and predisposing factors remain to be determined. Here, we report the clinicopathologic, immunohistochemical, and molecular genetic findings of three pericardial mesotheliomas without pleural involvement. Three cases diagnosed between 2004 and 2022 were included in the study and analyzed by immunohistochemistry and targeted next-generation sequencing (NGS); corresponding non-neoplastic tissue was sequenced in all cases. Two patients were female and one male, aged between 66 and 75 years. Two patients each had prior asbestos exposure and were smokers. Histologic subtypes were epithelioid in two cases and biphasic in one case. Immunohistochemical staining identified expression of cytokeratin AE1/AE3 and calretinin in all cases, D2-40 in two cases, and WT1 in one case. Staining for tumor suppressors revealed loss of p16, MTAP, and Merlin (NF2) expression in two cases, and loss of BAP1 and p53 in one case. Abnormal cytoplasmic BAP1 expression was observed in an additional case. Protein expression abnormalities correlated with NGS results, which showed concurrent complete genomic inactivation of CDKN2A/p16, CDKN2B, MTAP, and NF2 in two mesotheliomas and of BAP1 and TP53 in one mesothelioma each, respectively. In addition, one patient harbored a pathogenic BRCA1 germline mutation which resulted in biallelic inactivation in the mesothelioma. All mesotheliomas were mismatch repair proficient and showed several chromosomal gains and losses. All patients died from disease. In summary, our studies demonstrate that pericardial mesotheliomas share common morphologic, immunohistochemical, and molecular genetic features with pleural mesothelioma including recurrent genomic inactivation of canonical tumor suppressors. Our study adds new insights into the genetic landscape of primary pericardial mesothelioma and highlights BRCA1 loss as a potential contributing factor in a subset of cases, thereby contributing to refined precision diagnostics for this rare cancer.

Keywords: BRCA1; Mesothelioma; asbestos; cell cycle regulator; germline; next-generation sequencing; pericardium; tumor suppressor

DOI: https://doi.org/10.1016/j.modpat.2023.100237

Semin Respir Crit Care Med. 2023 Jun 12.

Intrapleural Anticancer Therapy for Malignant Pleural Diseases: Facts or Fiction?

Abhinav Agrawal, Udit Chaddha, Samira Shojaee, Fabien Maldonado.

Malignant pleural diseases involves both primary pleural malignancies (e.g., mesothelioma) as well as metastatic disease involving the pleura. The management of primary pleural malignancies remains a challenge, given their limited response to conventional treatments such as surgery, systemic chemotherapy, and immunotherapy. In this article, we aimed to review the management of primary pleural malignancy as well as malignant pleural effusion and assess the current state of intrapleural anticancer therapies. We review the role intrapleural chemotherapy, immunotherapy, and immunogene therapy, as well as oncolytic viral, therapy and intrapleural drug device combination. We further discuss that while the pleural space offers a unique opportunity for local therapy as an adjuvant option to systemic therapy and may help decrease some of the systemic side effects, further patient outcome-oriented research is needed to determine the exact role of these treatments within the armamentarium of currently available options.

DOI: https://doi.org/10.1055/s-0043-1769094

Cancer Treat Res. 2023 ;185 79-89

Traditional Treatment Approaches and Role of Immunotherapy in Lung Malignancy and Mesothelioma.

Mirza Tasnia Tamanna, Christopher Egbune.

There is no denying that many revolutions took place in the fight against cancer during the last decades. However, cancers have always managed to find new ways to challenge humankinds. Variable genomic epidemiology, socio-economic differences and limitations of widespread screening are the major concerns in cancer diagnosis and early treatment. A multidisciplinary approach is essentially to manage a cancer patient efficiently. Thoracic malignancies including lung cancers and pleural mesothelioma are accountable for little more than 11.6% of the global cancer burden [4]. Mesothelioma is one of the rare cancers, but concern is the incidences are increasing globally. However, the good news is first-line chemotherapy with the combination of immune checkpoints inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and mesothelioma has showed promising respond and improved overall survival (OS) in pivotal clinical trials [10]. ICIs are commonly referred as immunotherapy are antigens on the cancer cells, and inhibitors are the antibodies produce by the T cell defence system. By inhibiting immune checkpoints, the cancer cells become visible to be identified as abnormal cells and attack by the body's defence system [17]. The programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1) inhibitors are commonly used immune checkpoint blockers for anti-cancer treatment. PD-1/PD-L1 are proteins produced by immune cells and mimic by cancer cells that are implicated in inhibiting T cell response to regulate our immune system, which results tumour cells escaping the defence mechanism to achieve immune surveillance. Therefore, inhibiting immune checkpoints as well as monoclonal antibodies can lead to effective apoptosis of tumour cells [17]. Mesothelioma is an industrial disease caused by significant asbestos exposure. It is the cancer of the mesothelial tissue which presents in the lining of the mediastinum of pleura, pericardium and peritoneum, most commonly affected sites are pleura of the lung or chest wall lining [9] as route of asbestos exposure is inhalation. Calretinin is a calcium binding protein, typically over exposed in malignant mesotheliomas and the most useful marker even while initial changes take place [5]. On the other hand, Wilm's tumour 1 (WT-1) gene expression on the tumour cells can be related to prognosis as it can elicit immune response, thereby inhibit cell apoptosis. A systematic review and meta-analysis study conducted by Qi et al. has suggested that expression of WT-1 in a solid tumour is fatal however, it gives the tumour cell a feature of immune sensitivity which then acts positively towards the treatment with immunotherapy. Clinical significance of WT-1 oncogene in treatment is still hugely debatable and needs further attention [21]. Recently, Japan has reinstated Nivolumab in patients with chemo-refractory mesothelioma. According to NCCN guidelines, the salvage therapies include Pembrolizumab in PD-L1 positive patients and Nivolumab alone or with Ipilimumab in cancers irrespective of PD-L1 expression [9]. The checkpoint blockers have taken over the biomarker-based research and demonstrated impressive treatment options in immune sensitive and asbestos-related cancers. It can be expected that in near future the immune checkpoint inhibitors will be considered as approved first-line cancer treatment universally.

Keywords: Asbestos; Calretinin; Chemo-immunotherapy; Immune checkpoint inhibitors (ICIs); Lung cancer; Mesothelioma; Oncogene WT-1; PD-1; PD-L1

DOI: https://doi.org/10.1007/978-3-031-27156-4_5