scholarly journals Novel Therapeutic Targets and Immune Dysfunction in Malignant Pleural Mesothelioma

2022 ◽  
Vol 12 ◽  
Author(s):  
Moshe Lapidot ◽  
Srinivas Vinod Saladi ◽  
Ravi Salgia ◽  
Martin Sattler

Advances in the treatment of malignant pleural mesothelioma (MPM) have been disappointing, despite the apparent need for new therapeutic options for this rare and devastating cancer. Drug resistance is common and surgical intervention has brought benefits only to a subset of patients. MPM is a heterogenous disease with a surprisingly low mutation rate and recent sequencing efforts have confirmed alterations in a limited number of tumor suppressors that do not provide apparent insights into the molecular mechanisms that drive this malignancy. There is increasing evidence that epigenetic regulation leads to immune evasion and transformation in MPM. Further, the low efficacy of immune checkpoint inhibitors is consistent with a suppression of genes involved in the anti-tumor immune response. We review three promising emerging therapeutic targets (STAT3, KDM4A, heparanase) and highlight their potential effects on the immune response.

2017 ◽  
Vol 12 (11) ◽  
pp. S2019-S2020
Author(s):  
S. Gray ◽  
M. Breslin ◽  
S. Cregan ◽  
L. Quinn ◽  
S. Wennstedt ◽  
...  

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20565-e20565
Author(s):  
Ervin Saúl Enciso López ◽  
Efrain Isaias Camarin Sanchez ◽  
Daniela Vazquez Juarez ◽  
Alejandro Noguez-Ramos ◽  
Daniela Shveid Gerson ◽  
...  

e20565 Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer. Prognosis is generally poor, with a median overall survival (mOS) of approximately 12 months. MPM appears to be directly linked to immunosuppressive mechanisms, leading to use of checkpoint inhibitors for patients with this disease. Methods: We performed a retrospective chart review of patients with MPM at our institution between January 2015 to December 2020. All patients were over 18 years at the time of diagnosis of mesothelioma, a total of 8 patients were retrieved from the pathology database of The American British Cowdray Medical Center. The clinical-pathologic features collected were sex, age, performance status, risk factors, pTNM stage (AJCC 8th edition), histology type, sintomatology of onset, metastases sites and treatment. Clinical response rate and other outcomes were assessed. Descriptive statistics were used to describe a patient's demographic and disease characteristics. Results: 8 patients, aged 49 to 71 years (median of 65) at diagnosis of MPM were treated in our center. Both sex presented 4 patients in total. An identifiable risk factor was recorded in 4 patients (2 with asbesto exposure and 2 with heavy smoking). 7 patients (87.5%) had PS 0 or 1, the remaining has PS 2. The clinical stage at diagnosis was unresectable in 7 patients. 3 patients were assessed with PD-L1 expression (SP263 or 22C3), only one with expression of 20%. All patients received at least one scheme of chemotherapy prior to receiving immunotherapy, 25% received bevacizumab/platinum/anti-folate agents. Checkpoint inhibitors were introduced as a second line in 20% and in 80% has a third or more lines. Pembrolizumab was used in 20% and Nivolumab in 80%. The tumor responses with immunotherapy were as follows: partial response 12.5%, stable disease 75% and progressive disease 12.5%. Median progression-free survival of the first line treatment was 18.9 months (4.6-33.6 months), and for the line with checkpoint inhibitors was 11.2 weeks (7-21.2). In the full cohort, mOS was 37.0 months (95% CI:14.5-39.6). According to histology, the mOS for epithelioid-type was 36.6 months and for biphasic-type was 14.6 months (p = 0.42). mOS was 37.0 months for the group with immunotherapy and 15.0 months for those with standard chemotherapy (p = 0.14). The most frequently reported immune mediated adverse events were hypothyroidism and colitis (each one with one patient). Conclusions: In this real-world analysis, mOS was superior to those obtained in the MAPS2 trial (mOS 11.9 months), despite the fact that 80% of the population that received immunotherapy was in third or more lines. Limitations include limited numbers of patients, retrospective review, single institution, and inclusión of many heavily pretreated patients. Also molecular and immunohistochemical results such as PD-L1 status were only available on a limited number of patients.


Biomarkers ◽  
2016 ◽  
Vol 21 (6) ◽  
pp. 551-561 ◽  
Author(s):  
Jenette Creaney ◽  
Ian M. Dick ◽  
A. W. (Bill) Musk ◽  
Nola J. Olsen ◽  
Bruce W. S. Robinson

2021 ◽  
Author(s):  
Lili Su ◽  
Yonggang Wang ◽  
Daowei Li ◽  
Xingguang Wang ◽  
Bin Liang ◽  
...  

Abstract Malignant pleural mesothelioma (MPM) is a highly aggressive and lethal malignancy; however, its molecular origins remain largely unknown. The purpose of this study was to use transcriptomics to explore the molecular mechanisms of MPM tumorigenesis toward gaining a better understanding of disease development. The transcriptomes from MPM tissues and paired normal pleural tissues were compared to identify significantly differentially expressed genes. These genes were then subject to Gene Ontology analysis to explore pathways that are dysregulated in MPM, and The Cancer Genome Atlas (TCGA) gene expression profile data were analyzed to assess the correlation between the significantly dysregulated pathways and patient survival. Moreover, three independent transcriptomic datasets were used to validate the association between significantly dysregulated genes and the clinical features of MPM. We identified 136 up-regulated and 599 down-regulated genes in MPM tissues as compared to normal pleural tissues. Functional enrichment analysis showed that the up-regulated genes were mainly associated with mitotic nuclear division, whereas the down-regulated genes were mainly associated with transforming growth factor beta (TGF-β) signaling. The 14 most significantly up-regulated mitotic nuclear division-related genes were more likely to be highly expressed in pathological subtypes with higher malignancy, whereas the down-regulated TGF-β pathway-related gene PPARGC1A displayed the opposite trend. In the TCGA dataset, up-regulation of mitotic nuclear division-related genes was associated with a poor prognosis, whereas down-regulation of TGF-β pathway-related genes was associated with a positive prognosis. The down-regulated PPARGC1A were further validated by immunohistochemical analysis. In summary, the correlation between up-regulation of mitotic nuclear division-related genes and down-regulation of the TGF-β pathway-related gene PPARGC1A with overall survival indicates an important role for these genes in MPM development and progression.


2021 ◽  
Vol 22 (22) ◽  
pp. 12216
Author(s):  
Valeria Ramundo ◽  
Giada Zanirato ◽  
Elisabetta Aldieri

Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and is characterized by a very difficult pharmacological approach. One of the molecular mechanisms associated with cancer onset and invasiveness is the epithelial-to-mesenchymal transition (EMT), an event induced by different types of inducers, such as transforming growth factor β (TGFβ), the main inducer of EMT, and oxidative stress. MPM development and metastasis have been correlated to EMT; On one hand, EMT mediates the effects exerted by asbestos fibers in the mesothelium, particularly via increased oxidative stress and TGFβ levels evoked by asbestos exposure, thus promoting a malignant phenotype, and on the other hand, MPM acquires invasiveness via the EMT event, as shown by an upregulation of mesenchymal markers or, although indirectly, some miRNAs or non-coding RNAs, all demonstrated to be involved in cancer onset and metastasis. This review aims to better describe how EMT is involved in driving the development and invasiveness of MPM, in an attempt to open new scenarios that are useful in the identification of predictive markers and to improve the pharmacological approach against this aggressive cancer.


Author(s):  
Zito Marino Federica ◽  
Sabetta Rosalaura ◽  
Ronchi Andrea ◽  
Marina Accardo ◽  
Italo Francesco Angelillo ◽  
...  

2020 ◽  
Vol 27 (24) ◽  
pp. 4062-4086 ◽  
Author(s):  
Karine Flem-Karlsen ◽  
Øystein Fodstad ◽  
Caroline E. Nunes-Xavier

B7-H3 belongs to the B7 family of immune checkpoint proteins, which are important regulators of the adaptive immune response and emerging key players in human cancer. B7-H3 is a transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells, tumor endothelial cells, but can also be present in intra- and extracellular vesicles. Additionally, B7-H3 may be present as a circulating soluble isoform in serum and other body fluids. B7-H3 is overexpressed in a variety of tumor types, in correlation with poor prognosis. B7-H3 is a promising new immunotherapy target for anti-cancer immune response, as well as a potential biomarker. Besides its immunoregulatory role, B7-H3 has intrinsic pro-tumorigenic activities related to enhanced cell proliferation, migration, invasion, angiogenesis, metastatic capacity and anti-cancer drug resistance. B7-H3 has also been found to regulate key metabolic enzymes, promoting the high glycolytic capacity of cancer cells. B7-H3 receptors are still not identified, and little is known about the molecular mechanisms underlying B7-H3 functions. Here, we review the current knowledge on the involvement of B7-H3 in human cancer.


Author(s):  
Piotr Januszyk ◽  
Krzysztof Januszyk ◽  
Magdalena Wierzbik-Strońska ◽  
Dariusz Boroń ◽  
Beniamin Grabarek

Background: It is important to understand the molecular mechanisms involved in cancer drug resistance and to study the activity of new drugs, e.g. salinomycin. Objective: The purpose of the study was to analyze changes in the expression of genes associated with drug resistance in the Ishikawa endometrial cancer cell line when treated with salinomycin. In addition, changes in the level of miRNA potentially regulating these mRNAs were evaluated. Results: The following was observed about the number of mRNAs differentiating the cell culture exposed to the drug compared to a control culture: H-12 vs C - 9 mRNAs, H_24 vs C – 6 mRNAs, H_48 vs C - 1 mRNA. It was noted that 4 of the 9 differentiating mRNAs were characteristic for 12 hours of exposure to the salinomycin and they correspond to the following genes: TUFT1, ABCB1, MTMR11, MX2. After 24 hours, 2 mRNAs were characteristic for this time of incubation cells with salinomycin: TUFT1, MYD88 and after 48 hours, SLC30A5 could also be observed. The highest differences in expression were indicated for TUFT1, MTMR11, SLC30A5. The highest influence probability was determined between TUFT1 and hsamiR-3188 (FC + 2.48), MTMR11and has-miR-16 (FC -1.74), and between SLC30A5 and hsa-miR-30d (FC -2.01). Materials and Methods: Endometrial cancer cells were treated with 1 µM of salinomycin for 12, 24 and 48 hour periods. Untreated cells were a control culture. The molecular analysis consists of mRNA and miRNA microarray analysis and the RTqPCR technique. Conclusions: Salinomycin induces changes in the activity of mRNA and miRNA participating in drug resistance, however the observed changes in character are an expected result of anti-cancer treatment.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20070-e20070
Author(s):  
Adithya Balasubramanian ◽  
Adrian Pick ◽  
Beena Kumar ◽  
Zdenka Prodanovic ◽  
Prashant Joshi ◽  
...  

e20070 Background: Malignant Pleural Mesothelioma (MPM) is a rare but fatal disease related to asbestos exposure, with historic survival in the order of 9 to 17 months. Chemotherapy is associated with only a modest benefit. The advent of immunotherapy has heralded significantly improved outcomes using checkpoint inhibitors in an as yet ill-defined cohort. We aim to identify predictive and prognostic biomarkers in a series of patients (pts) with MPM and describe survival data. Methods: A retrospective audit was undertaken of pts with MPM diagnosed between 2013 and 2017 at a single tertiary centre in Melbourne, Australia (Monash Health). Data relating to patient outcomes and clinicopathological features were obtained through medical reports. Further immunostains are being performed on archived tissue for PDL-1 status. Results: 65 pts were identified, of whom 52 (80.0%) were male. Median age was 73 years (range 44-90). 52 pts were noted to be ECOG 0-1. 42 pts (64.6%) were noted to have suspected asbestos exposure. Epithelioid MPM was the most common subtype, noted in 41 pts (63.1%) (table 1). 8 pts (12.3%) presented with stage IV disease. 16 pts (24.6%) received checkpoint inhibitor therapy, with 10 (63 %) in the second/third line setting. Median overall survival (OS) was 19.8 months (95% CI 13.3-26.3) in the whole cohort.Patient characteristics associated with poor OS were: presence of weight loss (P = 0.001), chest pain (p = 0.08) and ECOG 2 (p = 0.04). Pts with sarcomatoid histology who received immune checkpoint inhibitors in any line of treatment had significantly prolonged OS compared to other histologies. 3-year survival was 80% in this group while median OS was not reached (p = 0.04). This difference was not seen with other histologies. Conclusions: The evolving landscape of treatment in MPM appears to show promise in improving OS. In this unselected case series, our data is consistent with historic controls in terms of survival and prognostic factors. The finding of significantly improved survival with immune checkpoint inhibitors in the sarcomatoid histology is exciting and warrants further exploration. Further data on PDL1 status will be presented.


Lung Cancer ◽  
2013 ◽  
Vol 79 ◽  
pp. S30
Author(s):  
Y. Gao ◽  
B.M. Mohamed ◽  
A. Prina-Mello ◽  
K.J. O'Byrne ◽  
S.G. Gray

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