scholarly journals Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 508
Author(s):  
Emanuela Di Gregorio ◽  
Gianmaria Miolo ◽  
Asia Saorin ◽  
Elena Muraro ◽  
Michela Cangemi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Overall Survival ◽  
Clinical Outcome ◽  
Malignant Pleural Mesothelioma ◽  
Therapeutic Option ◽  
Enrichment Analysis ◽  
Metabolic Effects ◽  
Pleural Mesothelioma ◽  
Polyamine Biosynthesis ◽  
The Individual

Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment.

Computational genomic analysis of PARK7 interactome reveals high BBS1 gene expression as a prognostic factor favoring survival in malignant pleural mesothelioma

2015 ◽  
Vol 309 (7) ◽  
pp. L677-L686 ◽  
Author(s):  
Georgios D. Vavougios ◽  
Evgeniy I. Solenov ◽  
Chrissi Hatzoglou ◽  
Galina S. Baturina ◽  
Liubov E. Katkova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Differential Gene Expression ◽  
Malignant Pleural Mesothelioma ◽  
Meta Analysis ◽  
Genomic Analysis ◽  
Enrichment Analysis ◽  
Differentially Expressed ◽  
Pleural Mesothelioma ◽  
Differential Gene

The aim of our study was to assess the differential gene expression of Parkinson protein 7 (PARK7) interactome in malignant pleural mesothelioma (MPM) using data mining techniques to identify novel candidate genes that may play a role in the pathogenicity of MPM. We constructed the PARK7 interactome using the ConsensusPathDB database. We then interrogated the Oncomine Cancer Microarray database using the Gordon Mesothelioma Study, for differential gene expression of the PARK7 interactome. In ConsensusPathDB, 38 protein interactors of PARK7 were identified. In the Gordon Mesothelioma Study, 34 of them were assessed out of which SUMO1, UBC3, KIAA0101, HDAC2, DAXX, RBBP4, BBS1, NONO, RBBP7, HTRA2, and STUB1 were significantly overexpressed whereas TRAF6 and MTA2 were significantly underexpressed in MPM patients ( network 2). Furthermore, Kaplan-Meier analysis revealed that MPM patients with high BBS1 expression had a median overall survival of 16.5 vs. 8.7 mo of those that had low expression. For validation purposes, we performed a meta-analysis in Oncomine database in five sarcoma datasets. Eight network 2 genes (KIAA0101, HDAC2, SUMO1, RBBP4, NONO, RBBP7, HTRA2, and MTA2) were significantly differentially expressed in an array of 18 different sarcoma types. Finally, Gene Ontology annotation enrichment analysis revealed significant roles of the PARK7 interactome in NuRD, CHD, and SWI/SNF protein complexes. In conclusion, we identified 13 novel genes differentially expressed in MPM, never reported before. Among them, BBS1 emerged as a novel predictor of overall survival in MPM. Finally, we identified that PARK7 interactome is involved in novel pathways pertinent in MPM disease.

56: Multiple RTK targeting as a therapeutic option in malignant pleural mesothelioma

Lung Cancer ◽  
2017 ◽  
Vol 103 ◽  
pp. S26
Author(s):  
A. Baird ◽  
D. Easty ◽  
B.M. Mohamed ◽  
M. Jarzabek ◽  
L. Shiels ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Therapeutic Option ◽  
Pleural Mesothelioma

scholarly journals Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival

2020 ◽  
Vol 14 (6) ◽  
pp. 1207-1223 ◽  
Author(s):  
Lisa Quetel ◽  
Clément Meiller ◽  
Jean‐Baptiste Assié ◽  
Yuna Blum ◽  
Sandrine Imbeaud ◽  
...  
Keyword(s):  
Overall Survival ◽  
Malignant Pleural Mesothelioma ◽  
Tumor Heterogeneity ◽  
Genetic Alterations ◽  
Pleural Mesothelioma

scholarly journals TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1484
Author(s):  
Bernard Staumont ◽  
Majeed Jamakhani ◽  
Chrisostome Costa ◽  
Fabian Vandermeers ◽  
Sathya Neelature Sriramareddy ◽  
...  
Keyword(s):  
Rna Interference ◽  
Growth Factor ◽  
Tumor Growth ◽  
Mouse Models ◽  
Differentially Expressed Genes ◽  
Malignant Pleural Mesothelioma ◽  
Transforming Growth Factor ◽  
Therapeutic Option ◽  
Differentially Expressed ◽  
Pleural Mesothelioma

Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy.

Phase II Study of Pemetrexed Plus Carboplatin in Malignant Pleural Mesothelioma

2006 ◽  
Vol 24 (9) ◽  
pp. 1443-1448 ◽  
Author(s):  
Giovanni L. Ceresoli ◽  
Paolo A. Zucali ◽  
Adolfo G. Favaretto ◽  
Francesco Grossi ◽  
Paolo Bidoli ◽  
...  
Keyword(s):  
Overall Survival ◽  
Disease Control ◽  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Objective Response ◽  
Dose Intensity ◽  
Pleural Mesothelioma ◽  
Standard Regimen ◽  
Time Curve ◽  
Grade 3

Purpose This multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM). Patients and Methods Chemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m2 and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B12 supplementation. Pemetrexed was provided within the Expanded Access Program. Results A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to progression was 6.5 months; median overall survival time was 12.7 months. Compliance to treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible. Conclusion Treatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM. Disease control rate, time to disease progression, and overall survival were similar to the results achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination could be an alternative option for these patients.

scholarly journals OA13.03 Long-Term Overall Survival for Patients with Malignant Pleural Mesothelioma on Pembrolizumab Enrolled in KEYNOTE-028

2017 ◽  
Vol 12 (1) ◽  
pp. S294 ◽  
Author(s):  
Evan Alley ◽  
Juanita Lopez ◽  
Armando Santoro ◽  
Anne Morosky ◽  
Sanatan Saraf ◽  
...  
Keyword(s):  
Overall Survival ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma
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