bims-mesote 2022-10-16 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2022–10–16
seven papers selected by
Laura Mannarino, Humanitas Research

Exploring MicroRNA and Exosome Involvement in Malignant Pleural Mesothelioma Drug Response.
Comparison of Survival by Multimodal Treatment Regimen Among Malignant Pleural Mesothelioma Patients in an Integrated Health System.
Unraveling tumor microenvironment heterogeneity in malignant pleural mesothelioma identifies biologically distinct immune subtypes enabling prognosis determination.
Systematic Review and Meta-Analysis of Pleurectomy/Decortication versus Extrapleural Pneumonectomy in the Treatment of Malignant Pleural Mesothelioma.
Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma.
The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy.
Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma.

Cancers (Basel). 2022 Sep 30. pii: 4784. [Epub ahead of print]14(19):

Exploring MicroRNA and Exosome Involvement in Malignant Pleural Mesothelioma Drug Response.

Ben Johnson, Ling Zhuang, Emma M Rath, Man Lee Yuen, Ngan Ching Cheng, Huaikai Shi, Steven Kao, Glen Reid, Yuen Yee Cheng.

  Malignant pleural mesothelioma (MPM) is a deadly thoracic malignancy and existing treatment options are limited. Chemotherapy remains the most widely used first-line treatment regimen for patients with unresectable MPM, but is hampered by drug resistance issues. The current study demonstrated a modest enhancement of MPM cell sensitivity to chemotherapy drug treatment following microRNA (miRNA) transfection in MPM cell lines, albeit not for all tested miRNAs. This effect was more pronounced for FAK (PND-1186) small molecule inhibitor treatment; consistent with previously published data. We previously established that MPM response to survivin (YM155) small molecule inhibitor treatment is unrelated to basal survivin expression. Here, we showed that MPM response to YM155 treatment is enhanced following miRNA transfection of YM155-resistant MPM cells. We determined that YM155-resistant MPM cells secrete a higher level of exosomes in comparison to YM155-sensitive MPM cells. Despite this, an exosome inhibitor (GW4896) did not enhance MPM cell sensitivity to YM155. Additionally, our study showed no evidence of a correlation between the mRNA expression of inhibitor of apoptosis (IAP) gene family members and MPM cell sensitivity to YM155. However, two drug transporter genes, ABCA6 and ABCA10, were upregulated in the MPM cell lines and correlated with poor sensitivity to YM155.

Keywords:  chemotherapy drug; drug response; exosome; inhibitor of apoptosis; malignant pleural mesothelioma; microRNA; small molecule inhibitor; survivin

DOI:  https://doi.org/10.3390/cancers14194784
Clin Lung Cancer. 2022 Sep 17. pii: S1525-7304(22)00202-9. [Epub ahead of print]

Comparison of Survival by Multimodal Treatment Regimen Among Malignant Pleural Mesothelioma Patients in an Integrated Health System.

Kian C Banks, Stephanie Ossowski, Yun-Yi Hung, Diana S Hsu, Simon K Ashiku, Ashish R Patel, Jeffrey B Velotta, J Marie Suga.

   BACKGROUND: Optimal therapy for malignant pleural mesothelioma (MPM) remains unclear. We compared overall survival in patients with MPM after various multimodal treatment regimens including combinations of immunotherapy, chemotherapy, and surgery.
PATIENTS AND METHODS: We examined MPM patients treated within our integrated health system from January 1, 2009 to December 31, 2020. Patients were grouped based on treatment regimen: chemotherapy alone (CT), immunotherapy with or without chemotherapy (iCT), surgery with chemotherapy (sCT), and surgery with immunotherapy and chemotherapy (siCT). We analyzed baseline characteristics and overall patient survival among these groups and several subgroups.
RESULTS: One hundred seventy-nine patients were included. Among the study groups, there was no difference in age, sex, race/ethnicity, Charlson Comorbidity Index, or Eastern Cooperative Oncology Group performance status. Patients treated with CT (N = 109), iCT (N = 35), sCT (N = 26), and siCT (N = 9) had median (95% confidence interval) survivals of 11.7 (9.9-16.3), 18.2 (14.5-29.8), 20.7 (11.6-37.2), and 22.6 (19.7-37.8) months, respectively (P < .001). Median survival among patients with and without immunotherapy was 19.7 (17.4-29.8) and 12.3 (10.6-17.3) months, respectively (P = .023). Median survival among patients with and without surgery was 21.7 (17.6-34.8) and 13.6 (11.5-17.3) months, respectively (P = .007). Patients with biphasic/sarcomatoid subtypes who received immunotherapy experienced 76.2% (55.8%-100.0%) 12 month survival vs. 13.6% (4.8%-39.0%) among those who did not (P < .001).
CONCLUSION: MPM patients receiving surgery and immunotherapy as part of multimodal treatment regimens experienced the longest survival. Surgery and immunotherapy are each associated with survival. Further investigations are warranted to assess the benefit of immunotherapy within multimodal treatment regimens for MPM.

Keywords:  Cancer; Immunotherapy; Outcomes; Surgery; Therapy

DOI:  https://doi.org/10.1016/j.cllc.2022.09.003
Front Oncol. 2022 ;12 995651

Unraveling tumor microenvironment heterogeneity in malignant pleural mesothelioma identifies biologically distinct immune subtypes enabling prognosis determination.

Kaidi Yang, Tongxin Yang, Tao Yang, Ye Yuan, Fang Li.

   Background: Malignant pleural mesothelioma (MPM) is a rare and intractable disease exhibiting a remarkable intratumoral heterogeneity and dismal prognosis. Although immunotherapy has reshaped the therapeutic strategies for MPM, patients react with discrepant responsiveness.
Methods: Herein, we recruited 333 MPM patients from 5 various cohorts and developed an in-silico classification system using unsupervised Non-negative Matrix Factorization and Nearest Template Prediction algorithms. The genomic alterations, immune signatures, and patient outcomes were systemically analyzed across the external TCGA-MESO samples. Machine learning-based integrated methodology was applied to identify a gene classifier for clinical application.
Results: The gene expression profiling-based classification algorithm identified immune-related subtypes for MPMs. In comparison with the non-immune subtype, we validated the existence of abundant immunocytes in the immune subtype. Immune-suppressed MPMs were enriched with stroma fraction, myeloid components, and immunosuppressive tumor-associated macrophages (TAMs) as well exhibited increased TGF-β signature that informs worse clinical outcomes and reduced efficacy of anti-PD-1 treatment. The immune-activated MPMs harbored the highest lymphocyte infiltration, growing TCR and BCR diversity, and presented the pan-cancer immune phenotype of IFN-γ dominant, which confers these tumors with better drug response when undergoing immune checkpoint inhibitor (ICI) treatment. Genetically, BAP1 mutation was most commonly found in patients of immune-activated MPMs and was associated with a favorable outcome in a subtype-specific pattern. Finally, a robust 12-gene classifier was generated to classify MPMs with high accuracy, holding promise value in predicting patient survival.
Conclusions: We demonstrate that the novel classification system can be exploited to guide the identification of diverse immune subtypes, providing critical biological insights into the mechanisms driving tumor heterogeneity and responsible for cancer-related patient prognoses.

Keywords:  immune subtypes; immunotherapy; machine learning-based gene classifier; malignant pleural mesothelioma; prognosis

DOI:  https://doi.org/10.3389/fonc.2022.995651
J Clin Med. 2022 Sep 22. pii: 5544. [Epub ahead of print]11(19):

Systematic Review and Meta-Analysis of Pleurectomy/Decortication versus Extrapleural Pneumonectomy in the Treatment of Malignant Pleural Mesothelioma.

Federica Danuzzo, Sebastiano Maiorca, Gianluca Bonitta, Mario Nosotti.

   OBJECTIVE: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant cancer for which there are poor treatment options. Extrapleural pneumonectomy (EPP) and pleurectomy decortication (P/D) are the two most used surgical procedures in patients with resectable disease. We reviewed the available literature in order to compare the overall survival and postoperative complications of EPP and P/D and to provide evidence for the best procedure in the treatment of MPM.
METHODS: We performed a systematic review of the literature, including studies from August 2018 to May 2022. The primary outcome was 5-year overall survival (OS) and the secondary outcomes were 30-day mortality, 90-day mortality and peri-operative complications.
RESULTS: Thirteen studies were considered, including a total of 1624 patients treated with EPP and 2147 treated with P/D. The estimated pooled HR showed a significant lower hazard for P/D compared to EPP in terms of OS (HR = 0.76; 95% CI from 0.62 to 0.94; p < 0.001). In 12 studies, the risk for 30-day mortality was lower for patients treated with P/D (RR = 0.49; 95% CI from 0.31 to 0.76; p = <0.01), whereas only five studies reported 90-day mortality, and no statistically significant difference between EPP and P/D was found (RR = 0.71; 95% CI from 0.47 to 1.07; p = 0.10). The OS restricted mean survival time difference meta-analysis (RMSDT) confirms the superior survival of P/D on the EPP, a superiority that increases from 0.54 months at one year to 4.23 at five years. The incidence of postoperative empyema, atrial fibrillation, bleeding and bronchopleural fistula was significantly increased in the EPP group except for prolonged air leakage, which is only characteristic of P/D.
CONCLUSIONS: Using two different statistical methods, this meta-analysis suggests that long-term survival after surgical treatment for resectable MPM is greater for patients undergoing P/D. Long-term survival had never been previously analyzed with appropriate tests; on the contrary, our result is consistent with the previous meta-analyses and reinforces the evidence of lower 30-day mortality and the prevalence of postoperative complications in P/D versus EPP patients. The recent introduction of innovative therapeutic schemes, both adjuvant and neoadjuvant therapy, keeps the discussion on surgical strategy open and will require new studies.

Keywords:  EPP; malignant pleural mesothelioma; mesothelioma; mpm; pleurectomy; pleurectomy/decortication (P/D); pneumonectomy

DOI:  https://doi.org/10.3390/jcm11195544
Int J Mol Sci. 2022 Oct 08. pii: 11949. [Epub ahead of print]23(19):

Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma.

Darya Karatkevich, Haibin Deng, Yanyun Gao, Emilio Flint, Ren-Wang Peng, Ralph Alexander Schmid, Patrick Dorn, Thomas Michael Marti.

  Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy, which consists of concurrent treatment with pemetrexed and cisplatin. Pemetrexed limits tumor growth by inhibiting critical metabolic enzymes involved in nucleotide synthesis. Cisplatin causes direct DNA damage, such as intra-strand and inter-strand cross-links, which are repaired by the nucleotide excision repair pathway, which depends on relatively high nucleotide levels. We hypothesized that prolonged pretreatment with pemetrexed might deplete nucleotide pools, thereby sensitizing cancer cells to subsequent cisplatin treatment. The MPM cell lines ACC-MESO-1 and NCI-H28 were treated for 72 h with pemetrexed. Three treatment schedules were evaluated by initiating 24 h of cisplatin treatment at 0 h (concomitant), 24 h, and 48 h relative to pemetrexed treatment, resulting in either concomitant administration or pemetrexed pretreatment for 24 h or 48 h, respectively. Multicolor flow cytometry was performed to detect γH2AX (phosphorylation of histone H2AX), a surrogate marker for the activation of the DNA damage response pathway. DAPI staining of DNA was used to analyze cell cycle distribution. Forward and side scatter intensity was used to distinguish subpopulations based on cellular size and granularity, respectively. Our study revealed that prolonged pemetrexed pretreatment for 48 h prior to cisplatin significantly reduced long-term cell growth. Specifically, pretreatment for 48 h with pemetrexed induced a cell cycle arrest, mainly in the G2/M phase, accumulation of persistent DNA damage, and induction of a senescence phenotype. The present study demonstrates that optimizing the treatment schedule by pretreatment with pemetrexed increases the efficacy of the pemetrexed-cisplatin combination therapy in MPM. We show that the observed benefits are associated with the persistence of treatment-induced DNA damage. Our study suggests that an adjustment of the treatment schedule could improve the efficacy of the standard chemotherapy regimen for MPM and might improve patient outcomes.

Keywords:  DNA damage; chemotherapy; cisplatin; malignant pleural mesothelioma; pemetrexed; schedule-dependent treatment; senescence

DOI:  https://doi.org/10.3390/ijms231911949
Cell Death Discov. 2022 Oct 11. 8(1): 416

The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy.

Guilong Tanzhu, Liu Chen, Gang Xiao, Wen Shi, Haiqin Peng, Dikang Chen, Rongrong Zhou.

Tumor Treating Fields (TTFields) is a physical therapy that uses moderate frequency (100-300 kHz) and low-intensity (1-3 V/cm) alternating electric fields to inhibit tumors. Currently, the Food and Drug Administration approves TTFields for treating recurrent or newly diagnosed glioblastoma (GBM) and malignant pleural mesothelioma (MPM). The classical mechanism of TTFields is mitotic inhibition by hindering the formation of tubulin and spindle. In addition, TTFields inhibits cell proliferation, invasion, migration and induces cell death, such as apoptosis, autophagy, pyroptosis, and cell cycle arrest. Meanwhile, it regulates immune function and changes the permeability of the nuclear membrane, cell membrane, and blood-brain barrier. Based on the current researches on TTFields in various tumors, this review comprehensively summarizes the in-vitro effects, changes in pathways and molecules corresponding to relevant parameters of TTFields (frequency, intensity, and duration). In addition, radiotherapy and chemotherapy are common tumor treatments. Thus, we also pay attention to the sequence and dose when TTFields combined with radiotherapy or chemotherapy. TTFields has inhibitory effects in a variety of tumors. The study of TTFields mechanism is conducive to subsequent research. How to combine common tumor therapy such as radiotherapy and chemotherapy to obtain the maximum benefit is also a problem that's worthy of our attention.

DOI: https://doi.org/10.1038/s41420-022-01206-y
Int J Mol Sci. 2022 Sep 24. pii: 11248. [Epub ahead of print]23(19):

Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma.

Iacopo Gesmundo, Francesca Pedrolli, Nicoletta Vitale, Alessia Bertoldo, Giulia Orlando, Dana Banfi, Giuseppina Granato, Ramesh Kasarla, Federico Balzola, Silvia Deaglio, Renzhi Cai, Wei Sha, Mauro Papotti, Ezio Ghigo, Andrew V Schally, Riccarda Granata.

  Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM.

Keywords:  GHRH antagonists; chemotherapeutic drugs; pleural mesothelioma

DOI:  https://doi.org/10.3390/ijms231911248