bims-mesote 2022-06-19 papers

Issue of 2022–06–19
six papers selected by
Laura Mannarino, Humanitas Research

Life Sci. 2022 Jun 13. pii: S0024-3205(22)00416-7. [Epub ahead of print] 120716

Repurposing therapeutics for malignant pleural mesothelioma (MPM) - Updates on clinical translations and future outlook.

Nishant S Kulkarni, Vivek Gupta.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare malignancy affecting the mesothelial cells in the pleural lining surrounding the lungs. First approved chemotherapy against MPM was a platinum/antifolate (cisplatin/pemetrexed) (2003). Since then, no USFDA approvals have gone through for small molecules as these molecules have not been proven to be therapeutically able in later stages of clinical studies. An alternative to conventional chemotherapy can be utilization of monoclonal antibodies, which are proven to improve patient survival significantly as compared to conventional chemotherapy (Nivolumab + Ipilimumab, 2020).
AREA COVERED: Drug repurposing has been instrumental in drug discovery for rare diseases such as MPM and multiple repositioned small molecule therapies and immunotherapies are currently being tested for its applicability in MPM management. This article summarizes essential breakthroughs along the pre-clinical and clinical developmental stages of small molecules and monoclonal antibodies for MPM management.
EXPERT OPINION: For rare diseases such as malignant pleural mesothelioma, a drug repurposing strategy can be adapted as it eases the financial burden on pharmaceutical companies along with fast-tracking development. With the rise of multiple small molecule repurposed therapies and innovations in localized treatment, MPM therapeutics are bound to be more effective in this decade.

Keywords: Chemotherapy; Immunotherapy; Malignant pleural mesothelioma; Repurposing; Targeted therapies

DOI: https://doi.org/10.1016/j.lfs.2022.120716

JCO Precis Oncol. 2022 Jun;6 e2100422

Molecular Characterization of Mesothelioma: Impact of Histologic Type and Site of Origin on Molecular Landscape.

Ibiayi Dagogo-Jack, Russell W Madison, Jochen K Lennerz, Kuei-Ting Chen, Julia F Hopkins, Alexa B Schrock, Lauren L Ritterhouse, Ashley Lester, Keith A Wharton, Mari Mino-Kenudson, Natalie Danziger, Yin P Hung, Douglas A Mata, Jeffrey S Ross.

PURPOSE: Mesothelioma is an aggressive malignancy with heterogeneous outcomes that are partly driven by the differential efficacy of existing therapies across histologic types and sites of origin. Large-scale molecular analysis of mesothelioma and its subtypes has the potential to inform future therapeutic strategies.
MATERIALS AND METHODS: We analyzed 1,294 mesotheliomas {980 pleural (malignant pleural mesothelioma [MPM]) and 314 peritoneal (malignant peritoneal mesothelioma [MPeM])} using next-generation sequencing, determined programmed death ligand-1 (PD-L1) expression and histology in a subset of cases, and assessed MTAP/CDKN2A copy-number status by fluorescence in situ hybridization and T-cell infiltration in an independent cohort.
RESULTS: The molecular landscape of MPM was characterized by inactivating alterations in CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (34%), and NF2 (33%). Compared with epithelioid MPM, nonepithelioid (ie, biphasic and sarcomatoid) MPM had identical tumor mutational burden (median 1.25 mut/Mb, P = .63), more commonly expressed PD-L1 (74% v 51%, P = .02), and was more likely to harbor MTAP, CDKN2A, and CDKN2B copy loss (P < .05). Fluorescence in situ hybridization confirmed that homozygous MTAP loss was enriched in nonepithelioid MPM. Relative to MPM, MPeM had comparable tumor mutational burden and PD-L1 expression. The molecular profile of MPeM was similar to MPM, with the distinction that PBRM1 alterations occurred at higher frequency (16% v 7%, P < .01). ALK rearrangements were only observed in MPeM.
CONCLUSION: Regardless of histology and location, the molecular landscape of mesothelioma primarily consists of inactivating alterations in tumor suppressor genes, with enrichment of certain alterations in distinct subsets (eg, MTAP loss in nonepithelioid tumors). Given the limited efficacy of current therapies for this disease, novel approaches targeting recurring alterations should be explored.

DOI: https://doi.org/10.1200/PO.21.00422

Balkan Med J. 2022 Jun 13.

Serum Expression Levels of Certain miRNAs in Predicting Diagnosis, Prognosis, and Response to Chemotherapy in Malignant Pleural Mesothelioma.

Muzaffer Metintaş, Güntülü Ak, Cansu Özbayer, Filiz Boğar, Selma Metintaş.

Background: miRNAs are involved in tumor pathogenesis and can therefore be determined in the primary tumor, plasma and serum, and body fluids. As in various cancers, their role in the diagnosis, prognosis, and treatment of patients with malignant pleural mesothelioma (MPM) may be important.
Aims: To analyze the predictive value of miR-16-5p, miR-29c-3p, miR-31-5p, miR-125a-5p, miR-320a, miR-484 and miR-532-5p expressions for diagnosis, prognosis and response to treatment in patients with MPM.
Study Design: Prospective case-control study.
Methods: In the first phase of the study, blood samples were collected from 101 MPM patients before chemotherapy and from 24 healthy donors (HDs). In the second phase, the blood samples were collected from 74 MPM patients who had received chemotherapy when the best overall response and disease recurrence were determined. A quantitative real-time polymerase chain reaction was undertaken to detect the miRNA expression levels. The miRNA expression profiles of MPM patients were compared with those of HDs. The associations between the expression levels of miRNAs and prognosis and response to treatment were then evaluated.
Results: All miRNAs, except miR-31-5p, were expressed differently in MPM relative to that in HDs. The expression level of miR-16-5p decreased when compared with that of HDs, and the expression levels of miR-29c-3p, miR-125a-5p, miR-320a, miR-484, and miR-532-5p increased when compared with that of HDs. The sensitivity and specificity values of miR-29c-3p, miR-125a-5p, miR-320a, miR-484, and miR-532-5p for discriminating MPM from HDs were 85.9% and 59.1%, 95.1% and 62.5%, 87.1% and 79.2%, 82.2% and 58.3%, and 69.3% and 82.6%, respectively. After adjusting for the histological subtype, stage, and treatment, the miR-29c-3p, miR-125a-5p, and miR-484 were associated with longer survival. The miRNA expression levels did not change longitudinally for the determination of chemotherapy response and recurrence.
Conclusion: miRNAs may be useful in diagnosing patients with MPM and provides helpful information in determining the prognosis of patients.

DOI: https://doi.org/10.4274/balkanmedj.galenos.2022.2022-3-26

EClinicalMedicine. 2022 Jun;48 101432

Active symptom control with or without oral vinorelbine in patients with relapsed malignant pleural mesothelioma (VIM): A randomised, phase 2 trial.

Dean A Fennell, Catharine Porter, Jason Lester, Sarah Danson, Paul Taylor, Michael Sheaff, Robin M Rudd, Aarti Gaba, Sara Busacca, Lisette Nixon, Georgina Gardner, Liz Darlison, Charlotte Poile, Cathy Richards, Peter-Wells Jordan, Gareth Griffiths, Angela Casbard.

Background: Currently, there is no US Food and Drug Administration approved therapy for patients with pleural mesothelioma who have relapsed following platinum-doublet based chemotherapy. Vinorelbine has demonstrated useful clinical activity in mesothelioma, however its efficacy has not been formally evaluated in a randomised setting. BRCA1 expression is required for vinorelbine induced apoptosis in preclinical models. Loss of expression may therefore correlate with vinorelbine resistance.
Methods: In this randomised, phase 2 trial, patients were eligible if they met the following criteria: age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, histologically confirmed pleural mesothelioma, post platinum-based chemotherapy, and radiological evidence of disease progression. Consented patients were randomised 2:1 to either active symptom control with oral vinorelbine versus active symptom control (ASC) every 3 weeks until disease progression, unacceptable toxicity or withdrawal at an initial dose of 60 mg/m2 increasing to 80 mg/m2 post-cycle 1. Randomisation was stratified by histological subtype, white cell count, gender, ECOG performance status and best response during first-line therapy. The study was open label. The primary endpoint was progression-free survival (PFS), measured from randomisation to time of event (or censoring). Analyses were carried out according to intention-to-treat (ITT) principles. Recruitment and trial follow-up are complete. This trial is registered with ClinicalTrials.gov, number NCT02139904.
Findings: Between June 1, 2016 and Oct 31, 2018, we performed a randomised phase 2 trial in 14 hospitals in the United Kingdom. 225 patients were screened for eligibility, of whom 154 were randomly assigned to receive either ASC + vinorelbine (n = 98) or ASC (n = 56). PFS was significantly longer for ASC+vinorelbine compared with ASC alone; 4.2 months (interquartile range (IQR) 2.2-8.0) versus 2.8 months (IQR 1.4-4.1) for ASC, giving an unadjusted hazard ratio (HR) of 0·60 (80% CI upper limit 0.7, one-sided unadjusted log rank test p = 0.002); adjusted HR 0.6 (80% CI upper limit 0.7, one-sided adjusted log rank test p < 0.001). BRCA1 did not predict resistance to ASC+vinorelbine. Neutropenia was the most common grades 3, 4 adverse events in the ASC +vinorelbine arm.
Interpretation: Vinorelbine plus ASC confers clinical benefit to patients with relapsed pleural mesothelioma who have progressed following platinum-based doublet chemotherapy.
Funding: This study was funded by Cancer Research UK (grant CRUK A15569).

Keywords: BRCA1; Mesothelioma; Pleural; Randomised; Relapsed; Vinorelbine

DOI: https://doi.org/10.1016/j.eclinm.2022.101432

Thorac Cancer. 2022 Jun 15.

Diagnostic pitfall in a large cell lung cancer with testicular metastasis synchronous malignant pleural mesothelioma patient: A case report.

Lisha Jiang, Veylenta A De Souza, Nithin M George, Nitya P Rai, Ming Shi, Guowei Che.

Large cell lung cancer metastases to the testis are scarce, although it is the most common malignancy and the most common site of metastases for breast, colorectal and kidney cancers. We hereby report a 28-year-old male patient admitted to our hospital with a chief complaint of scrotal enlargement, accompanied by chest pain and progressive dyspnea. The definite diagnosis was malignant pleural mesothelioma with the synchronous occurrence of large cell lung cancer with testicular metastasis. Sophisticated clinical manifestation of symptoms led to a time-consuming diagnosis, while the patient's condition deteriorated rapidly. Herein, we present this case to share our hard-learnt experience to increase clinician awareness and contribute to the information in the literature.

Keywords: large cell lung cancer; malignant pleural mesothelioma; testicular metastasis

DOI: https://doi.org/10.1111/1759-7714.14472