Genomic characterization of malignant pleural mesothelioma and associated clinical outcomes

Markowitz, P.; Patel, Malini; Groisberg, Roman; Aisner, Joseph; Jabbour, Salma K.; De, Subhajyoti; Ganesan, Shridar; Malhotra, Jyoti

doi:10.1016/j.ctarc.2020.100232

Cited by 10 publications

(8 citation statements)

References 12 publications

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“…Preclinically, ADI‐PEG20 combined with a taxane potentiates gemcitabine cytotoxicity, and is an approach that may have utility in patients with squamous NSCLC 41 . Interestingly, our NSCLC cohort data validate studies showing high rates of ASS1 loss in non‐epithelioid mesothelioma, where p53 mutations have been identified to the exclusion of epithelioid mesothelioma, and underlie similar poor outcomes to platinum–pemetrexed chemotherapy 42,43 …”

Section: Discussionsupporting

confidence: 65%

Phase 1, pharmacogenomic, dose‐expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1‐deficient non‐squamous non‐small cell lung cancer

et al. 2021

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Introduction We evaluated the arginine‐depleting enzyme pegargiminase (ADI‐PEG20; ADI) with pemetrexed (Pem) and cisplatin (Cis) (ADIPemCis) in ASS1‐deficient non‐squamous non‐small cell lung cancer (NSCLC) via a phase 1 dose‐expansion trial with exploratory biomarker analysis. Methods Sixty‐seven chemonaïve patients with advanced non‐squamous NSCLC were screened, enrolling 21 ASS1‐deficient subjects from March 2015 to July 2017 onto weekly pegargiminase (36 mg/m2) with Pem (500 mg/m2) and Cis (75 mg/m2), every 3 weeks (four cycles maximum), with maintenance Pem or pegargiminase. Safety, pharmacodynamics, immunogenicity, and efficacy were determined; molecular biomarkers were annotated by next‐generation sequencing and PD‐L1 immunohistochemistry. Results ADIPemCis was well‐tolerated. Plasma arginine and citrulline were differentially modulated; pegargiminase antibodies plateaued by week 10. The disease control rate was 85.7% (n = 18/21; 95% CI 63.7%–97%), with a partial response rate of 47.6% (n = 10/21; 95% CI 25.7%–70.2%). The median progression‐free and overall survivals were 4.2 (95% CI 2.9–4.8) and 7.2 (95% CI 5.1–18.4) months, respectively. Two PD‐L1‐expressing (≥1%) patients are alive following subsequent pembrolizumab immunotherapy (9.5%). Tumoral ASS1 deficiency enriched for p53 (64.7%) mutations, and numerically worse median overall survival as compared to ASS1‐proficient disease (10.2 months; n = 29). There was no apparent increase in KRAS mutations (35.3%) and PD‐L1 (<1%) expression (55.6%). Re‐expression of tumoral ASS1 was detected in one patient at progression (n = 1/3). Conclusions ADIPemCis was safe and highly active in patients with ASS1‐deficient non‐squamous NSCLC, however, survival was poor overall. ASS1 loss was co‐associated with p53 mutations. Therapies incorporating pegargiminase merit further evaluation in ASS1‐deficient and treatment‐refractory NSCLC.

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Section: Discussionsupporting

confidence: 65%

Phase 1, pharmacogenomic, dose‐expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1‐deficient non‐squamous non‐small cell lung cancer

et al. 2021

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“…With a highly unfavorable prognosis, malignant mesothelioma is a rare, incurable, aggressive and highly lethal malignancy originating from the lining layers of the viscera such as the pleura, peritoneum or pericardium [ 17 , 136 , 137 , 138 , 139 , 140 ]. Mesothelioma is divided into three histological subtypes: epithelioid, sarcomatoid, and biphasic [ 15 ].…”

Section: Tumourigenesis Associated With Expression Of Setdb1mentioning

confidence: 99%

The Updating of Biological Functions of Methyltransferase SETDB1 and Its Relevance in Lung Cancer and Mesothelioma

Sun

et al. 2021

IJMS

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SET domain bifurcated 1 (SETDB1) is a histone H3 lysine 9 (H3K9) methyltransferase that exerts important effects on epigenetic gene regulation. SETDB1 complexes (SETDB1-KRAB-KAP1, SETDB1-DNMT3A, SETDB1-PML, SETDB1-ATF7IP-MBD1) play crucial roles in the processes of histone methylation, transcriptional suppression and chromatin remodelling. Therefore, aberrant trimethylation at H3K9 due to amplification, mutation or deletion of SETDB1 may lead to transcriptional repression of various tumour-suppressing genes and other related genes in cancer cells. Lung cancer is the most common type of cancer worldwide in which SETDB1 amplification and H3K9 hypermethylation have been indicated as potential tumourigenesis markers. In contrast, frequent inactivation mutations of SETDB1 have been revealed in mesothelioma, an asbestos-associated, locally aggressive, highly lethal, and notoriously chemotherapy-resistant cancer. Above all, the different statuses of SETDB1 indicate that it may have different biological functions and be a potential diagnostic biomarker and therapeutic target in lung cancer and mesothelioma.

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“…Homozygous deletion of p16/ CDKN2A is very common in MPM, and is associated with worse prognosis [ 60 , 61 , 62 ]. Between 30% and 74% of MPM patients show alterations in CDKN2A [ 63 , 64 , 65 ].…”

Section: Histological and Molecular Characteristicsmentioning

confidence: 99%

“…Mouse models showed asbestos-independent development of mesothelioma in populations with NF2 mutations [ 71 , 72 ]. Alterations in NF2 can be found in 19–53% of patients with MPM, while mutations in LATS2 have been reported in 11% of MPM [ 33 , 64 , 73 ].…”

Section: Histological and Molecular Characteristicsmentioning

confidence: 99%

Current Management and Future Perspective in Pleural Mesothelioma

Shah

Klotz

Glade

2022

Cancers

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Pleural mesothelioma is an aggressive malignancy arising from pleural mesothelial cell lining, predominantly associated with prior exposure to asbestos. The ban on asbestos use has led to its lower incidence in many countries, but globally the disease burden is expected to rise. Therefore, well-planned research is needed to develop more effective, tolerable and affordable drugs. The development of novel treatment has been too slow, with only two regimens of systemic therapy with robust phase 3 data approved formally to date. The treatment scenario for resectable disease remains controversial. However, recent developments in the understanding of disease and clinical trials have been encouraging, and may add better treatment options in the coming years. In this review, we discuss the current treatment options for pleural mesothelioma and shed light on some recent studies and ongoing trials.

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Genomic characterization of malignant pleural mesothelioma and associated clinical outcomes

Cited by 10 publications

References 12 publications

Phase 1, pharmacogenomic, dose‐expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1‐deficient non‐squamous non‐small cell lung cancer

Phase 1, pharmacogenomic, dose‐expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1‐deficient non‐squamous non‐small cell lung cancer

The Updating of Biological Functions of Methyltransferase SETDB1 and Its Relevance in Lung Cancer and Mesothelioma

Current Management and Future Perspective in Pleural Mesothelioma

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