bims-mesote 2021-10-03 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2021–10–03
twelve papers selected by
Laura Mannarino, Humanitas Research

Malignant Pleural Mesothelioma-Does Ki67 Make the Grade?
Management of Pleural Effusion Secondary to Malignant Mesothelioma.
BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma.
A novel therapeutic strategy targeting the mesenchymal phenotype of malignant pleural mesothelioma by suppressing LSD1.
Immune Checkpoint Inhibitor Uptake in Real-World Patients With Malignant Pleural Mesothelioma.
Ki67 (MIB-1) as a Prognostic Marker for Clinical Decision Making Before Extended Pleurectomy Decortication in Malignant Pleural Mesothelioma.
Inhibition of CDK4/6 Overcomes Primary Resistance to PD-1 Blockade in Malignant Mesothelioma.
Phase 2 Study of YS110, a Recombinant Humanized Anti-CD26 Monoclonal Antibody, in Japanese Patients With Advanced Malignant Pleural Mesothelioma.
Clinical Efficacy and Safety of Nivolumab in Japanese Patients With Malignant Pleural Mesothelioma: 3-Year Results of the MERIT Study.
Localized malignant mesothelioma in the stomach and mediastinum.
Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1-Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms.
Matrix Metalloproteinases as Biomarkers and Treatment Targets in Mesothelioma: A Systematic Review.

JTO Clin Res Rep. 2021 May;2(5): 100170

Malignant Pleural Mesothelioma-Does Ki67 Make the Grade?

Owen W J Prall.

DOI: https://doi.org/10.1016/j.jtocrr.2021.100170
J Clin Med. 2021 Sep 19. pii: 4247. [Epub ahead of print]10(18):

Management of Pleural Effusion Secondary to Malignant Mesothelioma.

Valeria Musso, Cristina Diotti, Alessandro Palleschi, Davide Tosi, Alberto Aiolfi, Paolo Mendogni.

  Malignant pleural mesothelioma (MPM) is a highly aggressive pleural tumour which has been epidemiologically linked to occupational exposure to asbestos. MPM is often associated with pleural effusion, which is a common cause of morbidity and whose management remains a clinical challenge. In this review, we analysed the literature regarding the diagnosis and therapeutic options of pleural effusion secondary to mesothelioma. Our aim was to provide a comprehensive view on this subject, and a new algorithm was proposed as a practical aid to clinicians dealing with patients suffering from pleural effusion.

Keywords:  indwelling pleural catheter; malignant pleural effusion; malignant pleural mesothelioma; mesothelioma; talc poudrage

DOI:  https://doi.org/10.3390/jcm10184247
J Biol Chem. 2021 Sep 28. pii: S0021-9258(21)01026-7. [Epub ahead of print] 101223

BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma.

Yuki Ishii, Krishna K Kolluri, Adam Pennycuick, Xidan Zhang, Ersilia Nigro, Doraid Alrifai, Elaine Borg, Mary Falzon, Khalid Shah, Neelam Kumar, Sam M Janes.

  Malignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the pleura, with few available treatment options. We recently reported loss of function of the nuclear deubiquitinase BRCA1-associated protein 1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptors 4 (DR4) and 5 (DR5). Using tissue microarrays (TMAs) of tumour samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptor expression. BAP1 knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wild-type BAP1, but not catalytically-inactive mutant BAP1, reduced promoter activities of DR4 and DR5, suggesting deubiquitinase activity is required for the regulation of gene expression. Co-IP studies demonstrated direct binding of BAP1 to the transcription factor Ying Yang 1 (YY1), and ChIP assays revealed BAP1 and YY1 to be enriched in the promoter regions of DR4 and DR5. Knockdown of YY1 also increased DR4 and DR5 expression and sensitivity to TRAIL. These results suggest that BAP1 and YY1 cooperatively repress transcription of TRAIL receptors. Our finding that BAP1 directly regulates the extrinsic apoptotic pathway will provide new insights into the role of BAP1 in the development of MPM and other cancers with frequent BAP1 mutations.

Keywords:  BAP1; TRAIL; YY1; apoptosis; cancer therapy; receptor regulation; tumor cell biology

DOI:  https://doi.org/10.1016/j.jbc.2021.101223
Mol Cancer Res. 2021 Sep 30. pii: molcanres.MCR-21-0230-E.2021. [Epub ahead of print]

A novel therapeutic strategy targeting the mesenchymal phenotype of malignant pleural mesothelioma by suppressing LSD1.

Aditya Wirawan, Ken Tajima, Fumiyuki Takahashi, Yoichiro Mitsuishi, Wira Winardi, Moulid Hidayat, Daisuke Hayakawa, Naohisa Matsumoto, Kenta Izumi, Tetsuhiko Asao, Ryo Ko, Naoko Shimada, Kazuya Takamochi, Kenji Suzuki, Masaaki Abe, Okio Hino, Yoshitaka Sekido, Kazuhisa Takahashi.

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial-mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and ATAC-seq to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK-AKT-GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance. Implications: This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0230
JTO Clin Res Rep. 2021 Jun;2(6): 100188

Immune Checkpoint Inhibitor Uptake in Real-World Patients With Malignant Pleural Mesothelioma.

Roger Y Kim, Nandita Mitra, Stephen J Bagley, Melina E Marmarelis, Andrew R Haas, Katharine A Rendle, Anil Vachani.

   Introduction: Since the July 2017 National Comprehensive Cancer Network (NCCN) malignant pleural mesothelioma (MPM) guideline revision recommended second-line immune checkpoint inhibitors (ICIs), studies have suggested a greater response to ICI among patients with nonepithelioid MPM. Nevertheless, little is known regarding adoption of ICI in routine practice and if uptake differs by histologic subtype. Our objectives were to evaluate the real-world uptake of second-line ICI among patients with MPM and to reveal its association with histologic subtype.
Methods: This was a multicenter, retrospective cohort study of real-world patients with MPM receiving at least two lines of systemic therapy between 2011 and 2019. We found the uptake of second-line ICI over time and evaluated the association between histologic subtype and ICI use, adjusting for relevant patient demographic and clinical factors.
Results: Among the 426 patients with MPM in our cohort, 310 had epithelioid and 116 nonepithelioid histologic subtype. The median age was 73 years (interquartile range: 67-78). Overall, 144 patients (33.8%) received second-line ICI and 282 (66.2%) traditional chemotherapy. ICI uptake began in early 2015 before the NCCN guideline revision and increased rapidly to 2019. After the 2017 NCCN guideline revision, patients with nonepithelioid MPM histologic subtypes had more than 3 times the odds of receiving second-line ICI (OR = 3.26; 95% confidence interval: 1.41-7.54).
Conclusions: Among real-world patients with MPM, second-line ICI uptake began over two years before the 2017 NCCN guideline recommendations and was associated with nonepithelioid histologic subtype after contemporary studies suggested increased clinical benefit in this population, reflecting prompt integration of scientific discovery into clinical practice.

Keywords:  Histology; Immunotherapy; Mesothelioma; Real-world evidence; Uptake

DOI:  https://doi.org/10.1016/j.jtocrr.2021.100188
JTO Clin Res Rep. 2021 Apr;2(4): 100155

Ki67 (MIB-1) as a Prognostic Marker for Clinical Decision Making Before Extended Pleurectomy Decortication in Malignant Pleural Mesothelioma.

Robert A Belderbos, Alexander P W M Maat, Sara J Baart, Eva V E Madsen, Ad J J C Bogers, Robin Cornelissen, Joachim G J V Aerts, Edris A F Mahtab, Jan H von der Thüsen.

   Introduction: The role of surgery for early stage malignant pleural mesothelioma (MPM) remains controversial. Current expert opinion is only to treat patients surgically as part of multimodality therapy. It is still challenging to identify patients who will not benefit from surgery. We specifically evaluated tumor-related parameters in combination with clinical parameters to identify prognostic markers for survival.
Methods: Clinical data of 27 consecutive patients with MPM treated with extended pleurectomy and decortication within a multimodality approach were collected and analyzed. Several tumor (immuno-)histopathologic characteristics were determined on resected tumor material, among which MTAP and Ki67 (MIB-1). Univariable and multivariable analyses served to correlate clinical and tumor-related parameters to overall survival (OS) and progression-free survival (PFS).
Results: The median PFS (mPFS) was 15.3, and the median OS (mOS) was 26.5 months. Patients with a Ki67 score greater than 10% had a significantly shorter PFS (mPFS = 8.81 versus 25.35 mo, p = 0.001) and OS (mOS 19.7 versus 44.5 mo, p = 0.002) than those with a Ki67 score less than or equal to 10. Receiver operating characteristic curve analysis for Ki67 revealed an area under the curve of 0.756 with a sensitivity of 90% and specificity of 71% for a cutoff of 10% for Ki67. Patients with loss of MTAP had a significantly shorter mPFS (9 versus 21.1 mo, p = 0.014) and mOS (19.7 versus 42.6 mo, p = 0.047) than those without MTAP loss.
Conclusions: In our study, Ki67 was prognostic for OS and PFS in patients with MPM treated with extended pleurectomy/decortication in a multimodality approach. Determination of Ki67 before surgery combined with specific clinical parameters could assist in clinical decision making by identifying patients, with high Ki67, who are unlikely to benefit from surgery.

Keywords:  Extended pleurectomy decortication; MTAP; Malignant pleural mesothelioma; Prognostic marker; ki-67

DOI:  https://doi.org/10.1016/j.jtocrr.2021.100155
Ann Thorac Surg. 2021 Sep 27. pii: S0003-4975(21)01670-2. [Epub ahead of print]

Inhibition of CDK4/6 Overcomes Primary Resistance to PD-1 Blockade in Malignant Mesothelioma.

Hee-Jin Jang, Cynthia Y Truong, Eric M Lo, Hudson M Holmes, Daniela Ramos, Maheshwari Ramineni, Ju-Seog Lee, Daniel Y Wang, Massimo Pietropaolo, R Taylor Ripley, Bryan M Burt, Hyun-Sung Lee.

   BACKGROUND: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remain unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.
METHODS: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (four responders and four non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model.
RESULTS: Immunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion of CDKN2A was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by CDK4/6 inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a(-/-) AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 or CDK4/6 inhibitor alone.
CONCLUSIONS: We identified a therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in more than 40% of patients with MPM who demonstrate loss of CDKN2A.

Keywords:  CDK4/6 inhibitor; CDKN2A; immune checkpoint inhibitors; mesothelioma; systems immunology

DOI:  https://doi.org/10.1016/j.athoracsur.2021.08.054
JTO Clin Res Rep. 2021 Jun;2(6): 100178

Phase 2 Study of YS110, a Recombinant Humanized Anti-CD26 Monoclonal Antibody, in Japanese Patients With Advanced Malignant Pleural Mesothelioma.

Kazuhiko Nakagawa, Takashi Kijima, Morihito Okada, Masahiro Morise, Motoyasu Kato, Katsuya Hirano, Nobukazu Fujimoto, Mitsuhiro Takenoyama, Hiroshi Yokouchi, Yuichiro Ohe, Toyoaki Hida, Keisuke Aoe, Takumi Kishimoto, Masato Hirokawa, Hironori Matsuki, Yutaro Kaneko, Taketo Yamada, Chikao Morimoto, Masayuki Takeda.

   Introduction: YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study.
Methods: The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest).
Results: The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab-groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths.
Conclusions: The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated.

Keywords:  CD26; Japanese; Malignant mesothelioma; Phase 2; YS110

DOI:  https://doi.org/10.1016/j.jtocrr.2021.100178
JTO Clin Res Rep. 2021 Mar;2(3): 100135

Clinical Efficacy and Safety of Nivolumab in Japanese Patients With Malignant Pleural Mesothelioma: 3-Year Results of the MERIT Study.

Nobukazu Fujimoto, Morihito Okada, Takashi Kijima, Keisuke Aoe, Terufumi Kato, Kazuhiko Nakagawa, Yuichiro Takeda, Toyoaki Hida, Kuninobu Kanai, Jun Hirano, Yuichiro Ohe.

   Introduction: We examined the long-term efficacy and safety of nivolumab, a human monoclonal antibody that inhibits interactions between the programmed cell death protein-1 receptor and its ligands (programmed death-ligand 1 and programmed death-ligand 2), in Japanese patients with malignant pleural mesothelioma (MPM).
Methods: Japanese patients with previously treated MPM (one or two regimens) were enrolled in a single-arm, phase 2 study and received nivolumab intravenously 240 mg every 2 weeks until progressive disease or unacceptable toxicity. The primary end point was the centrally assessed objective response rate. Other end points included overall survival (OS), progression-free survival (PFS), treatment-related adverse events, and patient-reported outcomes (Lung Cancer Symptom Scale for mesothelioma and EuroQOL visual analog scale). Patient enrollment started on June 16, 2016. Here, we report 3-year follow-up data (cutoff date: November 12, 2019).
Results: Thirty-four patients were enrolled. The centrally assessed objective response rate was previously reported (29.4%). The 2- and 3-year OS rates were 35.3% and 23.5%, respectively, and the corresponding PFS rates were 17.0% and 12.7%. Median OS and PFS were 17.3 and 5.9 months, respectively. Eight patients were alive at 3 years of follow-up. Nivolumab was well tolerated and no new safety signals were found. The patient-reported outcomes were maintained without marked deteriorations during the study.
Conclusions: Our results reveal clinically relevant long-term efficacy and safety of nivolumab for the treatment of MPM.

Keywords:  Japan; Malignant pleural mesothelioma; Nivolumab; Programmed death-1

DOI:  https://doi.org/10.1016/j.jtocrr.2020.100135
Interact Cardiovasc Thorac Surg. 2021 Sep 29. pii: ivab276. [Epub ahead of print]

Localized malignant mesothelioma in the stomach and mediastinum.

Tanita Drejer Jeppesen, Anette Højsgaard, Daniel Kjær, Thomas Decker Christensen.

  Localized malignant mesothelioma is rare. It has a histological pattern identical to diffuse malignant mesothelioma but without diffuse serosal spread. Localized malignant mesothelioma typically originates from the pleura, peritoneum or pericardium, but can occasionally develop from organs. Our cases represent what might be the largest mediastinal localized malignant mesothelioma described and the first presentation of the epithelioid type in the stomach of an adult.

Keywords:  Localized malignant mesothelioma; Mediastinum; Stomach

DOI:  https://doi.org/10.1093/icvts/ivab276
JTO Clin Res Rep. 2020 Nov;1(4): 100093

Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1-Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms.

Peter W Szlosarek, Melissa M Phillips, Iuliia Pavlyk, Jeremy Steele, Jonathan Shamash, James Spicer, Sanjeev Kumar, Simon Pacey, Xiaoxing Feng, Amanda Johnston, John Bomalaski, Graeme Moir, Kelvin Lau, Stephen Ellis, Michael Sheaff.

   Introduction: Pegargiminase (ADI-PEG 20; ADI) degrades arginine and potentiates pemetrexed (Pem) cytotoxicity in argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). We conducted a phase 1 dose-expansion study at the recommended phase 2 dose of ADI-PEG 20 with Pem and cisplatin (ADIPemCis), to further evaluate arginine-lowering therapy in ASS1-deficient MPM and explore the mechanisms of resistance.
Methods: A total of 32 patients with ASS1-deficient MPM (11 epithelioid; 10 biphasic;11 sarcomatoid) who were chemonaive received weekly intramuscular pegargiminase (36 mg/m2) with Pem (500 mg/m2) and cisplatin (75 mg/m2) intravenously, every 3 weeks (six cycles maximum). Maintenance pegargiminase was permitted until disease progression or withdrawal. Safety, pharmacodynamics, immunogenicity, and efficacy were determined. Biopsies were performed in progressing patients to explore the mechanisms of resistance to pegargiminase.
Results: The treatment was well tolerated. Most adverse events were of grade 1/2, whereas four nonhematologic grade 3/4 adverse events related to pegargiminase were reversible. Plasma arginine decreased whereas citrulline increased; this was maintained by 18 weeks of ADIPemCis therapy. The disease control rate in 31 assessed patients was 93.5% (n = 29 of 31; 95% confidence interval [CI]: 78.6%-99.2%), with a partial response rate of 35.5% (n = 11 of 31; 95% CI: 19.2%-54.6%). The median progression-free and overall survivals were 5.6 (95% CI: 4.0-6.0) and 10.1 (95% CI: 6.1-11.1) months, respectively. Progression biopsies on pegargiminase revealed a statistically significant influx of macrophages (n = 6; p = 0.0255) and patchy tumoral ASS1 reexpression (n = 2 of 6). In addition, we observed increased tumoral programmed death-ligand 1-an ADI-PEG 20 inducible gene-and the formation of CD3-positive T lymphocyte aggregates on disease progression (n = 2 of 5).
Conclusions: The dose expansion of ADIPemCis confirmed the high clinical activity and good tolerability in ASS1-deficient poor-prognosis mesothelioma, underpinning an ongoing phase 3 study (ClinicalTrials.govNCT02709512). Notably, resistance to pegargiminase correlated with marked macrophage recruitment and-along with the tumor immune microenvironment-warrants further study to optimize arginine deprivation for the treatment of mesothelioma.

Keywords:  ADIPemCis; ASS1; Arginine; Macrophages; Mesothelioma

DOI:  https://doi.org/10.1016/j.jtocrr.2020.100093
Biomolecules. 2021 Aug 25. pii: 1272. [Epub ahead of print]11(9):

Matrix Metalloproteinases as Biomarkers and Treatment Targets in Mesothelioma: A Systematic Review.

Danijela Štrbac, Vita Dolžan.

  Metalloproteinases (MMPs) have an important role in tissue remodeling and have been shown to have an effect on tumor progression, invasion, metastasis formation, and apoptosis in several tumors, including mesothelioma. Mesothelioma is a rare tumor arising from pleura and peritoneum and is frequently associated with asbestos exposure. We have performed a systematic search of PubMed.gov and ClinicalTrials.gov databases to retrieve and review three groups of studies: studies of MMPs expression in tumor tissue or body fluids in patients with mesothelioma, studies of MMPs genetic variability, and studies of MMPs as potential novel drug targets in mesothelioma. Several studies of MMPs in mesothelioma tissues reported a link between higher expression levels of commonly studied MMPs and clinical parameters, such as overall survival. Fewer studies have investigated genetic variability of MMP genes. Nevertheless, these studies suggested that certain genetic variants in MMP genes can have either protective or tumor-promoting effects on mesothelioma patients. MMPs have been also reported as novel drug targets, but so far no clinical trials of MMP inhibitors are registered in mesothelioma. In conclusion, MMPs play an important role in mesothelioma, but further studies are needed to elucidate the potentials of MMPs as biomarkers and drug targets in mesothelioma.

Keywords:  biomarker; drug target; genetic variability; mesothelioma; metalloproteinases

DOI:  https://doi.org/10.3390/biom11091272