The lack of effective therapeutic agents to treat malignant pleural mesothelioma leads to signifi... more The lack of effective therapeutic agents to treat malignant pleural mesothelioma leads to significant research interest in clinical trials of repositioned and novel therapeutics. This chapter presents a nonexhaustive summary of clinical trials related to mesothelioma utilizing different approaches ranging from vaccine immunotherapy to cancer stemness inhibition. Details of the intervention, phase, study population, design, and purpose are provided for each trial.
YTHDF1 is a well-characterized m6A reader protein that is essential for protein translation, stem... more YTHDF1 is a well-characterized m6A reader protein that is essential for protein translation, stem cell self-renewal, and embryonic development. YTHDF1 regulates target gene expression by diverse molecular mechanisms, such as promoting protein translation or modulating the stability of mRNA. The cellular levels of YTHDF1 are precisely regulated by a complicated transcriptional, post-transcriptional, and post-translational network. Very solid evidence supports the pivotal role of YTHDF1 in embryonic development and human cancer progression. In this review, we discuss how YTHDF1 influences both the physiological and pathological biology of the central nervous, reproductive and immune systems. Therefore we focus on some relevant aspects of the regulatory role played by YTHDF1 as gene expression, complex cell networking: stem cell self-renewal, embryonic development, and human cancers progression. We propose that YTHDF1 is a promising future cancer biomarker for detection, progression, a...
Lung cancer is the leading cause of cancer-related deaths worldwide. Despite the recent advent of... more Lung cancer is the leading cause of cancer-related deaths worldwide. Despite the recent advent of promising new targeted therapies, lung cancer diagnostic strategies still have difficulty in identifying the disease at an early stage. Therefore, the characterizations of more sensible and specific cancer biomarkers have become an important goal for clinicians. Circular RNAs are covalently close, endogenous RNAs without 5′ end caps or 3′poly (A) tails and have been characterized by high stability, abundance, and conservation as well as display cell/tissue/developmental stage-specific expressions. Numerous studies have confirmed that circRNAs act as microRNA (miRNA) sponges, RNA-binding protein, and transcriptional regulators; some circRNAs even act as translation templates that participate in multiple pathophysiological processes. Growing evidence have confirmed that circRNAs are involved in the pathogenesis of lung cancers through the regulation of proliferation and invasion, cell cyc...
Abstract Malignant pleural mesothelioma (MPM) is characterized by a notoriously poor prognosis th... more Abstract Malignant pleural mesothelioma (MPM) is characterized by a notoriously poor prognosis that is generally treated through a combination of radiotherapy, surgery, and chemotherapy. Though these approaches have shown benefit in other cancers, survival for MPM remains poor. Treatments for MPM may be palliative or curative, with the intention and approach used generally being dependent on the stage of the disease. Antifolates and platin-based chemotherapy remain the first-line therapy for MPM, though there is no standard second-line therapy. Due to this numerous new approaches are under investigation including immunotherapy and targeted therapy.
Endonuclease VIII-like (NEIL) 1 and 3 proteins eliminate oxidative DNA base damage and psoralen D... more Endonuclease VIII-like (NEIL) 1 and 3 proteins eliminate oxidative DNA base damage and psoralen DNA interstrand crosslinks through initiation of base excision repair. Current evidence points to a DNA replication associated repair function of NEIL1 and NEIL3, correlating with induced expression of the proteins in S/G2 phases of the cell cycle. However previous attempts to express and purify recombinant human NEIL3 in an active form have been challenging. In this study, both human NEIL1 and NEIL3 have been expressed and purified from E. coli, and the DNA glycosylase activity of these two proteins confirmed using single- and double-stranded DNA oligonucleotide substrates containing the oxidative bases, 5-hydroxyuracil, 8-oxoguanine and thymine glycol. To determine the biochemical role that NEIL1 and NEIL3 play during DNA replication, model replication fork substrates were designed containing the oxidized bases at one of three specific sites relative to the fork. Results indicate that w...
Aim: To report our experience with a multi-modality regimen involving pleurectomy/decortication, ... more Aim: To report our experience with a multi-modality regimen involving pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy in patients with malignant pleural mesothelioma. Method: Prospective study of all patients receiving this multimodality regimen at Guy's & St Thomas' hospital between September 2004 and August 2010. All patients had pleurectomy/ decortication through thoracotomy, received prophylactic radiotherapy postoperatively (21 Gy in 3 fractions) and completed adjuvant chemotherapy (pemetrexed and cisplatin). Nine patients underwent extended resection involving diaphragm (n = 4), lobectomy (n = 3), segmentectomy (n = 2) or SVC (n = 1). All were followed up in the clinic at 1, 6 months and then 6 monthly. Result: Thirty-nine patients completed the multimodality therapy (100%). Thirty day mortality was nil. Ten patients (25.6%) experienced complications: persistent air leak (n = 6, 15%), chylothorax (n = 4, 10%), ARDS (n = 1, 2.5%). Sixteen patients died and 23 patients are still alive at follow-up. Median survival is 29.5 months (CI 19.7 39.2 months), one-year survival is 91.8 % and 2-year survival 65.5%. Macroscopically complete resection (R0-R1) is significantly associated with longer survival versus non-radical resection (R2) (median survival 45.1 months versus 21.1 months, p = 0.005). Patients with epithelioid histology (n = 27) tend to have longer survival than patients with biphasic/sarcomatoid histology (n = 12) (median survival 42.1 months versus 22.8 months, p = 0.069). Conclusion: Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy is a well tolerated multi-modality regimen associated with low mortality and morbidity. This therapeutic plan compares favourably with other regimens including extrapleural pneumonectomy and radical radiotherapy.
Malignant mesothelioma (MM) still remains a therapeutic and diagnostic problem to which new thera... more Malignant mesothelioma (MM) still remains a therapeutic and diagnostic problem to which new therapeutic perspectives are being continuously tried and tested. Three different primary cultures (MMGe-1, MES MM 98, and MES 1) and one immortalized cell line (MSTO 211 H) of human MM were studied in order to evaluate the HER-2/neu expression. Three out of four cell lines showed a different level of c-erbB-2 expression, the highest being detected on the MSTO 211 H cell line (fibroblastic phenotype), whereas MMGe-1 resulted negative. The effect of the anti-HER-2/neu antibody (Trastuzumab) alone, and in combination with cisplatin (CDDP) at different doses (ranging from 0.1 to 100 microg/ml), was studied on all the c-erB-2 positive cell lines. Trastuzumab was able to inhibit cell proliferation in a time-dependent manner, with growth inhibition also obtained at low concentrations (0.1-1 microg/ml). Combined treatment with Trastuzumab (10 microg/ml) and CDDP (1 microg/ml) showed synergism. Our results were encouraging, and suggest a rationale for further investigations in a clinical setting.
Malignant mesothelioma (MMe) is a rare neoplasm with few therapeutic options available. The lands... more Malignant mesothelioma (MMe) is a rare neoplasm with few therapeutic options available. The landscape of effective therapy for this disease remained unchanged in the last two decades. Recently, however, the introduction of Immune Checkpoint Inhibitors (ICIs) led to small, but nevertheless, promising improvements. However, many efforts are still needed to radically improve the prognosis of MMe. In this review, we analyze all those therapeutic strategies for MMe that are still in a preclinical or early clinical phase of development. In particular, we focus on novel antiangiogenic drugs and their possible combination with immunotherapy. Furthermore, we describe also more complex strategies such as microRNA-loaded vectors, oncolytic viruses, and engineered lymphocytes.
Background: Malignant pleural mesothelioma is a rare disease known to be resistant to conventiona... more Background: Malignant pleural mesothelioma is a rare disease known to be resistant to conventional therapies. A better understanding of mesothelioma biology may provide the rationale for new therapeutic strategies. In this regard, tumor cell lines development has been an important tool to study the biological properties of many tumors. However all the cell lines established so far were grown in medium containing at least 10 % serum, and it has been shown that primary cell lines cultured under these conditions lose their ability to differentiate, acquire gene expression profiles that differ from that of tissue specific stem cells or the primary tumor they derive from, and in some cases are neither clonogenic nor tumorigenic. Our work was aimed to establish from fresh human pleural mesothelioma samples cell cultures maintaining tumorigenic properties. Methods: The primary cell cultures, obtained from four human pleural mesotheliomas, were expanded in vitro in a low serum proliferation...
Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cau... more Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs) have been implicated in the initiation and progression of various cancers. LncRNA-AC087588.2 (ENSG00000274976) is a novel lncRNA that is abnormally expressed in diverse cancer types, including LUAD. However, the clinical significance, prognostic value, diagnostic value, immune role, and the potential biological function of AC087588.2 LUAD remain elusive. In this study, we found that AC087588.2 was upregulated and associated with a poor prognosis in LUAD. In addition, univariate and multivariate Cox regression analysis indicated that AC087588.2 could be an independent prognostic factor for LUAD. Functionally, the knockdown of AC087588.2 restrained LUAD cell proliferation and migration in vitro. Finally, we constructed a ceRNA network that included hsa-miR-30a-5p and four mRNAs (ANLN, POLR3G, EHBP1, and ERO1A) specific t...
The lack of effective therapies remains one of the main challenges for malignant pleural mesothel... more The lack of effective therapies remains one of the main challenges for malignant pleural mesothelioma (MPM). In this perspective, drug repositioning could accelerate the identification of novel treatments. We screened 1170 FDA-approved drugs on a SV40-immortalized mesothelial (MeT-5A) and five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) cell lines. Biological assays were carried out for 41 drugs, showing the highest cytotoxicity and for whom there were a complete lack of published literature in MPM. Cytotoxicity and caspase activation were evaluated with commercially available kits and cell proliferation was assayed using MTT assay and by clonogenic activity with standard protocols. Moreover, the five most effective drugs were further evaluated on patient-derived primary MPM cell lines. The most active molecules were cephalomannine, ouabain, alexidine, thonzonium bromide, and emetine. Except for alexidine, these drugs inhibited the clonogenic ability and caspase activati...
Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cau... more Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. Long noncoding RNAs (lncRNAs) have been implicated in the initiation and progression of various cancers. LncRNA-AC099850.3 is a novel lncRNA that is abnormally expressed in diverse cancer types including LUAD. However, the clinical significance, prognostic value, diagnostic value, immune role, and potential biological function of AC099850.3 LUAD remain elusive. In this study, we found that AC099850.3 was highly expressed in LUAD and associated with an advanced tumor stage, poor prognosis, and immune infiltration. Receiver operating curve analysis revealed the significant diagnostic ability of AC099850.3 (AUC=0.888). Functionally, the knockdown of AC099850.3 restrained LUAD cell proliferation and migration in vitro. Finally, we constructed a competitive endogenous RNAs (ceRNA) network that included hsa-miR-101-3p and 4 mRNAs (ESPL1, AURKB, BUB3, and ...
Oxidoreductase protein disulphide isomerases (PDI) are involved in the regulation of a variety of... more Oxidoreductase protein disulphide isomerases (PDI) are involved in the regulation of a variety of biological processes including the modulation of endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER-mitochondria communication and the balance between pro-survival and pro-death pathways. In the current study the role of the PDIA1 family member in breast carcinogenesis was investigated by measuring ROS generation, mitochondrial membrane disruption, ATP production and HLA-G protein levels on the surface of the cellular membrane in the presence or absence of PDIA1. The results showed that this enzyme exerted pro-apoptotic effects in estrogen receptor (ERα)-positive breast cancer MCF-7 and pro-survival in triple negative breast cancer (TNBC) MDA-MB-231 cells. ATP generation was upregulated in PDIA1-silenced MCF-7 cells and downregulated in PDIA1-silenced MDA-MB-231 cells in a manner dependent on the cellular redox status. Furthermore, MCF-7 and MDA-MB-231 cells in the presence of PDIA1 expressed higher surface levels of the non-classical human leukocyte antigen (HLA-G) under oxidative stress conditions. Evaluation of the METABRIC datasets showed that low PDIA1 and high HLA-G mRNA expression levels correlated with longer survival in both ERα-positive and ERα-negative stage 2 breast cancer patients. In addition, analysis of the PDIA1 vs. the HLA-G mRNA ratio in the subgroup of the living stage 2 breast cancer patients exhibiting low PDIA1 and high HLA-G mRNA levels revealed that the longer the survival time of the ratio was high PDIA1 and low HLA-G mRNA and occurred predominantly in ERα-positive breast cancer patients whereas in the same subgroup of the ERα-negative breast cancer mainly this ratio was low PDIA1 and high HLA-G mRNA. Taken together these results provide evidence supporting the view that PDIA1 is linked to several hallmarks of breast cancer pathways including the process of antigen processing and presentation and tumor immunorecognition.
Background Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the pleura, mainly r... more Background Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the pleura, mainly related to asbestos exposure. As in other solid tumors, malignant cells exhibit high glucose uptake and glycolytic rates with increased lactic acid efflux into the interstitial space. Lactate transport into and out of cells, crucial to maintaining intracellular pH homeostasis and glycolysis, is carried out by monocarboxylate transporters (MCTs) and the chaperone basigin (CD147). We set out to examine the clinical significance of basigin, MCT1 and MCT4 in the context of MPM and to evaluate their expression in relation to the evolution of the disease. Methods We used immunohistochemistry to measure the expression of basigin, MCT1 and MCT4 in a cohort of 135 individuals with MPM compared to a series of 15 non-MPM pleura specimens. Moreover, by Kaplan–Meier and Cox analyses we evaluated whether an expression over the average of these markers could be associated with the patients’ overall surv...
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jan 14, 2015
Dysregulation of long noncoding RNAs (lncRNAs) has been regarded as a primary feature of several ... more Dysregulation of long noncoding RNAs (lncRNAs) has been regarded as a primary feature of several human cancers. However, the genome-wide expression and functional significance of lncRNAs in non-small cell lung carcinomas (NSCLC) remains unclear. The aim of this study was to identify novel lncRNAs that may play an important role in contributing to NSCLC pathogenesis. We performed an integrative analysis of two NSCLC microarray datasets comprising 165 and 90 patients, respectively. The candidate lncRNAs were identified using the GSE19188 dataset, and then confirmed in the GSE18842 dataset. In addition, an independent cohort of 73 clinical samples were analyzed to validate the selected lncRNAs by quantitative real-time PCR analysis (qRT-PCR). With microarray gene expression analysis, we identified and validated a list of 64 lncRNAs significantly dysregulated in NSCLC tumors compared with normal lung tissues; and a panel of 181 lncRNAs that were specific to histological subtypes of NSCL...
IMPORTANCE Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) ar... more IMPORTANCE Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments. OBJECTIVE To directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003. DESIGN, SETTING, AND PARTICIPANTS This comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021. MAIN OUTCOMES AND MEASURES Patient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT. RESULTS A total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, −0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048). CONCLUSIONS AND RELEVANCE This comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial. Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the (continued) Key Points Question Are frontline therapies Open Access. This is an open access article distributed under the terms of the CC-BY License.
The lack of effective therapeutic agents to treat malignant pleural mesothelioma leads to signifi... more The lack of effective therapeutic agents to treat malignant pleural mesothelioma leads to significant research interest in clinical trials of repositioned and novel therapeutics. This chapter presents a nonexhaustive summary of clinical trials related to mesothelioma utilizing different approaches ranging from vaccine immunotherapy to cancer stemness inhibition. Details of the intervention, phase, study population, design, and purpose are provided for each trial.
YTHDF1 is a well-characterized m6A reader protein that is essential for protein translation, stem... more YTHDF1 is a well-characterized m6A reader protein that is essential for protein translation, stem cell self-renewal, and embryonic development. YTHDF1 regulates target gene expression by diverse molecular mechanisms, such as promoting protein translation or modulating the stability of mRNA. The cellular levels of YTHDF1 are precisely regulated by a complicated transcriptional, post-transcriptional, and post-translational network. Very solid evidence supports the pivotal role of YTHDF1 in embryonic development and human cancer progression. In this review, we discuss how YTHDF1 influences both the physiological and pathological biology of the central nervous, reproductive and immune systems. Therefore we focus on some relevant aspects of the regulatory role played by YTHDF1 as gene expression, complex cell networking: stem cell self-renewal, embryonic development, and human cancers progression. We propose that YTHDF1 is a promising future cancer biomarker for detection, progression, a...
Lung cancer is the leading cause of cancer-related deaths worldwide. Despite the recent advent of... more Lung cancer is the leading cause of cancer-related deaths worldwide. Despite the recent advent of promising new targeted therapies, lung cancer diagnostic strategies still have difficulty in identifying the disease at an early stage. Therefore, the characterizations of more sensible and specific cancer biomarkers have become an important goal for clinicians. Circular RNAs are covalently close, endogenous RNAs without 5′ end caps or 3′poly (A) tails and have been characterized by high stability, abundance, and conservation as well as display cell/tissue/developmental stage-specific expressions. Numerous studies have confirmed that circRNAs act as microRNA (miRNA) sponges, RNA-binding protein, and transcriptional regulators; some circRNAs even act as translation templates that participate in multiple pathophysiological processes. Growing evidence have confirmed that circRNAs are involved in the pathogenesis of lung cancers through the regulation of proliferation and invasion, cell cyc...
Abstract Malignant pleural mesothelioma (MPM) is characterized by a notoriously poor prognosis th... more Abstract Malignant pleural mesothelioma (MPM) is characterized by a notoriously poor prognosis that is generally treated through a combination of radiotherapy, surgery, and chemotherapy. Though these approaches have shown benefit in other cancers, survival for MPM remains poor. Treatments for MPM may be palliative or curative, with the intention and approach used generally being dependent on the stage of the disease. Antifolates and platin-based chemotherapy remain the first-line therapy for MPM, though there is no standard second-line therapy. Due to this numerous new approaches are under investigation including immunotherapy and targeted therapy.
Endonuclease VIII-like (NEIL) 1 and 3 proteins eliminate oxidative DNA base damage and psoralen D... more Endonuclease VIII-like (NEIL) 1 and 3 proteins eliminate oxidative DNA base damage and psoralen DNA interstrand crosslinks through initiation of base excision repair. Current evidence points to a DNA replication associated repair function of NEIL1 and NEIL3, correlating with induced expression of the proteins in S/G2 phases of the cell cycle. However previous attempts to express and purify recombinant human NEIL3 in an active form have been challenging. In this study, both human NEIL1 and NEIL3 have been expressed and purified from E. coli, and the DNA glycosylase activity of these two proteins confirmed using single- and double-stranded DNA oligonucleotide substrates containing the oxidative bases, 5-hydroxyuracil, 8-oxoguanine and thymine glycol. To determine the biochemical role that NEIL1 and NEIL3 play during DNA replication, model replication fork substrates were designed containing the oxidized bases at one of three specific sites relative to the fork. Results indicate that w...
Aim: To report our experience with a multi-modality regimen involving pleurectomy/decortication, ... more Aim: To report our experience with a multi-modality regimen involving pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy in patients with malignant pleural mesothelioma. Method: Prospective study of all patients receiving this multimodality regimen at Guy's & St Thomas' hospital between September 2004 and August 2010. All patients had pleurectomy/ decortication through thoracotomy, received prophylactic radiotherapy postoperatively (21 Gy in 3 fractions) and completed adjuvant chemotherapy (pemetrexed and cisplatin). Nine patients underwent extended resection involving diaphragm (n = 4), lobectomy (n = 3), segmentectomy (n = 2) or SVC (n = 1). All were followed up in the clinic at 1, 6 months and then 6 monthly. Result: Thirty-nine patients completed the multimodality therapy (100%). Thirty day mortality was nil. Ten patients (25.6%) experienced complications: persistent air leak (n = 6, 15%), chylothorax (n = 4, 10%), ARDS (n = 1, 2.5%). Sixteen patients died and 23 patients are still alive at follow-up. Median survival is 29.5 months (CI 19.7 39.2 months), one-year survival is 91.8 % and 2-year survival 65.5%. Macroscopically complete resection (R0-R1) is significantly associated with longer survival versus non-radical resection (R2) (median survival 45.1 months versus 21.1 months, p = 0.005). Patients with epithelioid histology (n = 27) tend to have longer survival than patients with biphasic/sarcomatoid histology (n = 12) (median survival 42.1 months versus 22.8 months, p = 0.069). Conclusion: Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy is a well tolerated multi-modality regimen associated with low mortality and morbidity. This therapeutic plan compares favourably with other regimens including extrapleural pneumonectomy and radical radiotherapy.
Malignant mesothelioma (MM) still remains a therapeutic and diagnostic problem to which new thera... more Malignant mesothelioma (MM) still remains a therapeutic and diagnostic problem to which new therapeutic perspectives are being continuously tried and tested. Three different primary cultures (MMGe-1, MES MM 98, and MES 1) and one immortalized cell line (MSTO 211 H) of human MM were studied in order to evaluate the HER-2/neu expression. Three out of four cell lines showed a different level of c-erbB-2 expression, the highest being detected on the MSTO 211 H cell line (fibroblastic phenotype), whereas MMGe-1 resulted negative. The effect of the anti-HER-2/neu antibody (Trastuzumab) alone, and in combination with cisplatin (CDDP) at different doses (ranging from 0.1 to 100 microg/ml), was studied on all the c-erB-2 positive cell lines. Trastuzumab was able to inhibit cell proliferation in a time-dependent manner, with growth inhibition also obtained at low concentrations (0.1-1 microg/ml). Combined treatment with Trastuzumab (10 microg/ml) and CDDP (1 microg/ml) showed synergism. Our results were encouraging, and suggest a rationale for further investigations in a clinical setting.
Malignant mesothelioma (MMe) is a rare neoplasm with few therapeutic options available. The lands... more Malignant mesothelioma (MMe) is a rare neoplasm with few therapeutic options available. The landscape of effective therapy for this disease remained unchanged in the last two decades. Recently, however, the introduction of Immune Checkpoint Inhibitors (ICIs) led to small, but nevertheless, promising improvements. However, many efforts are still needed to radically improve the prognosis of MMe. In this review, we analyze all those therapeutic strategies for MMe that are still in a preclinical or early clinical phase of development. In particular, we focus on novel antiangiogenic drugs and their possible combination with immunotherapy. Furthermore, we describe also more complex strategies such as microRNA-loaded vectors, oncolytic viruses, and engineered lymphocytes.
Background: Malignant pleural mesothelioma is a rare disease known to be resistant to conventiona... more Background: Malignant pleural mesothelioma is a rare disease known to be resistant to conventional therapies. A better understanding of mesothelioma biology may provide the rationale for new therapeutic strategies. In this regard, tumor cell lines development has been an important tool to study the biological properties of many tumors. However all the cell lines established so far were grown in medium containing at least 10 % serum, and it has been shown that primary cell lines cultured under these conditions lose their ability to differentiate, acquire gene expression profiles that differ from that of tissue specific stem cells or the primary tumor they derive from, and in some cases are neither clonogenic nor tumorigenic. Our work was aimed to establish from fresh human pleural mesothelioma samples cell cultures maintaining tumorigenic properties. Methods: The primary cell cultures, obtained from four human pleural mesotheliomas, were expanded in vitro in a low serum proliferation...
Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cau... more Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs) have been implicated in the initiation and progression of various cancers. LncRNA-AC087588.2 (ENSG00000274976) is a novel lncRNA that is abnormally expressed in diverse cancer types, including LUAD. However, the clinical significance, prognostic value, diagnostic value, immune role, and the potential biological function of AC087588.2 LUAD remain elusive. In this study, we found that AC087588.2 was upregulated and associated with a poor prognosis in LUAD. In addition, univariate and multivariate Cox regression analysis indicated that AC087588.2 could be an independent prognostic factor for LUAD. Functionally, the knockdown of AC087588.2 restrained LUAD cell proliferation and migration in vitro. Finally, we constructed a ceRNA network that included hsa-miR-30a-5p and four mRNAs (ANLN, POLR3G, EHBP1, and ERO1A) specific t...
The lack of effective therapies remains one of the main challenges for malignant pleural mesothel... more The lack of effective therapies remains one of the main challenges for malignant pleural mesothelioma (MPM). In this perspective, drug repositioning could accelerate the identification of novel treatments. We screened 1170 FDA-approved drugs on a SV40-immortalized mesothelial (MeT-5A) and five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) cell lines. Biological assays were carried out for 41 drugs, showing the highest cytotoxicity and for whom there were a complete lack of published literature in MPM. Cytotoxicity and caspase activation were evaluated with commercially available kits and cell proliferation was assayed using MTT assay and by clonogenic activity with standard protocols. Moreover, the five most effective drugs were further evaluated on patient-derived primary MPM cell lines. The most active molecules were cephalomannine, ouabain, alexidine, thonzonium bromide, and emetine. Except for alexidine, these drugs inhibited the clonogenic ability and caspase activati...
Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cau... more Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. Long noncoding RNAs (lncRNAs) have been implicated in the initiation and progression of various cancers. LncRNA-AC099850.3 is a novel lncRNA that is abnormally expressed in diverse cancer types including LUAD. However, the clinical significance, prognostic value, diagnostic value, immune role, and potential biological function of AC099850.3 LUAD remain elusive. In this study, we found that AC099850.3 was highly expressed in LUAD and associated with an advanced tumor stage, poor prognosis, and immune infiltration. Receiver operating curve analysis revealed the significant diagnostic ability of AC099850.3 (AUC=0.888). Functionally, the knockdown of AC099850.3 restrained LUAD cell proliferation and migration in vitro. Finally, we constructed a competitive endogenous RNAs (ceRNA) network that included hsa-miR-101-3p and 4 mRNAs (ESPL1, AURKB, BUB3, and ...
Oxidoreductase protein disulphide isomerases (PDI) are involved in the regulation of a variety of... more Oxidoreductase protein disulphide isomerases (PDI) are involved in the regulation of a variety of biological processes including the modulation of endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER-mitochondria communication and the balance between pro-survival and pro-death pathways. In the current study the role of the PDIA1 family member in breast carcinogenesis was investigated by measuring ROS generation, mitochondrial membrane disruption, ATP production and HLA-G protein levels on the surface of the cellular membrane in the presence or absence of PDIA1. The results showed that this enzyme exerted pro-apoptotic effects in estrogen receptor (ERα)-positive breast cancer MCF-7 and pro-survival in triple negative breast cancer (TNBC) MDA-MB-231 cells. ATP generation was upregulated in PDIA1-silenced MCF-7 cells and downregulated in PDIA1-silenced MDA-MB-231 cells in a manner dependent on the cellular redox status. Furthermore, MCF-7 and MDA-MB-231 cells in the presence of PDIA1 expressed higher surface levels of the non-classical human leukocyte antigen (HLA-G) under oxidative stress conditions. Evaluation of the METABRIC datasets showed that low PDIA1 and high HLA-G mRNA expression levels correlated with longer survival in both ERα-positive and ERα-negative stage 2 breast cancer patients. In addition, analysis of the PDIA1 vs. the HLA-G mRNA ratio in the subgroup of the living stage 2 breast cancer patients exhibiting low PDIA1 and high HLA-G mRNA levels revealed that the longer the survival time of the ratio was high PDIA1 and low HLA-G mRNA and occurred predominantly in ERα-positive breast cancer patients whereas in the same subgroup of the ERα-negative breast cancer mainly this ratio was low PDIA1 and high HLA-G mRNA. Taken together these results provide evidence supporting the view that PDIA1 is linked to several hallmarks of breast cancer pathways including the process of antigen processing and presentation and tumor immunorecognition.
Background Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the pleura, mainly r... more Background Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the pleura, mainly related to asbestos exposure. As in other solid tumors, malignant cells exhibit high glucose uptake and glycolytic rates with increased lactic acid efflux into the interstitial space. Lactate transport into and out of cells, crucial to maintaining intracellular pH homeostasis and glycolysis, is carried out by monocarboxylate transporters (MCTs) and the chaperone basigin (CD147). We set out to examine the clinical significance of basigin, MCT1 and MCT4 in the context of MPM and to evaluate their expression in relation to the evolution of the disease. Methods We used immunohistochemistry to measure the expression of basigin, MCT1 and MCT4 in a cohort of 135 individuals with MPM compared to a series of 15 non-MPM pleura specimens. Moreover, by Kaplan–Meier and Cox analyses we evaluated whether an expression over the average of these markers could be associated with the patients’ overall surv...
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jan 14, 2015
Dysregulation of long noncoding RNAs (lncRNAs) has been regarded as a primary feature of several ... more Dysregulation of long noncoding RNAs (lncRNAs) has been regarded as a primary feature of several human cancers. However, the genome-wide expression and functional significance of lncRNAs in non-small cell lung carcinomas (NSCLC) remains unclear. The aim of this study was to identify novel lncRNAs that may play an important role in contributing to NSCLC pathogenesis. We performed an integrative analysis of two NSCLC microarray datasets comprising 165 and 90 patients, respectively. The candidate lncRNAs were identified using the GSE19188 dataset, and then confirmed in the GSE18842 dataset. In addition, an independent cohort of 73 clinical samples were analyzed to validate the selected lncRNAs by quantitative real-time PCR analysis (qRT-PCR). With microarray gene expression analysis, we identified and validated a list of 64 lncRNAs significantly dysregulated in NSCLC tumors compared with normal lung tissues; and a panel of 181 lncRNAs that were specific to histological subtypes of NSCL...
IMPORTANCE Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) ar... more IMPORTANCE Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments. OBJECTIVE To directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003. DESIGN, SETTING, AND PARTICIPANTS This comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021. MAIN OUTCOMES AND MEASURES Patient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT. RESULTS A total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, −0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048). CONCLUSIONS AND RELEVANCE This comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial. Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the (continued) Key Points Question Are frontline therapies Open Access. This is an open access article distributed under the terms of the CC-BY License.
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Papers by Luciano Mutti