Journal of Experimental & Clinical Cancer Research

Our medical research library holds 25 studies published in Journal of Experimental & Clinical Cancer Research (2008–2025). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 25 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: BioMed Central
• Published: 1982 to the present, England
• Language: English
• ISSN: 0392-9078 (print), 1756-9966 (electronic)
• Its record in the NLM Catalog

2020s

• A combination of PD-1 and TIGIT immune checkpoint inhibitors elicits a strong anti-tumour response in mesothelioma. H. Shi, T.K. Yu, B. Johnson, et al. 2025;44(1):51. PubMed · Publisher · Free full text

  Abstract

  Background: Finding effective and curative treatment for mesothelioma remains challenging. While the introduction of immunotherapy combinations using ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have offered hope for some patients, a large proportion of mesothelioma cases, particularly the epithelial subtype, have minimal benefit from this.

  Methods: Our study was inspired by the results of the AdvanTG-105 phase I clinical trial, which showed partial response with anti-TIGIT/PD-1 treatment in two epithelioid mesothelioma patients. Here, we conducted a comprehensive in vivo experiment involving eight animal treatment groups administered with either PBS (control group), cisplatin/pemetrexed, anti-PD-1, anti-PD-1 + anti-CTLA-4, anti-TIGIT, anti-PD-1 + anti-TIGIT, anti-PD-1 + anti-CTLA-4 + anti-TIGIT, and cisplatin/pemetrexed + anti-PD-1 + anti-TIGIT.

  Results: Our results indicate that animals receiving anti-PD-1 + TIGIT exhibited a superior anti-tumour response, with 90% of the treatment group exhibiting an objective response, compared to 60%, 20% and 40% for the standard-of-care anti-PD-1 + CTLA-4, single-agent anti-PD-1 and cisplatin/pemetrexed treatment groups, respectively. Animals receiving anti-PD-1 + TIGIT displayed a significantly reduced average tumour size, with improved weight and survival rates, and fewer adverse effects than those receiving anti-PD-1 + CTLA-4 treatment. Anti-PD-1 + TIGIT-treated animals achieved complete tumour regression, with heightened effector CD8 + T cell and NK cell activity, remaining tumour-free for over 300 days without immune-related adverse events. After initial tumour elimination, anti-PD-1 + TIGIT-treated animals showed no tumour regrowth in the rechallenge experiment.

  Conclusion: These findings provide rationale for the development of an anti-PD-1 + TIGIT combination immunotherapy trial for mesothelioma patients.

  © 2025. The Author(s).

• CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma. F. Torricelli, B. Donati, V. Manicardi, et al. 2025;44(1):256. PubMed · Publisher · Free full text

  Abstract

  Introduction: Diffuse Pleural Mesothelioma (DPM) is a rare and incurable cancer. Immune checkpoint inhibitors (ICIs) marked some advances but only for a limited fraction of patients. Improving response prediction to ICIs is currently a clinical need in DPM. Deletion of CDKN2A gene, in chr9p21.3, is one of the most frequent alterations in DPM. As in other settings, deletion of CDKN2A locus has been associated with an immunosuppressive phenotype. Here we investigated the consequences of CDKN2A deletion (CDKN2Adel) on the tridimensional organization and function of immune infiltrate in DPM.

  Methods: A retrospective cohort of 89 DPMs was analyzed and assessed for CDKN2Adel through digital droplet PCR. Immune-profiling was assessed by analyzing 770 immune-related genes by digital profiling. Finally, morphologically resolved, high-dimensional transcriptomic approach was used to reconstruct the spatial architecture of immune-tumor interaction in wild-type and deleted FFPE samples.

  Results: CDKN2Adel was detected in 41.5% of DPMs and was associated with reduced survival (p = 0.04). Bulk gene expression identified 373 differentially expressed genes, of which 98.6% were downregulated in CDKN2Adel samples. These genes were enriched in several immune categories, suggesting significant immune deprivation in deleted tumors. Deconvolution analysis confirmed a major depletion of infiltrating immune cells including effector populations. Spatial transcriptomics revealed that this immunosuppressive phenotype was different according to histotype and prominent in the sarcomatoid lesions.

  Conclusion: These data demonstrated that CDKN2Adel deeply affects the spatial organization of immune microenvironment by depleting immune-signaling and reducing or preventing immune infiltration, supporting the potential implementation of this alteration as ICIs predictive biomarker in DPM.

  © 2025. The Author(s).

• DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy. M.F. Lofiego, R. Tufano, E. Bello, et al. 2025;44(1):58. PubMed · Publisher · Free full text

  Abstract

  Background: Co-targeting of immune checkpoint inhibitors (ICI) CTLA-4 and PD-1 has recently become the new first-line standard of care therapy of pleural mesothelioma (PM) patients, with a significant improvement of overall survival (OS) over conventional chemotherapy. The analysis by tumor histotype demonstrated greater efficacy of ICI therapy compared to standard chemotherapy in non-epithelioid (non-E) vs. epithelioid (E) PM, although some E PM patients also benefit from ICI treatment. This evidence suggests that molecular tumor features, beyond histotype, could be relevant to improve the efficacy of ICI therapy in PM. Among these, tumor DNA methylation emerges as a promising factor to explore, due to its potential role in driving the immune phenotype of cancer cells. Therefore, we utilized a panel of cultured PM cells of different histotype to provide preclinical evidence supporting the role of the tumor methylation landscape, along with its pharmacologic modulation, to prospectively improve the efficacy of ICI therapy of PM patients.

  Methods: The methylome profile (EPIC array) of distinct E (n = 5) and non-E (n = 9) PM cell lines was analyzed, followed by integrated analysis with their associated transcriptomic profile (Clariom S array), before and after in vitro treatment with the DNA hypomethylating agent (DHA) guadecitabine. The most variable methylated probes were selected to calculate the methylation score (CIMP index) for each cell line at baseline. Genes that were differentially expressed (DE) and differentially methylated (DM) were then selected for gene ontology analysis.

  Results: The CIMP index stratified PM cell lines into two distinct classes, CIMP (hyper-methylated; n = 7) and LOW (hypo-methylated; n = 7), regardless of their E or non-E histotype. Integrated methylome and transcriptome analyses revealed that CIMP PM cells exhibited a substantial number of hyper-methylated, silenced genes, which negatively impacted their immune phenotype compared to LOW PM cells. Treatment with DHA reverted the methylation-driven immune-compromised profile of CIMP PM cells and enhanced the constitutive immune-favorable profile of LOW PM cells.

  Conclusion: The study highlighted the relevance of DNA methylation in shaping the constitutive immune classification of PM cells, independent of their histological subtypes. The identified role of DHA in shifting the phenotype of PM cells towards an immune-favorable state highlights its potential for evaluation in phase I/II clinical trials investigating the efficacy of epigenetic-based ICI combinations to reverse cancer immune resistance mechanisms.

  © 2025. The Author(s).

• FL496, an FL118-derived small molecule, induces growth inhibition, senescence, and apoptosis of malignant pleural mesothelioma (MPM) cells, and exhibits anti-MPM tumor efficacy strikingly superior to the pemetrexed-cisplatin combination. I.A.M. Aljahdali, X. Ling, W. Wu, et al. 2025;44(1):293. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) responds poorly to chemotherapy and is a highly progressive malignancy with a median survival time of only 6-9 months. Therefore, the development of anti-MPM tumor agents with high efficacy and low toxicity is urgent and addresses an unmet need for MPM patients.

  Methods: Medicinal chemistry synthesis of small molecules based on the FL118 drug platform were further comparatively investigated using multiple MPM and osteosarcoma cell/tumor in vitro and/or in vivo models. The method includes cell viability assay, Western blot analysis, colony formation assay, immunocytochemical staining, β-galactosidase senescence staining, flow cytometry, DNA fragmentation cell death detection, vector-free CRISPR-Cas9-mediated gene knockout, bioinformatic analysis, FL496 efficacy determination using severe combined immunodeficiency (SCID) mice with human MPM tumor, and immunohistochemistry (IHC) analysis of MPM tumors.

  Results: Here, we report that we identified a novel FL118-derived small molecule (FL496). FL496 appears to be strikingly more effective in inhibiting MPM tumor growth in MPM tumor animal models than the currently most prevalent pemetrexed-cisplatin combination in the clinic. The treatment of MPM cells with FL496 rapidly induced p53 and p21 accumulation, and Rb and p-Rb inhibition, which were associated with MPM cell senescence and G1/G0 arrest and apoptosis. Knockout (KO) of the TP53/p53 gene decreased the ability of FL496 to inhibit MPM cell growth (i.e., increase FL496 IC50 values) and colony formation. FL496-treated MPM cells resulted in strong inhibition of the expression of survivin, Mcl-1, Bcl-2, Bcl-XL, and the induction of active caspase-3, cleaved PARP, and PUMA, which were further confirmed using MPM tumor tissues via IHC analysis. High survivin in MPM patients' tumors is associated with poor patient survival. Similar to FL118, FL496 treatment reduces DDX5 expression in MPM cells, but FL496 is more potent than FL118 in inhibiting MPM cell growth. Therefore, the mechanism of action (MOA) of FL496 overlaps with, but is likely beyond the scope of FL118 MOA, which needs further investigation.

  Conclusions: Together, these results indicate that FL496 is a promising anti-MPM small molecule, and its high anti-MPM potential is worthy of being further explored as a monotherapeutic agent to treat MPM patients in clinical trials.

  © 2025. The Author(s).

• miRNA-503 inhibition exerts anticancer effects and reduces tumor growth in mesothelioma. M. Piccioni, F. Di Meo, A. Valentino, et al. 2025;44(1):65. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant mesothelioma (MM) is a rare and aggressive form of cancer that affects the mesothelial surfaces, associated with exposure to asbestos fibres. To date, no cure is available for MM and therapeutically approved treatments are based on the use of platinum compounds often used in combination with other drugs. We have previously analysed the efficacy of a cisplatin/piroxicam (CDDP/P) combined treatment showing that this treatment was able to reduce in vivo tumor growth. Several studies reported that platinum-drug sensitivity in cancer is connected to modulation of the expression of non-coding RNAs. In this study we analysed if the CDDP/P treatment was able to modulate miRNAs expression in MM.

  Methods: miRNA sequencing performed on MSTO-211 H cells treated with CDDP with CDDP/P led us to identify miRNA-503 - downregulated by CDDP/P - as a novel miRNA that acts as an oncomiR in MM. The effect of miRNA-503 inhibition was evaluated in vitro in mesothelioma cells analysing apoptosis induction and reduction of cancer properties. Inhibition of miR-503 expression in vivo, was analysed in ectopic mouse model of MM by using LNP encapsulating anti-mir-503 and miR-503 expression was evaluated in human MM samples.

  Results: In vitro and in vivo analysis confirmed miR-503 acts as oncogene in MM since its inhibition was able to reduce cell cancer properties and tumor growth in ectopic mouse model of MM. Its expression was found upregulated in human MM patients compared to normal pleura. Bioinformatic analysis indicated BTG1, CCNG1, EDG1, and TIMP2 as putative target genes of miRNA-503. These genes showed an opposite expression compared to miR-503 levels both in cells and in MM samples. Finally, microarray analysis indicated that miR-503 inhibition affected the expression of the well-known MM biomarkers: CXCL8, SERPINE1 and Osteopontin.

  Conclusions: Our study is the first reporting an oncomiR role for miR-503 in MM and suggests that its inactivation could have a clinical value in MM patients. This study reveals that miRNA-503 acts as an oncomiR in MM suggesting that its inhibition, through LNP delivery, has the potential to be considered as a novel therapeutic strategy in MM.

  © 2025. The Author(s).

• Ecteinascidin synthetic analogues: a new class of selective inhibitors of transcription, exerting immunogenic cell death in refractory malignant pleural mesothelioma. I.C. Salaroglio, P. Aviles, J. Kopecka, et al. 2024;43(1):327. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma (MPM) is a highly chemo-refractory and immune-evasive tumor that presents a median overall survival of 12-14 months when treated with chemotherapy and immunotherapy. New anti-tumor therapies as well as the concomitant reactivation of immune destruction are urgently needed to treat patients with this tumor. The aim of this work is to investigate the potential effect of ecteinascidin derivatives as lurbinectedin as new first-line treatment option in MPM, alone and in combination with immunotherapy.

  Methods: The antitumor activity of ecteinascidin synthetic analogues: lurbinectedin, ecubectedin and PM54 was evaluated in an array of patient-derived MPM cells in terms of cell proliferation, cell cycle, apoptosis, DNA damage and repair. Immunoblot was used to assess the cGAS/STING pathway. ELISA and flow cytometry-based assays were used to evaluate immunogenic cell death parameters and the effect on the immunophenotype in autologous peripheral blood monocyte-MPM cells co-cultures. Patient-derived xenografts (PDX) in humanized mice were used to evaluate the efficacy of ecteinascidins in vivo.

  Results: Lurbinectedin, ecubectedin, and PM54 were effective in reducing cell proliferation and migration, as well as inducing S-phase cell cycle arrest and DNA damage in malignant pleural mesothelioma cells. These effects were more pronounced compared to the standard first-line treatment (platinum-based plus pemetrexed). Mechanistically, the drugs downregulated DNA repair genes, activated the cGAS/STING pathway, and promoted the release of pro-inflammatory cytokines. They also induced immunogenic cell death of mesothelioma cells, enhancing the activation of anti-tumor CD8+T-cells and natural killer cells while reducing tumor-tolerant T-regulatory cells and myeloid-derived suppressor cells in ex vivo co-cultures. These promising results were also observed in humanized patient-derived xenograft models, where the drugs were effective in reducing tumor growth and increasing the ratio anti-tumor/pro-tumor infiltrating immune populations, either alone or combined with the anti-PD-1L atezolizumab.

  Conclusions: Collectively, these findings reveal a previously unknown mechanism of action of ecteinascidins that merits further investigation for potential clinical applications in the treatment of MPM, as new first line treatment in monotherapy or in association with immunotherapy.

  © 2024. The Author(s).

• Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin. A. Ries, D. Flehberger, A. Slany, et al. 2023;42(1):27. PubMed · Publisher · Free full text

  Abstract

  Background: Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, PM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several malignancies. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on PM cells.

  Methods: Meso-CAFs were isolated from surgical specimens of PM patients and analyzed by array comparative genomic hybridization, next generation sequencing, transcriptomics and proteomics. Human PM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, as well as the response to small molecule inhibitors, cisplatin and pemetrexed treatment was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis.

  Results: Meso-CAFs show a normal diploid genotype without gene copy number aberrations typical for PM cells. They express CAF markers and lack PM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in significantly increased proliferation and migration of PM cells. A similar effect on PM cell growth and migration was induced by Meso-CAF-conditioned medium. Inhibition of c-Met with crizotinib, PI3K with LY-2940002 or WNT signaling with WNT-C59 significantly impaired the Meso-CAF-mediated growth stimulation of PM cells in co-culture at concentrations not affecting the PM cells alone. Meso-CAFs did not provide protection of PM cells against cisplatin but showed significant protection against the EGFR inhibitor erlotinib.

  Conclusions: Our study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on PM cell growth and migration, two key characteristics of PM aggressiveness, indicating a major role of Meso-CAFs in driving PM progression. Moreover, we identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for novel therapeutic strategies against PM.

  © 2023. The Author(s).

• Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy. A. Singh, N. Pruett, S. Dixit, et al. 2023;42(1):304. PubMed · Publisher · Free full text

  Abstract

  Background: Diffuse pleural mesothelioma (DPM) is an aggressive therapy-resistant cancer with unique molecular features. Numerous agents have been tested, but clinically effective ones remain elusive. Herein, we propose to use a small molecule CBL0137 (curaxin) that simultaneously suppresses nuclear factor-κB (NF-κB) and activates tumor suppressor p53 via targeting FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone critical for DNA repair.

  Methods: We used DPM cell lines, murine models (xeno- and allo-grafts), plus DPM patient samples to characterize anti-tumor effects of CBL0137 and to delineate specific molecular mechanisms.

  Results: We verified that CBL0137 induced cell cycle arrest and apoptosis. We also discovered that DPM is a FACT-dependent cancer with overexpression of both subunits structure-specific recognition protein 1 (SSRP1), a poor prognosis indicator, and suppressor of Ty 16 (SUPT16H). We defined several novel uses of CBL0137 in DPM therapy. In combination with cisplatin, CBL0137 exhibited additive anti-tumor activity compared to monotherapy. Similarly, CBL0137 (systemic) could be combined with other novel agents like microRNA-215 (intrapleural) as a more effective regimen. Importantly, we established that CBL0137 induces immunogenic cell death that contributes to activating immune response pathways in DPM. Therefore, when CBL0137 is combined with dual immune checkpoint inhibitors DPM tumor growth is significantly suppressed.

  Conclusions: We identified an unrecognized molecular vulnerability of DPM based on FACT dependency. CBL0137 alone and in several combinations with different therapeutics showed promising efficacy, including that of improved anti-tumor immunity. Overall, these preclinical findings suggest that CBL0137 could be ideally suited for use in DPM clinical trials.

  © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

• Artichoke phytocomplex modulates serum microRNAs in patients exposed to asbestos: a first step of a phase II clinical trial. P. Muti, A. Sacconi, C. Pulito, et al. 2022;41(1):255. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant pleural mesothelioma is a highly aggressive tumor associated with asbestos exposure. There are few effective treatment options for mesothelioma, and patients have a very poor prognosis. Mesothelioma has the potential to represent an appropriate disease to prevent because of its strong association with asbestos exposure and the long latency from exposure to the disease on-set.

  Methods: In the present study, we tested biological activity and toxicity of an artichoke freeze-dried extract (AWPC) as potential complementary preventive/early stage treatment agent for mesothelioma. This phase II clinical study then was conducted in 18 male-patients with evidence of radiographic characteristics related to asbestos exposure such as asbestosis or benign pleural disease as surrogate disease for mesothelioma clinical model.

  Results: We investigate AWPC biological activity assessing its effect on mesothelin serum level, a glycoprotein with low expression in normal mesothelial cells and high expression in mesothelioma and asbestos related diseases. We also assess the AWPC effect on circulating miRNAs, as novel biomarkers of both cancer risk and response to therapeutic targets. While we found a small and not significant effect of AWPC on mesothelin serum levels, we observed that AWPC intake modulated 11 serum miRNAs related to gene-pathways connected to mesothelioma etiology and development. In terms of toxicity, we also did not observe any severe adverse effects associated to AWPC treatment, only gastro-intestinal symptoms were reported by five study participants.

  Conclusions: We observed an interesting AWPC effect on miRNAs which targets modulate mesothelioma development. New and much larger clinical studies based on follow-up of workers exposed to asbestos are needed to corroborate the role of AWPC in prevention and early treatment of mesothelioma.

  Trial Registration: ClinicalTrials.gov, NCT02076672 . Registered 03/03/2014.

  © 2022. The Author(s).

• Complexity of progranulin mechanisms of action in mesothelioma. E. Ventura, C. Xie, S. Buraschi, et al. 2022;41(1):333. PubMed · Publisher · Free full text

  Abstract

  Background: Mesothelioma is an aggressive disease with limited therapeutic options. The growth factor progranulin plays a critical role in several cancer models, where it regulates tumor initiation and progression. Recent data from our laboratories have demonstrated that progranulin and its receptor, EphA2, constitute an oncogenic pathway in bladder cancer by promoting motility, invasion and in vivo tumor formation. Progranulin and EphA2 are expressed in mesothelioma cells but their mechanisms of action are not well defined. In addition, there are no data establishing whether the progranulin/EphA2 axis is tumorigenic for mesothelioma cells.

  Methods: The expression of progranulin in various mesothelioma cell lines derived from all major mesothelioma subtypes was examined by western blots on cell lysates, conditioned media and ELISA assays. The biological roles of progranulin, EphA2, EGFR, RYK and FAK were assessed in vitro by immunoblots, human phospho-RTK antibody arrays, pharmacological (specific inhibitors) and genetic (siRNAs, shRNAs, CRISPR/Cas9) approaches, motility, invasion and adhesion assays. In vivo tumorigenesis was determined by xenograft models. Focal adhesion turnover was evaluated biochemically using focal adhesion assembly/disassembly assays and immunofluorescence analysis with focal adhesion-specific markers.

  Results: In the present study we show that progranulin is upregulated in various mesothelioma cell lines covering all mesothelioma subtypes and is an important regulator of motility, invasion, adhesion and in vivo tumor formation. However, our results indicate that EphA2 is not the major functional receptor for progranulin in mesothelioma cells, where progranulin activates a complex signaling network including EGFR and RYK. We further characterized progranulin mechanisms of action and demonstrated that progranulin, by modulating FAK activity, regulates the kinetic of focal adhesion disassembly, a critical step for cell motility.

  Conclusion: Collectively, our results highlight the complexity of progranulin oncogenic signaling in mesothelioma, where progranulin modulate functional cross-talks between multiple RTKs, thereby suggesting the need for combinatorial therapeutic approaches to improve treatments of this aggressive disease.

  © 2022. The Author(s).

• Landscape of immune-related signatures induced by targeting of different epigenetic regulators in melanoma: implications for immunotherapy. A. Anichini, A. Molla, G. Nicolini, et al. 2022;41(1):325. PubMed · Publisher · Free full text

  Abstract

  Background: Improvement of efficacy of immune checkpoint blockade (ICB) remains a major clinical goal. Association of ICB with immunomodulatory epigenetic drugs is an option. However, epigenetic inhibitors show a heterogeneous landscape of activities. Analysis of transcriptional programs induced in neoplastic cells by distinct classes of epigenetic drugs may foster identification of the most promising agents.

  Methods: Melanoma cell lines, characterized for mutational and differentiation profile, were treated with inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), BET proteins (JQ1 and OTX-015), and enhancer of zeste homolog 2 (GSK126). Modulatory effects of epigenetic drugs were evaluated at the gene and protein levels. Master molecules explaining changes in gene expression were identified by Upstream Regulator (UR) analysis. Gene set enrichment and IPA were used respectively to test modulation of guadecitabine-specific gene and UR signatures in baseline and on-treatment tumor biopsies from melanoma patients in the Phase Ib NIBIT-M4 Guadecitabine + Ipilimumab Trial. Prognostic significance of drug-specific immune-related genes was tested with Timer 2.0 in TCGA tumor datasets.

  Results: Epigenetic drugs induced different profiles of gene expression in melanoma cell lines. Immune-related genes were frequently upregulated by guadecitabine, irrespective of the mutational and differentiation profiles of the melanoma cell lines, to a lesser extent by givinostat, but mostly downregulated by JQ1 and OTX-015. GSK126 was the least active drug. Quantitative western blot analysis confirmed drug-specific modulatory profiles. Most of the guadecitabine-specific signature genes were upregulated in on-treatment NIBIT-M4 tumor biopsies, but not in on-treatment lesions of patients treated only with ipilimumab. A guadecitabine-specific UR signature, containing activated molecules of the TLR, NF-kB, and IFN innate immunity pathways, was induced in drug-treated melanoma, mesothelioma and hepatocarcinoma cell lines and in a human melanoma xenograft model. Activation of guadecitabine-specific UR signature molecules in on-treatment tumor biopsies discriminated responding from non-responding NIBIT-M4 patients. Sixty-five % of the immune-related genes upregulated by guadecitabine were prognostically significant and conferred a reduced risk in the TCGA cutaneous melanoma dataset.

  Conclusions: The DNMT inhibitor guadecitabine emerged as the most promising immunomodulatory agent among those tested, supporting the rationale for usage of this class of epigenetic drugs in combinatorial immunotherapy approaches.

  © 2022. The Author(s).

• SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma. I.C. Salaroglio, D.C. Belisario, P. Bironzo, et al. 2022;41(1):75. PubMed · Publisher · Free full text

  Abstract

  Background: The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results.

  Methods: Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat.

  Results: In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8+T-lymphocytes. The SKP2 component of SCF complex was identified as the main driver of sensitivity to MLN4924 and resistance to cisplatin. These findings were confirmed in a retrospective MPM patient series, where SKP2 high levels were associated with a worse response to platinum-based therapy and inferior survival.

  Conclusions: We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.

  © 2022. The Author(s).

• A vision of immuno-oncology: the Siena think tank of the Italian network for tumor biotherapy (NIBIT) foundation. M. Maio, M. Lahn, A.M. Di Giacomo, et al. 2021;40(1):240. PubMed · Publisher · Free full text

  Abstract

  Background: The yearly Think Tank Meeting of the Italian Network for Tumor Biotherapy (NIBIT) Foundation, brings together in Siena, Tuscany (Italy), experts in immuno-oncology to review the learnings from current immunotherapy treatments, and to propose new pre-clinical and clinical investigations in selected research areas. MAIN: While immunotherapies in non-small cell lung cancer and melanoma led to practice changing therapies, the same therapies had only modest benefit for patients with other malignancies, such as mesothelioma and glioblastoma. One way to improve on current immunotherapies is to alter the sequence of each combination agent. Matching the immunotherapy to the host's immune response may thus improve the activity of the current treatments. A second approach is to combine current immunotherapies with novel agents targeting complementary mechanisms. Identifying the appropriate novel agents may require different approaches than the traditional laboratory-based discovery work. For example, artificial intelligence-based research may help focusing the search for innovative and most promising combination partners.

  Conclusion: Novel immunotherapies are needed in cancer patients with resistance to or relapse after current immunotherapeutic drugs. Such new treatments may include targeted agents or monoclonal antibodies to overcome the immune-suppressive tumor microenvironment. The mode of combining the novel treatments, including vaccines, needs to be matched to the patient's immune status for achieving the maximum benefit. In this scenario, specific attention should be also paid nowadays to the immune intersection between COVID-19 and cancer.

  © 2021. The Author(s).

• Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma. M. Cioce, C. Canino, H. Pass, et al. 2021;40(1):344. PubMed · Publisher · Free full text

  Abstract

  Unlabelled: Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed.

  Methods: Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells.

  Results: We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug.

  Conclusions: AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.

  © 2021. The Author(s).

• Identification of novel COX-2 / CYP19A1 axis involved in the mesothelioma pathogenesis opens new therapeutic opportunities. B. Nuvoli, B. Antoniani, R. Libener, et al. 2021;40(1):257. PubMed · Publisher · Free full text

  Abstract

  Background: Based on previous studies highlighting that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of malignant pleural mesothelioma (MPM), and that aromatase (CYP19A1), an enzyme that plays a key role in estrogen biosynthesis, along with estradiol (E2) were expressed in MPM, this study aimed to investigate the possible interplay between COX-2 and CYP19A1 in the pathogenesis of mesothelioma, as well as the underlying mechanism.

  Methods: The interaction between COX-2 and CYP19A1 was first investigated on different MPM lines upon PGE2, and COX-2 inhibitor (rofecoxib) treatment by western blot, RT-PCR. The key regulatory pathways involved in the COX-2 and CYP19A1 axis were further studied in MPM cells, after rofecoxib and exemestane (CYP19A1 inhibitor) treatment in monotherapy and in combination, by cell cycle distribution, western blot, and combination index analysis. To explore the role of COX-2/CYP19A1 axis in 3D preclinical models of MPM cells, we analyzed the effect of combination of COX-2 and CYP19A1 inhibitors in mesosphere formation. Immunohistochemical analysis of MPM mesosphere and specimens was utilized to evaluate the involvement of COX-2 on the CYP19A1 activity and the relationship between E2 and COX-2.

  Results: PGE2 or rofecoxib treatment caused in MPM cells an increased or decreased, respectively, CYP19A1 expression at mRNA and protein levels. The effect of rofecoxib and exemestane combination in MPM cell proliferation was synergistic. Activation of caspase-3 and cleavage of PARP confirmed an apoptotic death for MPM cell lines. Increased expression levels of p53, p21, and p27, downregulation of cyclin D1 and inhibition of Akt activation (pAKT) were also found. The antagonistic effect of rofecoxib and exemestane combination found only in one cell line, was reverted by pretreatment with MK2206, a pAKT inhibitor, indicating pAKT as an actionable mediator in the COX-2-CYP19A1 axis. Reduction of size and sphere-forming efficiency in MPM spheres after treatment with both inhibitor and a decrease in COX-2 and E2 staining was found. Moreover, immunohistochemical analysis of 46 MPM samples showed a significant positive correlation between COX-2 and E2.

  Conclusions: Collectively, the results highlighted a novel COX-2/CYP19A1 axis in the pathogenesis of MPM that can be pharmacologically targeted, consequently opening up new therapeutic options.

  © 2021. The Author(s).

2010s

• Curcumin C3 complex®/Bioperine® has antineoplastic activity in mesothelioma: an in vitro and in vivo analysis. F. Di Meo, S. Filosa, M. Madonna, et al. 2019;38(1):360. PubMed · Publisher · Free full text

  Abstract

  Background: A major limitation in the treatment for malignant mesothelioma is related to serious side effects caused by chemotherapeutics and to the development of cancer-resistance. Advances in cancer therapies have been reached thanks to the introduction of alternative approaches, such as the use of phytochemicals. Curcumin-C3complex®/Bioperine® is a commercially standardized extract containing a ratio-defined mixture of three curcuminoids and piperine that greatly increase its bioavailability. Interestingly, the anticancer effect of this formulation has been described in different studies and several clinical trials have been started, but to our knowledge none refers to human mesothelioma.

  Methods: Curcumin-C3complex®/Bioperine® anticancer effect was evaluated in vitro in different human mesothelioma cell lines analysing cell proliferation, colony-forming assay, wound healing assays, invasion assay and FACS analysis. In vivo anticancer properties were analysed in a mesothelioma xenograft mouse model in CD1 Nude mice.

  Results: Curcumin-C3complex®/Bioperine® in vitro induced growth inhibition in all mesothelioma cell lines analysed in a dose- and time-depended manner and reduced self-renewal cell migration and cell invasive ability. Cell death was due to apoptosis. The analysis of the molecular signalling pathway suggested that intrinsic apoptotic pathway is activated by this treatment. This treatment in vivo delayed the growth of the ectopic tumours in a mesothelioma xenograft mouse model.

  Conclusions: Curcumin-C3complex®/Bioperine® treatment strongly reduces in vitro tumorigenic properties of mesothelioma cells by impairing cellular self-renewal ability, proliferative cell rate and cell migration and delays tumor growth in xenograft mouse model by reducing angiogenesis and increasing apoptosis. Considering that curcumin in vivo synergizes drug effects, its administration to treatment regimen may help to enhance drug therapeutic efficacy in mesothelioma. Our results suggest that implementation of standard pharmacological therapies with novel compounds may pave the way to develop alternative approaches to mesothelioma.

• Dropwort-induced metabolic reprogramming restrains YAP/TAZ/TEAD oncogenic axis in mesothelioma. C. Pulito, E. Korita, A. Sacconi, et al. 2019;38(1):349. PubMed · Publisher · Free full text

  Abstract

  Background: Over the past decade, newly designed cancer therapies have not significantly improved the survival of patients diagnosed with Malignant Pleural Mesothelioma (MPM). Among a limited number of genes that are frequently mutated in MPM several of them encode proteins that belong to the HIPPO tumor suppressor pathway.

  Methods: The anticancer effects of the top flower standardized extract of Filipendula vulgaris (Dropwort) were characterized in "in vitro" and "in vivo" models of MPM. At the molecular level, two "omic" approaches were used to investigate Dropwort anticancer mechanism of action: a metabolomic profiling and a phosphoarray analysis.

  Results: We found that Dropwort significantly reduced cell proliferation, viability, migration and in vivo tumor growth of MPM cell lines. Notably, Dropwort affected viability of tumor-initiating MPM cells and synergized with Cisplatin and Pemetrexed in vitro. Metabolomic profiling revealed that Dropwort treatment affected both glycolysis/tricarboxylic acid cycle as for the decreased consumption of glucose, pyruvate, succinate and acetate, and the lipid metabolism. We also document that Dropwort exerted its anticancer effects, at least partially, promoting YAP and TAZ protein ubiquitination.

  Conclusions: Our findings reveal that Dropwort is a promising source of natural compound(s) for targeting the HIPPO pathway with chemo-preventive and anticancer implications for MPM management.

• MTA1 promotes metastasis of MPM via suppression of E-cadherin. C. Xu, F. Hua, Y. Chen, et al. 2015;34:151. PubMed · Publisher · Free full text

  Abstract

  Background: Metastasis-associated gene 1(MTA1) has been identified as an oncogene in many tumors, and aberrant MTA1 expression has been linked to carcinogenesis and metastasis. We aim to investigate the mechanism of MTA1 and metastasis in malignant pleural mesothelioma (MPM).

  Methods: Real-time polymerase chain reaction (PCR) and immunohistochemical staining were employed to detect MTA1 and E-cadherin expression in MPM tissues and corresponding adjacent tissues. Stable clone with knock-down of MTA1 was generated with shRNA via lentivirus technology in MPM cell lines. Wound-healing assay, transwell assay and PCR array were carried out for detecting invasion and migration of MPM cells. Luciferase reporter assay was performed to validate the effect of MTA1 on E-cadherin.

  Results: MTA1 expression is up-regulated in MPM and shown a negative correlation with E-cadherin expression. MTA1 could enhance the invasion and migration of MPM cells via suppressing the expression of E-cadherin. MTA1 overexpression is associated with pathology, metastasis and survival rate of MPM patients.

  Conclusions: MTA1 plays an important role in Epithelial-to-mesenchymal transition (EMT) to promote metastasis via suppressing E-cadherin expression, resulting in a poor prognosis in MPM. MTA1 is a novel biomarker and indicative of a poor prognosis in MPM patients.

• CELLFOOD™ induces apoptosis in human mesothelioma and colorectal cancer cells by modulating p53, c-myc and pAkt signaling pathways. B. Nuvoli, R. Santoro, S. Catalani, et al. 2014;33(1):24. PubMed · Publisher · Free full text

  Abstract

  Background: CELLFOOD™ (CF) is a nutraceutical non-addictive, non-invasive, and completely non-toxic unique proprietary colloidal-ionic formula. Little is known about its effect on cancer cells in solid tumors. The aim of this study was to evaluate the effect that CF has on different cancer cell lines and the mechanism by which the nutraceutical works.

  Methods: The effect of CF on HFF (normal fibroblasts), Met5A (mesothelium), MSTO-211H, NCI-2452, Ist-Mes1, MPP89, Ist-Mes2 (mesothelioma), M14 (melanoma), H1650, H1975 (lung cancer), SKRB3 (breast cancer), and HCT-116 (colorectal cancer) cell growth was tested by cell proliferation and clonogenic assay. Among all of them, MSTO-211 and HCT-116 were analyzed for cell cycle by flow cytometry and western blot.

  Results: All human cancer lines were suppressed on cell growth upon 1:200 CF treatment for 24 and 48 hours. Death was not observed in HFF and Met5A cell lines. Cell cycle analysis showed an increased sub-G1 with reduction of G1 in MSTO-211 and a cell cycle arrest of in G1 in HCT116. Activation of caspase-3 and cleavage of PARP confirmed an apoptotic death for both cell lines. Increased expression levels of p53, p21, and p27, downregulation of c-myc and Bcl-2, and inhibition of Akt activation were also found in CF-treated MSTO-211 and HCT-116 cells.

  Conclusions: These findings ascertained an interaction between p53, c-myc, p21, p27, Bcl-2, PI3K/Akt pathway, and CF-induced apoptosis in MSTO-211H and HCT-116 cells, suggesting that CF acts as an important regulator of cell growth in human cancer cell lines. CF could be a useful nutraceutical intervention for prevention in colon cancer and mesothelioma.

• CK2α, over-expressed in human malignant pleural mesothelioma, regulates the Hedgehog signaling pathway in mesothelioma cells. S. Zhang, Y.L. Yang, Y. Wang, et al. 2014;33(1):93. PubMed · Publisher · Free full text

  Abstract

  Background: The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance and its activation is aberrant in several types of cancer including mesothelioma. Protein kinase CK2 affects several cell signaling pathways through the mechanism of phosphorylation.

  Methods: Protein and mRNA levels of CK2α and Gli1 were tested by quantitative RT-PCR and immunohistochemistry staining in mesothelioma samples and cell lines. Down-regulated Gli1 expression and transcriptional activity were demonstrated by RT-PCR, Western blot and luciferase reporter assay.

  Results: In this study, we show that CK2α is over-expressed and a positive regulator of Hegdehog/Gli1 signaling in human malignant pleural mesothelioma. First of all, we found that the mRNA levels of CK2α and Gli1 were broadly elevated and correlated (n = 52, r = 0.401, P < 0.05), compared with LP9 (a normal mesothelial cell line). We then investigated their expression at the protein level, and found that all the 7 mesothelioma cell lines tested showed positive staining in CK2α and Gli1 immunohistochemistry. Correlation analysis by Pearson test for CK2α and Gli1 expression in the 75 mesothelioma tumors and the 7 mesothelioma cell lines showed that the two protein expression was significantly correlated (n = 82, r = 0.554, P < 0.01). Furthermore, we demonstrated that Gli1 expression and transcriptional activity were down-regulated after CK2α was silenced in two mesothelioma cell lines (H28 and H2052). CK2α siRNA also down-regulated the expression of Hh target genes in these cell lines. Moreover, treatment with a small-molecule CK2α inhibitor CX-4945 led to dose-dependent inhibition of Gli1 expression and transcriptional activity. Conversely, forced over-expression of CK2α resulted in an increase in Gli1 transcriptional activity in H28 cells.

  Conclusions: Thus, we report for the first time that over-expressed CK2α positively regulate Hh/Gli1 signaling in human mesothelioma.

• SMO expression level correlates with overall survival in patients with malignant pleural mesothelioma. Y. Zhang, J. He, F. Zhang, et al. 2013;32(1):7. PubMed · Publisher · Free full text

  Abstract

  Background: Malignant mesothelioma is an aggressive, treatment-resistant tumor arising from mesothelium of pleura, peritoneum and pericardium. Despite current combined regimen, its prognosis remains dismal, calling for more effective targeted therapies. We investigated whether aberrant Hh activation may play a role in mesothelioma.

  Methods: SMO and SHH expression levels were analyzed in 46 mesothelioma tissue specimens with real-time RT-PCR, and correlation with survival was analyzed with univariate and multivariate Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test. We also examined multiple mesothelioma cell lines for SMO expression and the effect of Hh inhibition by a specific SMO antagonist on cell proliferation by MTS assay.

  Results: We observed strong correlation between higher SMO and SHH expression levels with poorer overall survival. Remarkably, Hh inhibition by a specific SMO inhibitor significantly suppressed cell proliferation in the mesothelioma cell lines examined.

  Conclusion: Our data strongly support that Hh signaling deregulation plays critical roles in proliferation of mesothelioma, and consistently exerts significant impact on prognosis of the disease. Therefore our findings revealed the hitherto unappreciated role of Hh activation in mesothelioma, and pinpointed Hh signaling antagonist as a potential new therapy against this devastating disease.

• Osteopontin induces growth of metastatic tumors in a preclinical model of non-small lung cancer. F. Shojaei, N. Scott, X. Kang, et al. 2012;31(1):26. PubMed · Publisher · Free full text

  Abstract

  Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein), is an integrin binding glyco-phosphoprotein produced by a variety of tissues. In cancer patients expression of OPN has been associated with poor prognosis in several tumor types including breast, lung, and colorectal cancers. Despite wide expression in tumor cells and stroma, there is limited evidence supporting role of OPN in tumor progression and metastasis. Using phage display technology we identified a high affinity anti-OPN monoclonal antibody (hereafter AOM1). The binding site for AOM1 was identified as SVVYGLRSKS sequence which is immediately adjacent to the RGD motif and also spans the thrombin cleavage site of the human OPN. AOM1 efficiently inhibited OPNa binding to recombinant integrin αvβ3 with an IC50 of 65 nM. Due to its unique binding site, AOM1 is capable of inhibiting OPN cleavage by thrombin which has been shown to produce an OPN fragment that is biologically more active than the full length OPN. Screening of human cell lines identified tumor cells with increased expression of OPN receptors (αvβ3 and CD44v6) such as mesothelioma, hepatocellular carcinoma, breast, and non-small cell lung adenocarcinoma (NSCLC). CD44v6 and αvβ3 were also found to be highly enriched in the monocyte, but not lymphocyte, subset of human peripheral blood mononuclear cells (hPBMCs). In vitro, OPNa induced migration of both tumor and hPBMCs in a transwell migration assay. AOM1 significantly blocked cell migration further validating its specificity for the ligand. OPN was found to be enriched in mouse plasma in a number of pre-clinical tumor model of non-small cell lung cancers. To assess the role of OPN in tumor growth and metastasis and to evaluate a potential therapeutic indication for AOM1, we employed a Kras(G12D-LSL)p53(fl/fl) subcutaneously implanted in vivo model of NSCLC which possesses a high capacity to metastasize into the lung. Our data indicated that treatment of tumor bearing mice with AOM1 as a single agent or in combination with Carboplatin significantly inhibited growth of large metastatic tumors in the lung further supporting a role for OPN in tumor metastasis and progression.

2000s

• Lung cancer gene expression database analysis incorporating prior knowledge with support vector machine-based classification method. P. Guan, D. Huang, M. He, et al. 2009;28(1):103. PubMed · Publisher · Free full text

  Abstract

  Background: A reliable and precise classification is essential for successful diagnosis and treatment of cancer. Gene expression microarrays have provided the high-throughput platform to discover genomic biomarkers for cancer diagnosis and prognosis. Rational use of the available bioinformation can not only effectively remove or suppress noise in gene chips, but also avoid one-sided results of separate experiment. However, only some studies have been aware of the importance of prior information in cancer classification.

  Methods: Together with the application of support vector machine as the discriminant approach, we proposed one modified method that incorporated prior knowledge into cancer classification based on gene expression data to improve accuracy. A public well-known dataset, Malignant pleural mesothelioma and lung adenocarcinoma gene expression database, was used in this study. Prior knowledge is viewed here as a means of directing the classifier using known lung adenocarcinoma related genes. The procedures were performed by software R 2.80.

  Results: The modified method performed better after incorporating prior knowledge. Accuracy of the modified method improved from 98.86% to 100% in training set and from 98.51% to 99.06% in test set. The standard deviations of the modified method decreased from 0.26% to 0 in training set and from 3.04% to 2.10% in test set.

  Conclusion: The method that incorporates prior knowledge into discriminant analysis could effectively improve the capacity and reduce the impact of noise. This idea may have good future not only in practice but also in methodology.

• Phenotype-dependent apoptosis signalling in mesothelioma cells after selenite exposure. G. Nilsonne, E. Olm, A. Szulkin, et al. 2009;28(1):92. PubMed · Publisher · Free full text

  Abstract

  Background: Selenite is a promising anticancer agent which has been shown to induce apoptosis in malignant mesothelioma cells in a phenotype-dependent manner, where cells of the chemoresistant sarcomatoid phenotype are more sensitive.

  Methods: In this paper, we investigate the apoptosis signalling mechanisms in sarcomatoid and epithelioid mesothelioma cells after selenite treatment. Apoptosis was measured with the Annexin-PI assay. The mitochondrial membrane potential, the expression of Bax, Bcl-XL, and the activation of caspase-3 were assayed with flow cytometry and a cytokeratin 18 cleavage assay. Signalling through JNK, p38, p53, and cathepsins B, D, and E was investigated with chemical inhibitors. Furthermore, the expression, nuclear translocation and DNA-binding activity of p53 was investigated using ICC, EMSA and the monitoring of p21 expression as a downstream event. Levels of thioredoxin (Trx) were measured by ELISA.

  Results: In both cell lines, 10 microM selenite caused apoptosis and a marked loss of mitochondrial membrane potential. Bax was up-regulated only in the sarcomatoid cell line, while the epithelioid cell line down-regulated Bcl-XL and showed greater caspase-3 activation. Nuclear translocation of p53 was seen in both cell lines, but very little p21 expression was induced. Chemical inhibition of p53 did not protect the cells from apoptosis. p53 lost its DNA binding ability after selenite treatment and was enriched in an inactive form. Levels of thioredoxin decreased after selenite treatment. Chemical inhibition of MAP kinases and cathepsins showed that p38 and cathepsin B had some mediatory effect while JNK had an anti-apoptotic role.

  Conclusion: We delineate pathways of apoptosis signalling in response to selenite, showing differences between epithelioid and sarcomatoid mesothelioma cells. These differences may partly explain why sarcomatoid cells are more sensitive to selenite.

• Piroxicam and intracavitary platinum-based chemotherapy for the treatment of advanced mesothelioma in pets: preliminary observations. E.P. Spugnini, S. Crispi, A. Scarabello, et al. 2008;27(1):6. PubMed · Publisher · Free full text

  Abstract

  Malignant Mesothelioma is an uncommon and very aggressive tumor that accounts for 1% of all the deaths secondary to malignancy in humans. Interestingly, this neoplasm has been occasionally described in companion animals as well. Aim of this study was the preclinical evaluation of the combination of piroxicam with platinum-based intracavitary chemotherapy in pets. Three companion animals have been treated in a three years period with this combination. Diagnosis was obtained by ultrasonographic exam of the body cavities that evidenced thickening of the mesothelium. A surgical biopsy further substantiated the diagnosis. After drainage of the malignant effusion from the affected cavity, the patients received four cycles of intracavitary CDDP at the dose of 50 mg/m2 every three weeks if dogs or four cycles of intracavitary carboplatin at the dose of 180 mg/m2 (every 3 weeks) if cats, coupled with daily administration of piroxicam at the dose of 0.3 mg/kg. The therapy was able to arrest the effusion in all patients for variable remission times: one dog is still in remission after 3 years, one dog died of progressive disease after 8 months and one cat died due to progressive neoplastic growth after six months, when the patient developed a mesothelial cuirass. The combination showed remarkable efficacy at controlling the malignant effusion secondary to MM in our patients and warrants further investigations.

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