RESUMEN
Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural tissue that lines the lungs and is mainly associated with long latency from asbestos exposure. This tumor has no effective therapeutic opportunities nowadays and has a very low five-year survival rate. In this sense, identifying molecular events that trigger the development and progression of this tumor is highly important to establish new and potentially effective treatments. We conducted a meta-analysis of genome-wide expression studies publicly available at the Gene Expression Omnibus (GEO) and ArrayExpress databases. The differentially expressed genes (DEGs) were identified, and we performed functional enrichment analysis and protein-protein interaction networks (PPINs) to gain insight into the biological mechanisms underlying these genes. Additionally, we constructed survival prediction models for selected DEGs and predicted the minimum drug inhibition concentration of anticancer drugs for MPM. In total, 115 MPM tumor transcriptomes and 26 pleural tissue controls were analyzed. We identified 1046 upregulated DEGs in the MPM samples. Cellular signaling categories in tumor samples were associated with the TNF, PI3K-Akt, and AMPK pathways. The inflammatory response, regulation of cell migration, and regulation of angiogenesis were overrepresented biological processes. Expression of SOX17 and TACC1 were associated with reduced survival rates. This meta-analysis identified a list of DEGs in MPM tumors, cancer-related signaling pathways, and biological processes that were overrepresented in MPM samples. Some therapeutic targets to treat MPM are suggested, and the prognostic potential of key genes is shown.
Asunto(s)
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Mesotelioma/genética , Mesotelioma/metabolismo , Fosfatidilinositol 3-Quinasas , Neoplasias Pleurales/genética , Neoplasias Pleurales/metabolismo , Neoplasias Pulmonares/patologíaRESUMEN
BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a rare but aggressive neoplasia that usually presents at advanced stages. Even though some advances have been achieved in the management of patients with MPM, this malignancy continuous to impose a deleterious prognosis for affected patients (12-18 months as median survival, and 5-10% 5-year survival rate), accordingly, the recognition of biomarkers that allow us to select the most appropriate therapy are necessary. METHODS: Immunohistochemistry semi-quantitative analysis was performed to evaluate four different biomarkers (ERCC1, RRM1, RRM2, and hENT-1) with the intent to explore if any of them was useful to predict response to treatment with continuous infusion gemcitabine plus cisplatin. Tissue biopsies from patients with locally advanced or metastatic MPM were analyzed to quantitatively asses the aforementioned biomarkers. Every included patient received treatment with low-dose gemcitabine (250 mg/m2) in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks as first-line therapy. RESULTS: From the 70 eligible patients, the mean and standard deviation (SD) for ERCC1, RRM1, RRM2 and hENT-1 were 286,178.3 (± 219, 019.8); 104,647.1 (± 65, 773.4); 4536.5 (± 5, 521.3); and 2458.7 (± 4, 983.4), respectively. Patients with high expression of RRM1 had an increased median PFS compared with those with lower expression (9.5 vs 4.8 months, p = < 0.001). Furthermore, high expression of RRM1 and ERCC1 were associated with an increased median OS compared with their lower expression counterparts; [(23.1 vs 7.2 months for RRM1 p = < 0.001) and (17.4 vs 9.8 months for ERCC1 p = 0.018)]. CONCLUSIONS: ERCC1 and RRM1 are useful biomarkers that predict better survival outcomes in patients with advanced MPM treated with continuous infusion of gemcitabine plus cisplatin.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Unión al ADN/metabolismo , Endonucleasas/metabolismo , Mesotelioma Maligno/tratamiento farmacológico , Mesotelioma Maligno/metabolismo , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/metabolismo , Ribonucleósido Difosfato Reductasa/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Cisplatino/administración & dosificación , Proteínas de Unión al ADN/genética , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Endonucleasas/genética , Femenino , Humanos , Inmunohistoquímica , Masculino , Mesotelioma Maligno/mortalidad , Mesotelioma Maligno/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias Pleurales/mortalidad , Neoplasias Pleurales/patología , Pronóstico , Ribonucleósido Difosfato Reductasa/genética , GemcitabinaRESUMEN
BACKGROUND: Promising results have been reported with immune checkpoint inhibitors (ICI) in a small proportion of MPM patients. MMR deficiency (dMMR) has been well described in several malignancies and was approved as a biomarker for anti-PD-1 inhibitors. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM including a subset of patients treated with immunotherapy. METHODS: Tumors of 159 MPM p diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR (MMR protein expression negative) and MMR intact (all MMR proteins positively expressed). We retrospectively collected clinical outcomes under standard chemotherapy and experimental immunotherapy in the entire cohort. RESULTS: MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. Twenty two patients received ICI with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1 m). The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8 m). In a multivariable model factors associated to improved mOS were PS 0, neutrophil-lymphocyte ratio (NLR) < 5 and epithelioid histology (p < 0.001). CONCLUSIONS: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate potential predictive biomarkers of ICI benefit in MPM.
Asunto(s)
Reparación de la Incompatibilidad de ADN , Proteínas de Unión al ADN/metabolismo , Mesotelioma Maligno/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pleurales/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunohistoquímica , Inmunoterapia , Masculino , Mesotelioma Maligno/genética , Mesotelioma Maligno/mortalidad , Mesotelioma Maligno/terapia , Inestabilidad de Microsatélites , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Homólogo 1 de la Proteína MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Neoplasias Pleurales/genética , Neoplasias Pleurales/mortalidad , Neoplasias Pleurales/terapia , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical PDT. Tissue oxygen, however, is not routinely monitored intraoperatively even though it is one of the three major components of treatment. Quantitative information about in vivo tissue oxygenation during PDT is desirable, because it enables reactive oxygen species explicit dosimetry (ROSED) for prediction of treatment outcome based on PDT-induced changes in tumor oxygen level. Here, we demonstrate ROSED in a clinical setting, Photofrin-mediated pleural photodynamic therapy, by utilizing tumor blood flow information measured by diffuse correlation spectroscopy (DCS). A DCS contact probe was sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (blood flow index) during intraoperative PDT treatment. Isotropic detectors were used to measure treatment light fluence and photosensitizer concentration. Blood-flow-derived tumor oxygen concentration, estimated by applying a preclinically determined conversion factor of 1.5 × 109 µMs cm-2 to the blood flow index, was used in the ROSED model to calculate the total reacted reactive oxygen species [ROS]rx. Seven patients and 12 different pleural sites were assessed and large inter- and intrapatient heterogeneities in [ROS]rx were observed although an identical light dose of 60 J cm-2 was prescribed to all patients.
Asunto(s)
Éter de Dihematoporfirina/uso terapéutico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias Pleurales/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Animales , Humanos , Ratones , Neoplasias Pleurales/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Malignant pleural mesothelioma (MPM) is the most common tumor of the pulmonary pleura. It is a rare and aggressive malignancy, generally associated with continuous occupational exposure to asbestos. Only a multimodal-approach to treatment, based on surgical resection, chemotherapy and/or radiation, has shown some benefits. However, the survival rate remains low. Nimotuzumab (h-R3), an anti-EGFR (epidermal growth factor receptor) humanized antibody, is proposed as a promising agent for the treatment of MPM. The aim of this research was to implement a procedure for nimotuzumab radiolabeling to evaluate its biodistribution and affinity for EGF (epidermal growth factor) receptors present in a mesothelioma xenograft. Nimotuzumab was radiolabeled with 67Ga; radiolabel efficiency, radiochemical purity, serum stability, and biodistribution were evaluated. Biodistribution and tumor uptake imaging studies by microSPECT/CT in mesothelioma xenografts revealed constant nimotuzumab uptake at the tumor site during the first 48 h after drug administration. In vivo studies using MPM xenografts showed a significant uptake of this radioimmunoconjugate, which illustrates its potential as a biomarker that could promote its theranostic use in patients with MPM.