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3 results on '"Molina-Pinelo,S"'

1. Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy

Author

Boyero, Laura, Sánchez-Gastaldo, Amparo, Alonso, Miriam, Noguera-Uclés, José Francisco, Molina-Pinelo, Sonia, Bernabé-Caro, Reyes, [Boyero,L, Noguera-Uclés,JF, Molina-Pinelo,S, Bernabé-Caro,R] Institute of Biomedicine of Seville (IBiS) (HUVR, CSIC, Universidad de Sevilla), Seville, Spain. [Sánchez-Gastaldo,A, Alonso,M, Bernabé-Caro,R] Medical Oncology Department, Hospital Universitario Virgen del Rocio, Seville, Spain. [Molina-Pinelo,S] Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain., and S.M.-P. is funded by the Ministry of Health and Social Welfare of Junta de Andalucía (Nicolas Monardes Program C-0040-201, and OH-0022-2018) and ISCIII (PI17/00033 and PI20/01109) (co-funded by the European Regional Development Fund) 'A way to make Europe'. L.B. is funded by the Ministry of Health and Social Welfare of Junta de Andalucía (RH-0051-2020).

Subjects
Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Recurrence [Medical Subject Headings], Neoplasias pulmonares, Carcinoma pulmonar de células pequeñas, Resistance mechanisms, NSCLC, Carcinoma de pulmón de células no pequeñas, Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [Medical Subject Headings], PD-1/PD-L1, Antígeno B7-H1, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Immune checkpoint inhibitors, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy [Medical Subject Headings], Inmunoterapia, Anatomy::Hemic and Immune Systems::Immune System::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes [Medical Subject Headings], Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Signal Transduction [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic [Medical Subject Headings], SCLC, Phenomena and Processes::Cell Physiological Phenomena::Cellular Microenvironment::Tumor Microenvironment [Medical Subject Headings], Receptor de muerte celular programada 1, Inhibidores de puntos de control inmunológico, Phenomena and Processes::Microbiological Phenomena::Microbiota [Medical Subject Headings], Anticuerpos monoclonales, Anthropology, Education, Sociology and Social Phenomena::Social Sciences::Quality of Life [Medical Subject Headings], Monoclonal antibodies, Immunotherapy, Lung cancer
Abstract

After several decades without maintained responses or long-term survival of patients with lung cancer, novel therapies have emerged as a hopeful milestone in this research field. The appearance of immunotherapy, especially immune checkpoint inhibitors, has improved both the overall survival and quality of life of patients, many of whom are diagnosed late when classical treatments are ineffective. Despite these unprecedented results, a high percentage of patients do not respond initially to treatment or relapse after a period of response. This is due to resistance mechanisms, which require understanding in order to prevent them and develop strategies to overcome them and increase the number of patients who can benefit from immunotherapy. This review highlights the current knowledge of the mechanisms and their involvement in resistance to immunotherapy in lung cancer, such as aberrations in tumor neoantigen burden, effector T-cell infiltration in the tumor microenvironment (TME), epigenetic modulation, the transcriptional signature, signaling pathways, T-cell exhaustion, and the microbiome. Further research dissecting intratumor and host heterogeneity is necessary to provide answers regarding the immunotherapy response and develop more effective treatments for lung cancer. Yes

Published
2020

2. The Roles of Imprinted SLC22A18 and SLC22A18AS Gene Overexpression Caused by Promoter CpG Island Hypomethylation as Diagnostic and Prognostic Biomarkers for Non-Small Cell Lung Cancer Patients

Author

José Francisco Noguera-Uclés, Miriam Alonso, Ana Salinas, Laura Boyero, Sonia Molina-Pinelo, Luis Paz-Ares, Johana Cristina Benedetti, Reyes Bernabé-Caro, Amparo Sanchez-Gastaldo, Juan Antonio Cordero Varela, Junta de Andalucía (España), Instituto de Salud Carlos III - ISCIII, Regional Government of Andalusia (España), Instituto de Salud Carlos III, [Noguera-Uclés,JF, Boyero,L, Salinas,A, Cordero Varela,JA, Benedetti,JC, Bernabé-Caro,R, Sánchez-Gastaldo,A, Alonso,M, Molina-Pinelo,S] Institute of Biomedicine of Seville (IBiS) (HUVR, CSIC, Universidad de Sevilla), Seville, Spain. [Benedetti,JC, Molina-Pinelo,S] Medical Oncology Department, Hospital Universitario Virgen del Rocío, Seville, Spain. [Paz-Ares,L, Molina-Pinelo,S] Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [Paz-Ares,L] H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. [Paz-Ares,L] Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain., and This research was funded by the Ministry of Health and Social Welfare of Junta de Andalucía (PI-0046-2012, Nicolas Monardes Program C-0040-2016), and Instituto de Salud Carlos III though the project PI17/00033 (Co-funded by European Regional Development Fund) 'A way to make Europe'.

Subjects
Cancer Research, Genomic imprinting, diagnostic, IMPT1, NSCLC, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Medicine, TUMOR-SUPPRESSOR, Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [Medical Subject Headings], Gene knockdown, TSSC5, Diagnóstico, Impresión genómica, IGF2, Chemicals and Drugs::Organic Chemicals::Sulfur Compounds::Amino Acids, Sulfur::Methionine::S-Adenosylmethionine [Medical Subject Headings], Prognosis, SLC22A18, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, genomic imprinting, EPIGENETICS, Oncology, CpG site, Metilación, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::DNA Methylation [Medical Subject Headings], DNA methylation, SLC22A18AS, Adenocarcinoma, Lung cancer, Neoplasias pulmonares, Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [Medical Subject Headings], Methylation, lcsh:RC254-282, Article, food, Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Carcinoma::Carcinoma, Squamous Cell [Medical Subject Headings], Diagnostic, Epigenetics, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic::Genomic Imprinting [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Progression [Medical Subject Headings], business.industry, biomarkers, Oncogenes, medicine.disease, TRANSPORTERS, food.food, Biomarcadores, Cancer research, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Neoplasm::Oncogenes [Medical Subject Headings], prognosis, GAIN, business, Ademetionine, Biomarkers
Abstract

Genomic imprinting is a process that involves one gene copy turned-off in a parent-of-origin-dependent manner. The regulation of imprinted genes is broadly dependent on promoter methylation marks, which are frequently associated with both oncogenes and tumor suppressors. The purpose of this study was to assess the DNA methylation patterns of the imprinted solute-carrier family 22 member 18 (SLC22A18) and SLC22A18 antisense (SLC22A18AS) genes in non-small cell lung cancer (NSCLC) patients to study their relevance to the disease. We found that both genes were hypomethylated in adenocarcinoma and squamous cell carcinoma patients. Due to this imprinting loss, SLC22A18 and SLC22A18AS were found to be overexpressed in NSCLC tissues, which is significantly more evident in lung adenocarcinoma patients. These results were validated through analyses of public databases of NSCLC patients. The reversed gene profile of both genes was achieved in vitro by treatment with ademetionine. We then showed that high SLC22A18 and SLC22A18AS expression levels were significantly associated with worsening disease progression. In addition, low levels of SLC22A18AS were also correlated with better overall survival for lung adenocarcinoma patients. We found that SLC22A18 and SLC22A18AS knockdown inhibits cell proliferation in vitro. All these results suggest that both genes may be useful as diagnostic and prognostic biomarkers in NSCLC, revealing novel therapeutic opportunities. This research was funded by the Ministry of Health and Social Welfare of Junta de Andalucia (PI-0046-2012, Nicolas Monardes Program C-0040-2016), and Instituto de Salud Carlos III though the project PI17/00033 (Co-funded by European Regional Development Fund) "A way to make Europe" Sí

Published
2020

3. FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their coexpression may predict FGFR-targeted therapy efficacy

Author

Santiago García, Luis Paz-Ares, Fernando Lopez-Rios, Jon Zugazagoitia, Sonia Molina-Pinelo, Laura Ojeda, Irene Ferrer, Sandra Muñoz-Galván, Elizabeth Guruceaga, Luis M. Montuenga, Silvestre Vicent, Cristina Cirauqui, Álvaro Quintanal-Villalonga, Amancio Carnero, Ángela Marrugal, [Quintanal-Villalonga,Á, Ferrer,I, Cirauqui,C, Marrugal,Á, Ojeda,L, García,S, Zugazagoitia,J, Paz-Ares,L] H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigacion Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. [Quintanal-Villalonga,Á] Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [Ferrer,I, Muñoz-Galván,S, Lopez-Rios,F, Montuenga,L, Vicent,S, Molina-Pinelo,S, Carnero,A, Paz-Ares,L] CIBERONC, Madrid, Spain. [Guruceaga,E] Bioinformatics Unit, Centre for Applied Medical Research (CIMA), Pamplona, Spain. [Guruceaga,E] PROTEORED, Madrid, Spain. [Zugazagoitia,J, Paz-Ares,L] Medical Oncology Department, Hospital Universitario Doce de Octubre. Madrid, Spain. [Muñoz-Galván,S, Carnero,A] Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain. [Lopez-Rios,F] Laboratorio de Dianas Terapeuticas, Hospital Universitario HM Sanchinarro, Madrid, Spain. [Montuenga,L, Vicent,S] Program in Solid Tumors, Centre for Applied Medical Research (CIMA), Pamplona, Spain. [Montuenga,L, Vicent,S] Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain. [Montuenga,L, Vicent,S] IdiSNA, Navarra Institute for Health Research, Pamplona, SPAIN. [Paz-Ares,L] Medical School, Universidad Complutense, Madrid, Spain., This work was funded by the Community of Madrid, the ISCIII cofunded by FEDER from Regional Development European Funds (European Union), the Spanish Ministry of Economy and Competitiveness, the Mutua Madrilena Foundation, the Ministry of Health and Social ~ Welfare of Junta de Andalucía, the AECC scientific foundation and the Spanish Ministry of Education, Culture and Sport. L.P.A. was funded by the Community of Madrid, CAM, (B2017/BMD3884), ISCIII (PIE15/00076, PI17/00778 and DTS17/00089) and CIBERONC (CD16/12/00442), and co-funded by FEDER from Regional Development European Funds (European Union). A.C. was funded by grants from the Spanish Ministry of Economy and Competitiveness Plan Estatal de I+D+I 2018 cofunded by FEDER: RTI2018-097455-B-I00, CIBER de Cancer (CB16/ 12/00275), co-funded by FEDER from Regional Development European Funds. S.M.P. is funded by the Mutua Madrilena Foundation ~ (2014) Ministry of Health and Social Welfare of Junta de Andalucía (PI-0046-2012, Nicolas Monardes Program C-0040-2016), ISCIII (PI17/00033), and co-funded by FEDER from Regional Development European Funds (European Union). I.F. is funded by the AECC scientific foundation (AIO2015) and Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía (PI-0029-2013) and ISCIII (PI16/ 01311) and co-funded by FEDER from Regional Development European Funds (European Union). A.Q. is funded by ISCIII (FI12/00429). L. O. is funded by the Spanish Ministry of Education, Culture and Sport (FPU13/02595). S.V. is supported by the Spanish Ministry of Economy and Competitiveness (MINECO, SAF2017-89944-R)., Comunidad de Madrid, Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), Fundación Mutua Madrileña, Junta de Andalucía, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Educación, Cultura y Deporte (España), European Regional Development Fund, Regional Government of Andalusia (España), Asociación Española Contra el Cáncer, European Regional Development Fund (ERDF/FEDER), Fundación Mutua Madrileña Automovilista, Gobierno de Andalucia, and Asociacion Espanola Contra el Cancer (AECC)

Subjects
0301 basic medicine, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], Lung Neoplasms, Research paper, medicine.medical_treatment, lcsh:Medicine, medicine.disease_cause, Piperazines, Targeted therapy, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, 0302 clinical medicine, Lung neoplasms, Carcinoma, Non-Small-Cell Lung, Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [Medical Subject Headings], Tumor Cells, Cultured, Organisms::Eukaryota::Animals [Medical Subject Headings], FGFR inhibitors, Receptor tipo 1 de factor de crecimiento de fibroblastos, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptor, Fibroblast Growth Factor, Type 1 [Medical Subject Headings], lcsh:R5-920, Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [Medical Subject Headings], Receptor tipo 4 de factor de crecimiento de fibroblastos, Anatomy::Cells::Cells, Cultured::Tumor Cells, Cultured [Medical Subject Headings], General Medicine, Cadherins, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptor, Fibroblast Growth Factor, Type 4 [Medical Subject Headings], Predictive biomarker, Fibroblast growth factor receptor, 030220 oncology & carcinogenesis, Benzamides, Female, lcsh:Medicine (General), Neoplasias pulmonares, Mice, Nude, Antineoplastic Agents, Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [Medical Subject Headings], General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, In vivo, Cell Line, Tumor, Biomarkers, Tumor, medicine, Chemicals and Drugs::Biological Factors::Biological Markers [Medical Subject Headings], Animals, Humans, Receptor, Fibroblast Growth Factor, Type 4, Receptor, Fibroblast Growth Factor, Type 1, Lung cancer, N-cadherin, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], business.industry, Fibroblast growth factor receptor 1, lcsh:R, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, Nude [Medical Subject Headings], Fibroblast growth factor receptor 4, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Cell Adhesion Molecules::Cadherins [Medical Subject Headings], medicine.disease, Isogenic human disease models, stomatognathic diseases, 030104 developmental biology, Biomarcadores, FGFR1, Check Tags::Female [Medical Subject Headings], Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Azoles::Pyrazoles [Medical Subject Headings], Drug Resistance, Neoplasm, Cancer research, FGFR4, Pyrazoles, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Piperazines [Medical Subject Headings], Carcinogenesis, business, Chemicals and Drugs::Organic Chemicals::Amides::Benzamides [Medical Subject Headings], Biomarkers, Cadherinas
Abstract

[Background] Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with limited success., [Methods] In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to determine the prognostic potential of the genes under study., [Findings] We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression., [Interpretation] Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy., This work was funded by the Community of Madrid, the ISCIII co-funded by FEDER from Regional Development European Funds (European Union), the Spanish Ministry of Economy and Competitiveness, the Mutua Madrileña Foundation, the Ministry of Health and Social Welfare of Junta de Andalucía, the AECC scientific foundation and the Spanish Ministry of Education, Culture and Sport.

Published
2020

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