Publications by authors named "Sonia Molina-Pinelo"

43 Publications

Identification of Predictive Biomarkers of Response to HSP90 Inhibitors in Lung Adenocarcinoma.

Int J Mol Sci 2021 Mar 3;22(5). Epub 2021 Mar 3.

CIBERONC, Respiratory Tract Tumors Program, 28029 Madrid, Spain.

Heat shock protein 90 (HSP90) plays an essential role in lung adenocarcinoma, acting as a key chaperone involved in the correct functioning of numerous highly relevant protein drivers of this disease. To this end, HSP90 inhibitors have emerged as promising therapeutic strategies, even though responses to them have been limited to date. Given the need to maximize treatment efficacy, the objective of this study was to use isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic techniques to identify proteins in human lung adenocarcinoma cell lines whose basal abundances were correlated with response to HSP90 inhibitors (geldanamycin and radicicol derivatives). From the protein profiles identified according to response, the relationship between lactate dehydrogenase B (LDHB) and DNA topoisomerase 1 (TOP1) with respect to sensitivity and resistance, respectively, to geldanamycin derivatives is noteworthy. Likewise, rhotekin (RTKN) and decaprenyl diphosphate synthase subunit 2 (PDSS2) were correlated with sensitivity and resistance to radicicol derivatives. We also identified a relationship between resistance to HSP90 inhibition and the p53 pathway by glucose deprivation. In contrast, arginine biosynthesis was correlated with sensitivity to HSP90 inhibitors. Further study of these outcomes could enable the development of strategies to improve the clinical efficacy of HSP90 inhibition in patients with lung adenocarcinoma.
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http://dx.doi.org/10.3390/ijms22052538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962034PMC
March 2021

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

Cancers (Basel) 2020 Dec 11;12(12). Epub 2020 Dec 11.

Institute of Biomedicine of Seville (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Seville, Spain.

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.
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http://dx.doi.org/10.3390/cancers12123729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763130PMC
December 2020

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

Cancers (Basel) 2020 Jul 27;12(8). Epub 2020 Jul 27.

Institute of Biomedicine of Seville (IBiS) (HUVR, CSIC, Universidad de Sevilla), 41013 Seville, Spain.

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 ( and antisense 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, and 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 and expression levels were significantly associated with worsening disease progression. In addition, low levels of 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.
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http://dx.doi.org/10.3390/cancers12082075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466018PMC
July 2020

Brief Report: Toll-like Receptor 9-1635A/G Polymorphism Is Associated With HIV-1 Rebound After Four Weeks of Interruption of Antiretroviral Therapy.

J Acquir Immune Defic Syndr 2020 10;85(2):252-256

Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC.

Objectives: This study aims to analyze the association of the presence of common polymorphisms [single nucleotide polymorphisms (SNPs)] on Toll-like receptors (TLRs), such as TLR9-1635A/G, TLR2-1892A/C, TLR2-2258G/A, TLR4-899A/G, and TLR4-1196C/T, with the viral rebound after stopping antiretroviral treatment (ART). CCR5-Δ32 deletion and HLA-A/HLA-B alleles were also analyzed.

Design: Interruption of ART may be required to investigate the outcome of strategies aimed to achieve drug-free HIV remission or cure. However, interruption of ART is currently not indicated. This was a retrospective longitudinal study that included 57 long-term suppressed HIV-1-infected individuals.

Methods: TLR SNPs were detected by real-time polymerase chain reaction (PCR). CCR5-Δ32 was analyzed by conventional PCR and HLA-A and HLA-B alleles by PCR-SSOP Luminex.

Results: HIV-1 RNA rebound at week 4 after treatment interruption positively correlated with pre-ART HIV-1 load (P = 0.025). The TLR9-1635AA genotype was independently associated with a higher HIV-1 rebound compared with those with AG + GG genotype (multivariate stepwise regression analysis, P = 0.004). Women had lower HIV-1 RNA load both at rebound and during the 72 weeks of follow-up compared with men (P < 0.05 at all time-points), whereas CD4 nadir and CD4 count set-point were similar according to sex. The pre-ART viral load was independently associated with the viral set-point (P = 0.001), whereas the presence of the HLA-A01 allele (P = 0.027) and the CD4 nadir (P = 0.001) were associated with the CD4 count set-point.

Conclusions: The association of the TLR9-1635AA genotype with a higher HIV-1 rebound suggests that this SNP may affect the results from strategies requiring interruption of ART aimed to cure HIV-1 infection.
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http://dx.doi.org/10.1097/QAI.0000000000002437DOI Listing
October 2020

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

EBioMedicine 2020 Mar 27;53:102683. Epub 2020 Feb 27.

H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain; Medical Oncology Department, Hospital Universitario Doce de Octubre. Madrid, Spain; Medical School, Universidad Complutense, Madrid, Spain.

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.
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http://dx.doi.org/10.1016/j.ebiom.2020.102683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047190PMC
March 2020

MicroRNAs as potential predictors of extreme response to tyrosine kinase inhibitors in renal cell cancer.

Urol Oncol 2020 07 18;38(7):640.e23-640.e29. Epub 2020 Feb 18.

Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain. Electronic address:

Background: MicroRNAs play an important role as modulators of gene expression in several biological processes and are closely related to development and cell differentiation regulation. Previous works have revealed a potential predictive role for miRNAs in different tumor types. This study aims to analyze the ability of miRNAs in segregating metastatic renal cell carcinoma patients according to their responses to tyrosine kinase inhibitors (TKIs).

Methods: Extreme responders were considered in the study and were defined as those patients that either had a long-term response (LR) (progression-free survival ˃11 months) or those that were primary refractory (PR) (progression as best response). The expression of 754 miRNAs was analyzed in tumor tissue of these 2 sets of patients.

Results: In a study cohort (n = 15) 4 miRNAs were significantly associated with patient response and differentially expressed in PR vs. LR (up-regulated in PR vs. LR: miR-425-5p, down-regulated in PR vs. LR: miR-139-3p, let-7d and let-7e). Further analysis in a validation cohort (n = 36) revealed similar results.

Conclusion: The present data strength the potential role of miRNAs as a tool to predict treatment outcomes in patients with metastatic renal cell carcinoma treated with TKIs.
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http://dx.doi.org/10.1016/j.urolonc.2020.01.012DOI Listing
July 2020

Epigenetics of lung cancer: a translational perspective.

Cell Oncol (Dordr) 2019 Dec 8;42(6):739-756. Epub 2019 Aug 8.

Unidad Clínica de Oncología Médica, Radioterapia y Radiofísica, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Avda. Manuel Siurot s/n, 41013, Seville, Spain.

Background: Lung cancer remains the most common cause of cancer-related death, with a 5-year survival rate of only 18%. In recent years, the development of targeted pharmacological agents and immunotherapies has substantially increased the survival of a subset of patients. However, most patients lack such efficacious therapy and are, thus, treated with classical chemotherapy with poor clinical outcomes. Therefore, novel therapeutic strategies are urgently needed. In recent years, the development of epigenetic assays and their application to cancer research have highlighted the relevance of epigenetic regulation in the initiation, development, progression and treatment of lung cancer.

Conclusions: A variety of epigenetic modifications do occur at different steps of lung cancer development, some of which are key to tumor progression. The rise of cutting-edge technologies such as single cell epigenomics is, and will continue to be, crucial for uncovering epigenetic events at a single cell resolution, leading to a better understanding of the biology underlying lung cancer development and to the design of novel therapeutic options. This approach has already led to the development of strategies involving single agents or combined agents targeting epigenetic modifiers, currently in clinical trials. Here, we will discuss the epigenetics of every step of lung cancer development, as well as the translation of these findings into clinical applications.
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http://dx.doi.org/10.1007/s13402-019-00465-9DOI Listing
December 2019

Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry.

Cells 2019 07 31;8(8). Epub 2019 Jul 31.

H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.

Heat shock protein 90 (HSP90) is an important chaperone in lung adenocarcinoma, with relevant protein drivers such as EGFR (epidermal growth factor receptor) and EML4-ALK (echinoderm microtubule-associated protein-like protein4 fused to anaplastic lymphoma kinase) depending on it for their correct function, therefore HSP90 inhibitors show promise as potential treatments for lung adenocarcinoma. To study responses to its inhibition, HSP90 was pharmacologically interrupted by geldanamycin and resorcinol derivatives or with combined inhibition of HSP90 plus HSP70 in lung adenocarcinoma cell lines. Two-dimensional electrophoresis was performed to identify proteomic profiles associated with inhibition which will help to understand the biological basis for the responses. HSP90 inhibition resulted in altered protein profiles that differed according the treatment condition studied. Results revealed 254 differentially expressed proteins after treatments, among which, eukaryotic translation initiation factor3 subunit I (eIF3i) and citrate synthase demonstrated their potential role as response biomarkers. The differentially expressed proteins also enabled signalling pathways involved in responses to be identified; these included apoptosis, serine-glycine biosynthesis and tricarboxylic acid cycle. The proteomic profiles identified here contribute to an improved understanding of HSP90 inhibition and open possibilities for the detection of potential response biomarkers which will be essential to maximize treatment efficacy in lung adenocarcinoma.
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http://dx.doi.org/10.3390/cells8080806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721529PMC
July 2019

A patent review of FGFR4 selective inhibition in cancer (2007-2018).

Expert Opin Ther Pat 2019 06 30;29(6):429-438. Epub 2019 May 30.

b CNIO-H12O Lung Clinical Cancer Research Unit , Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO) , Madrid , Spain.

Introduction: FGFR4 is a tyrosine kinase receptor which, under physiological conditions, is activated upon ligand binding in a highly regulated manner. This triggers downstream signaling related to proliferation and apoptosis resistance as well as other physiological processes. Many molecular alterations of the receptor and its ligands, specially FGF19, have been reported in several types of cancer, with special relevance in hepatocellular carcinoma. In addition, these have also been detected in other solid malignancies, including lung, breast, or colon cancer, among others.

Areas Covered: This review covers patent literature on specific FGFR4 inhibitors and their applications, published from 2007 to June 2018.

Expert Opinion: FGFR4 inhibition has gained relevance in oncology. A considerable number of patents disclosing different approaches to inhibit this receptor have been reported, displaying promising preclinical results for different cancer models. Currently, the safety and preliminary efficacy of several small molecule inhibitors targeting FGFR4 are under early phase clinical assessment, mainly in hepatocellular carcinoma patients. If positive results are derived from these trials, they will open the door for the application of FGFR4 small molecule inhibitors to a wide population of tumors of different types that harbor FGFR4-FGF19 signaling dysregulation.
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http://dx.doi.org/10.1080/13543776.2019.1624720DOI Listing
June 2019

FGFR4 increases EGFR oncogenic signaling in lung adenocarcinoma, and their combined inhibition is highly effective.

Lung Cancer 2019 05 8;131:112-121. Epub 2019 Feb 8.

H120-CNIO Lung Cancer Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; Medical Oncology Department, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; Medical School, Universidad Complutense, Madrid, Spain; CIBERONC, Madrid, Spain. Electronic address:

Objectives: Lung adenocarcinoma accounts for approximately half of lung cancer cases. Twenty to 50% of tumors of this type harbor mutations affecting epidermal growth factor receptor (EGFR) expression or activity, which can be therapeutically targeted. EGFR inhibitors in this context exhibit high efficacy and are currently used in the clinical setting. However, not all adenocarcinomas harboring EGFR mutations respond to therapy, so predictive biomarkers of therapeutic outcomes, as well as novel therapies sensitizing these tumors to EGFR inhibition, are needed.

Materials And Methods: We performed in vitro gene overexpression/silencing and tumorigenic surrogate assays, as well as in vitro and in vivo combination treatments with Fibroblast Growth Factor Receptor (FGFR)/EGFR inhibitors. At the clinical level, we determined FGFR4 expression levels in tumors from patients treated with EGFR inhibitors and correlated these with treatment response.

Results: We describe a cooperative interaction between EGFR and FGFR4, which results in their reciprocal activation with pro-oncogenic consequences in vitro and in vivo. This cooperation is independent of EGFR activating mutations and increases resistance to different EGFR inhibitors. At the therapeutic level, we provide evidence of the synergistic effects of the combination of EGFR and FGFR inhibitors in high FGFR4-expressing, EGFR-activated tumors in vitro and in vivo. Correlated with these results, we found that patients treated with EGFR inhibitors relapse earlier when their tumors exhibit high FGFR4 expression.

Conclusions: We propose a novel predictive biomarker for EGFR-targeted therapy, and a highly efficacious combinatory therapeutic strategy to treat EGFR-dependent; this may may extend the use of appropriate inhibitors beyond EGFR-mutated adenocarcinoma patients.
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http://dx.doi.org/10.1016/j.lungcan.2019.02.007DOI Listing
May 2019

FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy.

J Thorac Oncol 2019 04 9;14(4):641-655. Epub 2019 Jan 9.

H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain; Medical Oncology Department, University Hospital Doce de Octubre Madrid, Spain; Medical School, Complutense University, Madrid, Spain.

Introduction: There is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma.

Methods: We performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line- and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti-EGFR therapy-treated adenocarcinoma.

Results: We have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor-treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line- and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition.

Conclusion: These results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.
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http://dx.doi.org/10.1016/j.jtho.2018.12.021DOI Listing
April 2019

Long non-coding RNAs as monitoring tools and therapeutic targets in breast cancer.

Cell Oncol (Dordr) 2019 Feb 25;42(1):1-12. Epub 2018 Oct 25.

Unit of Integral Oncology, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Seville, Spain.

Background: Current therapeutic strategies that are used to combat breast cancer vary widely and largely depend on its clinicopathological features, including tumor subtype, size, stage, lymph node involvement, the presence of hormone receptors and/or HER2, as well as the degree of proliferative activity. Recent work has focused on improving our knowledge on the molecular mechanisms that underlie this complex disease. Most of the human genome is transcribed into RNAs that do not encode proteins. These noncoding RNAs may act as mediators in the regulation of gene expression. Based on their size and function, noncoding RNAs are classified into small noncoding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs). LncRNAs have been found to play key roles in relevant biological processes, including breast cancer. As such, lncRNAs have been proposed as diagnostic and prognostic biomarkers, as predictive biomarkers and as putative therapeutic targets.

Conclusions: In this review, we discuss the potential application of lncRNAs for the monitoring and treatment of breast cancer. We conclude that lncRNAs play important roles in the pathophysiology of this disease and may serve as putative therapeutic targets. As such, tumor-specific lncRNAs may be instrumental for improving current breast cancer clinical practices.
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http://dx.doi.org/10.1007/s13402-018-0412-6DOI Listing
February 2019

MAP17 predicts sensitivity to platinum-based therapy, EGFR inhibitors and the proteasome inhibitor bortezomib in lung adenocarcinoma.

J Exp Clin Cancer Res 2018 Aug 17;37(1):195. Epub 2018 Aug 17.

CIBER de Cáncer, ISCIII, Madrid, Spain.

Background: The high incidence and mortality of lung tumours is a major health problem. Therefore, the identification both of biomarkers predicting efficacy for therapies in use and of novel efficacious therapeutic agents is crucial to increase patient survival. MAP17 (PDZK1IP1) is a small membrane-bound protein whose upregulation is reported as a common feature in tumours from diverse histological origins. Furthermore, MAP17 is correlated with tumour progression.

Methods: We assessed the expression of MAP17 in preclinical models, including cell lines and patient-derived xenografts (PDXs), assessing its correlation with sensitivity to different standard-of-care drugs in lung adenocarcinoma, as well as novel drugs. At the clinical level, we subsequently correlated MAP17 expression in human tumours with patient response to these therapies.

Results: We show that MAP17 expression is induced during lung tumourigenesis, particularly in lung adenocarcinomas, and provide in vitro and in vivo evidence that MAP17 levels predict sensitivity to therapies currently under clinical use in adenocarcinoma tumours, including cisplatin, carboplatin and EGFR inhibitors. In addition, we show that MAP17 expression predicts proteasome inhibitor efficacy in this context and that bortezomib, an FDA-approved drug, may be a novel therapeutic approach for MAP17-overexpressing lung adenocarcinomas.

Conclusions: Our results indicate a potential prognostic role for MAP17 in lung tumours, with particular relevance in lung adenocarcinomas, and highlight the predictive pot0065ntial of this membrane-associated protein for platinum-based therapy and EGFR inhibitor efficacy. Furthermore, we propose bortezomib treatment as a novel and efficacious therapy for lung adenocarcinomas exhibiting high MAP17 expression.
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http://dx.doi.org/10.1186/s13046-018-0871-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098621PMC
August 2018

Corrigendum to "Proteomic-Based Approaches for the Study of Cytokines in Lung Cancer".

Dis Markers 2018 8;2018:1404780. Epub 2018 Jul 8.

Medical Oncology Department, Hospital Universitario Doce de Octubre and Centro Nacional de Investigaciones Oncológicas (CNIO), 28041 Madrid, Spain.

[This corrects the article DOI: 10.1155/2016/2138627.].
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http://dx.doi.org/10.1155/2018/1404780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057326PMC
July 2018

Histology-dependent prognostic role of pERK and p53 protein levels in early-stage non-small cell lung cancer.

Oncotarget 2018 Apr 13;9(28):19945-19960. Epub 2018 Apr 13.

H120-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación 12 de Octubre and CNIO, Madrid, Spain.

Lung tumors represent a major health problem. In early stage NSCLC tumors, surgical resection is the preferred treatment, but 30-55% of patients will relapse within 5 years after surgery. Thus, the identification of prognostic biomarkers in early stage NSCLC patients, especially those which are therapeutically addressable, is crucial to enhance survival of these patients. We determined the immunohistochemistry expression of key proteins involved in tumorigenesis and oncogenic signaling, p53, EGFR, pAKT and pERK, and correlated their expression level to clinicopathological characteristics and patient outcome. We found EGFR expression is higher in the squamous cell carcinomas than in adenocarcinomas (p=0.043), and that nuclear p53 staining correlated with lower differentiated squamous tumors (p=0.034). Regarding the prognostic potential of the expression of these proteins, high pERK levels proved to be an independent prognostic factor for overall (p<0.001) and progression-free survival (p<0.001) in adenocarcinoma patients, but not in those from the squamous histology, and high p53 nuclear levels were identified as independent prognostic factor for progression-free survival (p=0.031) only in squamous cell carcinoma patients. We propose a role as early prognostic biomarkers for pERK protein levels in adenocarcinoma, and for nuclear p53 levels in squamous cell lung carcinoma. The determination of these potential biomarkers in the adequate histologic context may predict the outcome of early stage NSCLC patients, and may offer a therapeutic opportunity to enhance survival of these patients.
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http://dx.doi.org/10.18632/oncotarget.24977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929438PMC
April 2018

The FGFR4-388arg Variant Promotes Lung Cancer Progression by N-Cadherin Induction.

Sci Rep 2018 02 5;8(1):2394. Epub 2018 Feb 5.

Medical Oncology Department, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.

The FGFR4-388Arg variant has been related to poor prognosis in several types of cancer, including lung cancer. The mechanism underlying this association has not been addressed in detail in patients with this pathology. Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro-oncogenic effects in NSCLC in vitro and in vivo. This variant induces the expression of EMT-related genes, such as N-cadherin, vimentin, Snail1 and Twist1. Indeed, the induction of N-cadherin protein expression by this variant is essential for its pro-tumorigenic role. The presence of the FGFR4-388Arg variant correlates with higher N-cadherin expression levels in clinical NSCLC samples and with poorer outcome in patients with FGFR expression. These results support the prognostic role of this FGFR variant in lung cancer and show that these effects may be mediated by the induction of N-cadherin expression and an EMT phenotype.
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http://dx.doi.org/10.1038/s41598-018-20570-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799167PMC
February 2018

Single nucleotide polymorphisms as prognostic and predictive biomarkers in renal cell carcinoma.

Oncotarget 2017 Dec 20;8(63):106551-106564. Epub 2017 Nov 20.

Instituto de Biomedicina de Sevilla, IBiS, Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Sevilla, Spain.

Despite major advances in the knowledge of the molecular basis of renal cell carcinoma, prognosis is still defined using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. With these premises, we aimed to analyse the expression and to determine the prognostic and predictive value of 64 key single nucleotide polymorphisms in 18 genes related with angiogenesis or metabolism of antiangiogenics in two cohorts of patients with localized and advanced renal cell cancer treated at our institution. The presence of the selected single nucleotide polymorphisms was correlated with clinical features, disease free survival, overall survival and response rate. In patients with localized renal cell cancer, 5 of these polymorphisms in 3 genes involved in angiogenesis predicted for worse disease free survival (VEGFR2: rs10013228; PDGFRA: rs2228230) or shorter overall survival (VEGFR2: rs10013228; VEGFR3: rs6877011, rs307826) ( < 0.05). Rs2071559 in VEGFR2 showed a protective effect ( = 0.01). In the advanced setting, 5 SNPs determined inferior overall survival (IL8: rs2227543, PRKAR1B: rs9800958, PDGFRB: rs2302273; = 0.05) or worse response rate (VEGFA: rs699947, rs3025010 ≤ 0.01)). Additionally 1 single nucleotide polymorphism in VEGFB predicted for better response rate rs594942 ( = 0.03). Genetic analysis of renal cell carcinoma patients might provide valuable prognostic/predictive information. A set of SNPs in genes critical to angiogenesis and metabolism of antiangiogenics drugs seem to determine post-surgical outcomes and treatment response in our series.
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http://dx.doi.org/10.18632/oncotarget.22533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739755PMC
December 2017

Coordinated downregulation of Spinophilin and the catalytic subunits of PP1, PPP1CA/B/C, contributes to a worse prognosis in lung cancer.

Oncotarget 2017 Dec 26;8(62):105196-105210. Epub 2017 Oct 26.

Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Sevilla, Spain.

The scaffold protein Spinophilin (Spinophilin, PPP1R9B) is one of the regulatory subunits of phosphatase-1 (PP1), directing it to distinct subcellular locations and targets. The loss of Spinophilin reduces PP1 targeting to pRb, thereby maintaining higher levels of phosphorylated pRb. Spinophilin is absent or reduced in approximately 40% of human lung tumors, correlating with the malignant grade. However, little is known about the relevance of the coordinated activity or presence of Spinophilin and its reported catalytic partners in the prognosis of lung cancer. In the present work, we show that the downregulation of Spinophilin, either by protein or mRNA, is related to a worse prognosis in lung tumors. This effect is more relevant in squamous cell carcinoma, SCC, than in adenocarcinoma. Downregulation of Spinophilin is related to a decrease in the levels of its partners PPP1CA/B/C, the catalytic subunits of PP1. A decrease in these subunits is also related to prognosis in SCC and, in combination with a decrease in Spinophilin, are markers of a poor prognosis in these tumors. The analysis of the genes that correlate to Spinophilin in lung tumors showed clear enrichment in ATP biosynthesis and protein degradation GO pathways. The analysis of the response to several common and pathway-related drugs indicates a direct correlation between the Spinophilin/PPP1Cs ratio and the response to oxaliplatin and bortezomib. This finding indicates that this ratio may be a good predictive biomarker for the activity of the drugs in these tumors with a poor prognosis.
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http://dx.doi.org/10.18632/oncotarget.22111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739631PMC
December 2017

Prognostic Role of the FGFR4-388Arg Variant in Lung Squamous-Cell Carcinoma Patients With Lymph Node Involvement.

Clin Lung Cancer 2017 11 10;18(6):667-674.e1. Epub 2017 May 10.

Department of Medical Oncology, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Medical School, Universidad Complutense, Madrid, Spain. Electronic address:

Background: The identification of prognostic biomarkers for lung squamous-cell carcinoma (SCC) pathology is crucial because of its poor prognosis. A variant of the FGFR4 (fibroblast growth factor receptor 4) gene, FGFR4-388Arg, has been associated with prognosis and is linked to oncogenesis in vitro in several types of cancer. We analyzed the association of this variant with prognosis and downstream signaling alteration in lung SCC patients.

Methods: The presence of the FGFR4-388Arg variant was determined in 114 formalin-fixed, paraffin-embedded lung SCC tissue samples by DNA genotyping and was correlated with clinicopathologic data. The activation of the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways was determined by immunohistochemistry, and its association with the presence of FGFR4-388Arg was analyzed.

Results: We found that tumor differentiation status and adjuvant chemotherapy administration could be independent prognostic factors for overall survival (OS) in lymph node-affected patients, as expected. The progression-free survival and OS of patients with lymph node involvement (n = 41) and the FGFR4-388Arg genotype were significantly lower than those of patients lacking this variant (P = .035 and P = .042, respectively). Importantly, multivariate analysis supported the independent prognostic role of the FGFR4-388Arg genotype in OS (P = .025). Regarding downstream signaling, the FGFR4-388Arg genotype was not correlated with altered AKT signaling but was associated with increased MAPK activation in the SCC tumor samples (P = .017).

Conclusion: The FGFR4-388Arg variant may represent a promising prognostic biomarker in SCC patients with lymph node involvement. For these patients, FGFR4 may be a potential therapeutic target.
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http://dx.doi.org/10.1016/j.cllc.2017.05.008DOI Listing
November 2017

Biological therapies in nonsmall cell lung cancer.

Eur Respir J 2017 03 2;49(3). Epub 2017 Mar 2.

Medical Oncology Dept, Hospital Universitario 12 de Octubre and Instituto de Investigación i+12, Madrid, Spain

Biological therapies have improved survival outcomes of advanced-stage nonsmall cell lung cancer (NSCLC). Genotype-directed therapies have changed treatment paradigms of patients with -mutant and -rearranged lung adenocarcinomas, and the list of druggable targets with demonstrated clinical actionability ( and ) continues to expand. Furthermore, we have incrementally understood the mechanisms of cancer immune evasion and foresee ways to effectively circumvent them, particularly at the immune checkpoint level. Drugs targeting the tumour immune-evasive PD-1 pathway have demonstrated remarkable treatment benefits in this disease, with a non-negligible fraction of patients potentially receiving long-term survival benefits. Herein, we briefly discuss the role of various medical disciplines in the management of advanced-stage NSCLC and review the most relevant biological therapies for this disease, with particular emphasis in genotype-directed therapies and immune checkpoint inhibitors.
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http://dx.doi.org/10.1183/13993003.01520-2016DOI Listing
March 2017

Numb-like (NumbL) downregulation increases tumorigenicity, cancer stem cell-like properties and resistance to chemotherapy.

Oncotarget 2016 09;7(39):63611-63628

Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Seville, Spain.

NumbL, or Numb-like, is a close homologue of Numb, and is part of an evolutionary conserved protein family implicated in some important cellular processes. Numb is a protein involved in cell development, in cell adhesion and migration, in asymmetric cell division, and in targeting proteins for endocytosis and ubiquitination. NumbL exhibits some overlapping functions with Numb, but its role in tumorigenesis is not fully known. Here we showed that the downregulation of NumbL alone is sufficient to increase NICD nuclear translocation and induce Notch pathway activation. Furthermore, NumbL downregulation increases epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related gene transcripts and CSC-like phenotypes, including an increase in the CSC-like pool. These data suggest that NumbL can act independently as a tumor suppressor gene. Furthermore, an absence of NumbL induces chemoresistance in tumor cells. An analysis of human tumors indicates that NumbL is downregulated in a variable percentage of human tumors, with lower levels of this gene correlated with worse prognosis in colon, breast and lung tumors. Therefore, NumbL can act as an independent tumor suppressor inhibiting the Notch pathway and regulating the cancer stem cell pool.
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http://dx.doi.org/10.18632/oncotarget.11553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325389PMC
September 2016

IL-11 and CCL-1: Novel Protein Diagnostic Biomarkers of Lung Adenocarcinoma in Bronchoalveolar Lavage Fluid (BALF).

J Thorac Oncol 2016 12 12;11(12):2183-2192. Epub 2016 Aug 12.

Biomedicine Institute of Seville-IBIS (Virgen del Rocio University Hospital, US, CSIC), Seville, Spain. Electronic address:

Introduction: Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are smoking-related diseases, with the presence of COPD itself increasing the risk for development of LC, probably owing to underlying inflammation. LC is typically detected at late stages of the disease and carries a poor prognosis. There is an unmet need for methods to facilitate the early detection of LC in high-risk subjects such as smokers.

Methods: The expression of inflammatory proteins in bronchoalveolar lavage fluid (BALF) samples was studied by antibody arrays in a prospective cohort of 60 smokers of more than 30 pack-years divided into four groups (control, patients with LC, patients with COPD, and patients with LC plus COPD). Relevant biomarkers were validated by Western blot. Additional validation with enzyme-linked immunosorbent assay (ELISA) was carried out on two independent controlled cohorts of 139 patients (control, patients with LC, patients with COPD, and patients with LC plus COPD) and 160 patients (control and patients with LC of all histological types).

Results: A total of 16 differentially expressed proteins in samples from patients with LC, COPD, and LC plus COPD were identified by antibody arrays and validated by Western blot and ELISA. C-C motif chemokine ligand 1 (CCL-1) and interleukin-11 (IL)-11 were selectively expressed in samples from patients with adenocarcinoma with or without COPD (p < 0.005). These proteins exhibited a remarkable diagnostic performance for lung adenocarcinoma in an independent cohort of 139 patients. Receiver operating characteristic curves showed that the optimum diagnostic cutoff value for IL-11 was 42 pg/mL (area under the curve = 0.93 [95% confidence interval: 0.896-0.975], sensitivity 90%, specificity 86%), whereas for CCL-1 it was 39.5 pg/mL (0.83 [95% confidence interval: 0.749-0.902], sensitivity 83%, and specificity 74%). Further validation of the ELISA biomarkers at the aforementioned cutoffs was performed in an additional cohort of 160 patients (20 controls, 66 patients with LC, and 74 patients with LC plus COPD). There was a significant correlation between BALF levels of IL-11 and CCL-1 (r = 0.76, p < 0.001), and the use of both biomarkers increased the diagnostic accuracy to 96.1% in the two validation cohorts. Appropriate diagnostic performance was observed for all subgroups regardless of stage at diagnosis, involvement of the bronchial tract, pack-years smoked, and number of cells in BALF.

Conclusions: IL-11 and CCL-1 are highly specific biomarkers with great accuracy for the diagnosis of lung adenocarcinoma in BALF specimens. Further study of these proteins as markers for the early diagnosis and screening of plasma and other biological materials is warranted.
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http://dx.doi.org/10.1016/j.jtho.2016.07.026DOI Listing
December 2016

Analysis of the immune microenvironment in resected non-small cell lung cancer: the prognostic value of different T lymphocyte markers.

Oncotarget 2016 08;7(33):52849-52861

Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain.

The prognosis of non-small cell lung cancer (NSCLC) remains poor and heterogeneous and new biomarkers are needed. As the immune system plays a pivotal role in cancer, the study of immune-related markers may provide valuable prognostic information of NSCLC. In 122 formalin-fixed, paraffin-embedded tumor tissue samples from early-stage NSCLC, tumor and tumor-near stromal areas were microdissected and gene expression levels of conventional and regulatory T cell markers were assessed by quantitative polymerase chain reaction. Also, the presence of infiltrating CD4+, CD8+, and FOXP3+ cells in tumor samples was assessed by immunohistochemistry. The relative proportion of conventional and regulatory T cells present in the tumor environment was assessed and found to be key to understand the importance that the immune system analysis has in the prognostics of NSCLC patients. The presence of CD8+ cells in the tumor compartment was associated with better outcome, whereas the presence of FOXP3+ cells was associated with worse overall survival. The negative prognostic value of combined biomarkers, indicating high levels of FOXP3 in the stroma and low levels of CD4 or CD8 in tumors, was observed at mRNA level and was validated by immunohistochemistry.In conclusion, the proportion of T helper and cytotoxic cells vs. regulatory T cells in different locations of the tumor microenvironment have opposite prognostic impacts in resected NSCLC.
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http://dx.doi.org/10.18632/oncotarget.10811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288153PMC
August 2016

Proteomic-Based Approaches for the Study of Cytokines in Lung Cancer.

Dis Markers 2016 30;2016:2138627. Epub 2016 Jun 30.

Medical Oncology Department, Hospital Universitario Doce de Octubre and Centro Nacional de Investigaciones Oncológicas (CNIO), 28041 Madrid, Spain.

Proteomic techniques are currently used to understand the biology of different human diseases, including studies of the cell signaling pathways implicated in cancer progression, which is important in knowing the roles of different proteins in tumor development. Due to its poor prognosis, proteomic approaches are focused on the identification of new biomarkers for the early diagnosis, prognosis, and targeted treatment of lung cancer. Cytokines are proteins involved in inflammatory processes and have been proposed as lung cancer biomarkers and therapeutic targets because it has been reported that some cytokines play important roles in tumor development, invasion, and metastasis. In this review, we aim to summarize the different proteomic techniques used to discover new lung cancer biomarkers and therapeutic targets. Several cytokines have been identified as important players in lung cancer using these techniques. We underline the most important cytokines that are useful as biomarkers and therapeutic targets. We also summarize some of the therapeutic strategies targeted for these cytokines in lung cancer.
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http://dx.doi.org/10.1155/2016/2138627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944034PMC
February 2017

Impact of DLK1-DIO3 imprinted cluster hypomethylation in smoker patients with lung cancer.

Oncotarget 2018 Jan 15;9(4):4395-4410. Epub 2016 Jul 15.

Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.

DNA methylation is important for gene expression and genome stability, and its disruption is thought to play a key role in the initiation and progression of cancer and other diseases. The cluster has been shown to be imprinted in humans, and some of its components are relevant to diverse pathological processes. The purpose of this study was to assess the methylation patterns of the cluster in patients with lung cancer to study its relevance in the pathogenesis of this disease. We found a characteristic methylation pattern of this cluster in smoking associated lung cancer, as compared to normal lung tissue. This methylation profile is not patent however in lung cancer of never smokers nor in lung tissue of COPD patients. We found 3 deregulated protein-coding genes at this locus: one was hypermethylated () and two were hypomethylated ( and ). Statistically significant differences were also detected in two different families of SNORDs, two miRNA clusters and four lncRNAs (, , and ). These findings were validated using data from the cancer genome atlas (TCGA) database. We have then showed an inverse correlation between DNA methylation and expression levels in 5 randomly selected genes. Several targets of miRNAs included in the cluster have been experimentally verified as tumor suppressors. All of these results suggest that the dysmethylation of the imprinted cluster could have a relevant role in the pathogenesis of lung cancer in current and former smokers and may be used for diagnostic and/or therapeutic purposes.
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http://dx.doi.org/10.18632/oncotarget.10611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796982PMC
January 2018

Current Challenges in Cancer Treatment.

Clin Ther 2016 Jul 2;38(7):1551-66. Epub 2016 May 2.

Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; Instituto de Investigación I+12. Lung Cancer Clinical Research Unit CNIO, I+12, Madrid, Spain. Electronic address:

Purpose: In this review, we highlight the current concepts and discuss some of the current challenges and future prospects in cancer therapy. We frequently use the example of lung cancer.

Methods: We conducted a nonsystematic PubMed search, selecting the most comprehensive and relevant research articles, clinical trials, translational papers, and review articles on precision oncology and immuno-oncology. Papers were prioritized and selected based on their originality and potential clinical applicability.

Findings: Two major revolutions have changed cancer treatment paradigms in the past few years: targeting actionable alterations in oncogene-driven cancers and immuno-oncology. Important challenges are still ongoing in both fields of cancer therapy. On the one hand, druggable genomic alterations are diverse and represent only small subsets of patients in certain tumor types, which limits testing their clinical impact in biomarker-driven clinical trials. Next-generation sequencing technologies are increasingly being implemented for molecular prescreening in clinical research, but issues regarding clinical interpretation of large genomic data make their wide clinical use difficult. Further, dealing with tumor heterogeneity and acquired resistance is probably the main limitation for the success of precision oncology. On the other hand, long-term survival benefits with immune checkpoint inhibitors (anti-programmed death cell protein-1/programmed death cell ligand-1[PD-1/L1] and anti-cytotoxic T lymphocyte antigen-4 monoclonal antibodies) are restricted to a minority of patients, and no predictive markers are yet robustly validated that could help us recognize these subsets and optimize treatment delivery and selection. To achieve long-term survival benefits, drug combinations targeting several molecular alterations or cancer hallmarks might be needed. This will probably be one of the most challenging but promising precision cancer treatment strategies in the future.

Implications: Targeting single molecular abnormalities or cancer pathways has achieved good clinical responses that have modestly affected survival in some cancers. However, this approach to cancer treatment is still reductionist, and many challenges need to be met to improve treatment outcomes with our patients.
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http://dx.doi.org/10.1016/j.clinthera.2016.03.026DOI Listing
July 2016

Gene expression profile predictive of response to chemotherapy in metastatic colorectal cancer.

Oncotarget 2015 Mar;6(8):6151-9

Laboratorio de Oncología Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.

Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal cancer (mCRC) for years. Response rates are only observed, however, in about half of treated patients, and there are no reliable tools to prospectively identify patients more likely to benefit from therapy. The purpose of our study was to identify a gene expression profile predictive of CT response in mCRC. Whole genome expression analyses (Affymetrix GeneChip HG-U133 Plus 2.0) were performed in fresh frozen tumor samples of 37 mCRC patients (training cohort). Differential gene expression profiles among the two study conditions (responders versus non-responders) were assessed using supervised class prediction algorithms. A set of 161 differentially expressed genes in responders (23 patients; 62%) versus non-responders (14 patients; 38%) was selected for further assessment and validation by RT-qPCR (TaqMan Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) in an independent multi-institutional cohort (53 mCRC patients). Seven of these genes were confirmed as significant predictors of response. Patients with a favorable predictive signature had significantly greater response rate (58% vs. 13%, p = 0.024), progression-free survival (61% vs. 13% at 1 year, HR = 0.32, p = 0.009) and overall survival (32 vs. 16 months, HR = 0.21, p = 0.003) than patients with an unfavorable gene signature. This is the first study to validate a gene-expression profile predictive of response to CT in mCRC patients. Larger and prospective confirmatory studies are required, however, in order to successfully provide oncologists with adequate tools to optimize treatment selection in routine clinical practice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467428PMC
http://dx.doi.org/10.18632/oncotarget.3152DOI Listing
March 2015

MiR-107 and miR-99a-3p predict chemotherapy response in patients with advanced colorectal cancer.

BMC Cancer 2014 Sep 7;14:656. Epub 2014 Sep 7.

Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Manuel Siurot s/n, 41013 Seville, Spain.

Background: MicroRNAs (miRNAs) are involved in numerous biological and pathological processes including colorectal cancer (CRC). The aim of our study was to evaluate the ability of miRNA expression patterns to predict chemotherapy response in a cohort of 78 patients with metastatic CRC (mCRC).

Methods: We examined expression levels of 667 miRNAs in the training cohort and evaluated their potential association with relevant clinical endpoints. We identified a miRNA profile that was analysed by RT-qPCR in an independent cohort. For a set of selected miRNAs, bioinformatic target predictions and pathway analysis were also performed.

Results: Eight miRNAs (let-7 g*, miR-107, miR-299-5p, miR-337-5p, miR-370, miR-505*, miR-889 and miR-99a-3p) were significant predictors of response to chemotherapy in the training cohort. In addition, overexpression of miR-107, miR-337-5p and miR-99a-3p, and underexpression of miR-889, were also significantly associated with improved progression-free and/or overall survival. MicroRNA-107 and miR-99a-3p were further validated in an independent cohort as predictive markers for chemotherapy response. In addition, an inverse correlation was confirmed in our study population between miR-107 levels and mRNA expression of several potential target genes (CCND1, DICER1, DROSHA and NFKB1).

Conclusions: MiR-107 and miR-99a-3p were validated as predictors of response to standard fluoropyrimidine-based chemotherapy in patients with mCRC.
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http://dx.doi.org/10.1186/1471-2407-14-656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167263PMC
September 2014

MicroRNA clusters: dysregulation in lung adenocarcinoma and COPD.

Eur Respir J 2014 Jun 17;43(6):1740-9. Epub 2014 Apr 17.

Instituto de Biomedicina de Sevilla (IBIS), HUVR, CSIC, Universidad de Sevilla, Seville, Spain Medical Oncology Dept, Hospital Universitario Virgen del Rocío, Seville, Spain

Lung adenocarcinoma and chronic obstructive pulmonary disease (COPD) are pulmonary diseases that share common aetiological factors (tobacco smoking) and probable dysregulated pathways. MicroRNAs (miRNAs) play an essential role in regulating numerous physiological and pathological processes. The purpose of this study was to assess global miRNA expression patterns in patients with COPD and/or adenocarcinoma to elucidate distinct regulatory networks involved in the pathogenesis of these two smoking-related diseases. Expression of 381 miRNAs was quantified by TaqMan Human MicroRNA A Array v2.0 in bronchoalveolar lavage fluid samples from 87 patients classified into four groups: COPD, adenocarcinoma, adenocarcinoma with COPD, and control (neither COPD nor adenocarcinoma). 11 differentially expressed miRNAs were randomly selected for validation in an independent cohort of 40 patients. Distinct miRNA expression profiles were identified and validated for each pathological group, involving 66 differentially expressed miRNAs. Four miRNA clusters (the mir-17-92 cluster and its paralogues, mir-106a-363 and mir-106b-25; and the miR-192-194 cluster) were upregulated in patients with adenocarcinoma and one miRNA cluster (miR-132-212) was upregulated in patients with COPD. These results contribute to unravelling miRNA-controlled networks involved in the pathogenesis of adenocarcinoma and COPD, and provide new tools of potential use as biomarkers for diagnosis and/or therapeutic purposes.
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http://dx.doi.org/10.1183/09031936.00091513DOI Listing
June 2014

MicroRNA-dependent regulation of transcription in non-small cell lung cancer.

PLoS One 2014 13;9(3):e90524. Epub 2014 Mar 13.

Molecular Oncology and New Therapies Group. Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain; Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain.

Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR-422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090524PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953115PMC
January 2016