Publications by authors named "Laura Ojeda"

6 Publications

  • Page 1 of 1

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

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

Blood Predictive Biomarkers for Patients With Non-small-cell Lung Cancer Associated With Clinical Response to Nivolumab.

Clin Lung Cancer 2020 01 30;21(1):75-85. Epub 2019 Aug 30.

Laboratory of Thoracic and Clinical-Translational Oncology, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain.

Background: Immunotherapy is a promising cancer treatment, but surrogate biomarkers of clinical efficacy have not been fully validated. The aim of this work was to evaluate several biomarkers as predictors of response to nivolumab monotherapy in patients with non-small-cell lung cancer.

Patients And Methods: Blood samples was collected at baseline, at 2 months after treatment start, and at disease progression. Lactate dehydrogenase level (LDH), neutrophils, and leukocyte values were obtained from medical record. Interleukin (IL)-8, IL-11, and kynurenine/tryptophan levels were determined by enzyme-linked immunosorbent assay. Total protein was extracted from circulating CD8+ T cells, and BCL-2 interacting mediator of cell death (BIM) protein expression tested by western blotting.

Results: Baseline LDH levels were significantly higher in non-responder patients than in those who responded (P = .045). The increase in indoleamine 2,3 dioxygenase activity was related to progression of disease, mainly in patients who did not respond to nivolumab treatment (P = .001). Increased levels of circulating IL-8 were observed in initially responding patients at time of progression, and it was related to lower overall survival (hazard ratio, 7.49; P = .025). A highest expression of BIM in circulating CD8+ T cells could be related to clinical benefit. The Student t test and Mann-Whitney U test were used to compare groups for continuous variables. Time to events was estimated using the Kaplan-Meier method, and compared by the log-rank test.

Conclusions: Changes in plasma LDH and IL-8, indoleamine 2,3 dioxygenase activity, and BIM expression in CD8+ T cells could be used to monitor and predict clinical benefit from nivolumab treatment in these patients.
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http://dx.doi.org/10.1016/j.cllc.2019.08.006DOI Listing
January 2020

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

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

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