Grupos Investigadores

Líneas de Investigación

  • Modelos animales de metástasis.
  • Mecanismos de resistencia a terapias dirigidas en cáncer de pulmón.
  • Mecanismos de metástasis.
  • Estudio de biomarcadores de resistencia al tratamiento oncológico y nuevas dianas terapéuticas.
  • Combinación de agentes en inmunoterapia del cáncer y marcadores predictivos de respuesta.
  • Aplicación clínica de distintos métodos de biopsia líquida en cáncer.

Palabras Clave

  • Mecanismos de resistencia
  • Mecanismos de metástasis
  • Inmunoterapia
  • Biopsia líquida en tumores sólidos
  • Biomarcadores predistivos

Publicaciones Científicas desde 2018

  • Autores: Alegre Martínez, Estíbaliz (Autor de correspondencia); Sandua Condado, Amaia; Calleja Aznarez, Sofía; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN 2045-2322 Vol.12 N° 1 2022 págs. 9752
    Resumen
    Breath tests used to evaluate carbohydrates malabsorption require baseline H2 and CH4 levels as low as possible. Test cancellation is recommended when exceeding certain cut-offs (H2 ¿ 20 ppm and CH4 ¿ 10 ppm). Although following preparation protocols, many patients have baseline levels above those cut-offs. We investigated if light walking can reduce baseline H2 and CH4 levels. We retrospectively analyzed baseline H2 and CH4 levels from 1552 breath tests. Baseline levels (B1), especially in H2, were lower when obtained at later hours of the day. In those with baseline levels above cut-off, re-sampling (B2) after light walking for one hour, decreased H2 levels 8 ppm (Q1-Q3: 1-18 ppm), and 2 ppm (Q1-Q3: 0-3 ppm) for CH4. Consequently, 40% of tests with elevated B1 levels, presented B2 levels below mentioned cut-offs. Ten percent of tests considered negative when using B1 for calculations, turned positive when using B2 instead. All positive tests when using B1 values, remained elevated when using B2. Re-sampling after light walking for one hour could allow test performance in those with previous elevated baseline levels, avoiding diagnosis delays. Using the second sample for delta calculations identifies positive patients for malabsorption that would have been considered negative.
  • Autores: Alegre Martínez, Estíbaliz; Varo Cenarruzabeitia, Nerea; Fernandez-Calle, P.; et al.
    Revista: CLINICAL CHEMISTRY AND LABORATORY MEDICINE
    ISSN 1434-6621 Vol.60 N° 7 2022 págs. 1003 - 1010
    Resumen
    Objectives Retrospective studies frequently assume analytes long-term stability at ultra-low temperatures. However, these storage conditions, common among biobanks and research, may increase the preanalytical variability, adding a potential uncertainty to the measurements. This study is aimed to evaluate long-term storage stability of different analytes at Methods Twenty-one analytes commonly measured in clinical laboratories were quantified in 60 serum samples. Samples were immediately aliquoted and frozen at <-70 degrees C, and reanalyzed after 11 +/- 3.9 years of storage. A change in concentration after storage was considered relevant if the percent deviation from the baseline measurement was significant and higher than the analytical performance specifications. Results Preanalytical variability (CVP) due to storage, determined by the percentage deviation, showed a noticeable dispersion. Changes were relevant for alanine aminotransferase, creatinine, glucose, magnesium, potassium, sodium, total bilirubin and urate. No significant differences were found in aspartate aminotransferase, calcium, carcinoembryonic antigen, cholesterol, C-reactive protein, direct bilirubin, free thryroxine, gamma-glutamyltransferase, lactate dehydrogenase, prostate-specific antigen, triglycerides, thyrotropin, and urea. As nonnegligible, CVP must remain included in reference change value formula, which was modified to consider whether one or two samples were frozen. Conclusions After long-term storage at ultra-low temperatures, there was a significant variation in some analytes that should be considered. We propose that reference change value formula should include the CVP when analyzing samples stored in these conditions.
  • Autores: Monteiro, C.; Miarka, L.; Perea-García, M.; et al.
    Revista: NATURE MEDICINE
    ISSN 1078-8956 Vol.28 N° 4 2022 págs. 752 - 765
    Resumen
    A comprehensive analysis of models of brain metastasis and multiple cohorts of patient samples identifies a targetable molecular mechanism underlying the resistance to whole-brain radiotherapy that can inform patient selection for personalized radiotherapy. Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-kappa B-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.
  • Autores: Campos-Silva, C.; Cáceres-Martell, Y.; Sánchez-Herrero, E.; et al.
    Revista: JOURNAL OF NANOBIOTECHNOLOGY
    ISSN 1477-3155 Vol.20 N° 1 2022 págs. 72
    Resumen
    Background: Extracellular vesicles (EVs), released by most cell types, provide an excellent source of biomarkers in biological fluids. However, in order to perform validation studies and screenings of patient samples, it is still necessary to develop general techniques permitting rapid handling of small amounts of biological samples from large numbers of donors. Results: Here we describe a method that, using just a few microliters of patient's plasma, identifies tumour markers exposed on EVs. Studying physico-chemical properties of EVs in solution, we demonstrate that they behave as stable colloidal suspensions and therefore, in immunocapture assays, many of them are unable to interact with a stationary functionalised surface. Using flocculation methods, like those used to destabilize colloids, we demonstrate that cationic polymers increase EV zeta-potential, diameter, and sedimentation coefficient and thus, allow a more efficient capture on antibody-coated surfaces by both ELISA and bead-assisted flow cytometry. These findings led to optimization of a protocol in microtiter plates allowing effective immunocapture of EVs, directly in plasma without previous ultracentrifugation or other EV enrichment. The method, easily adaptable to any laboratory, has been validated using plasma from lung cancer patients in which the epithelial cell marker EpCAM has been detected on EVs. Conclusions: This optimized high throughput, easy to automate, technology allows screening of large numbers of patients to phenotype tumour markers in circulating EVs, breaking barriers for the validation of proposed EV biomarkers and the discovery of new ones.
  • Autores: García del Muro, X. (Autor de correspondencia); Durán, I.; Pérez Gracia, José Luis; et al.
    Revista: CLINICAL GENITOURINARY CANCER
    ISSN 1558-7673 Vol.20 N° 4 2022 págs. 388.e1 - 388.e10
    Resumen
    Introduction: The therapeutic repertoire available for advanced renal cell carcinoma (RCC), including tyrosine kinase inhibitors (TKIs) and immunotherapy, required for molecular biomarkers for response. Patients and methods: This was a phase I to II trial on the combination of pazopanib with interferon-alpha (INF-2A) as first-line treatment for advanced RCC. The primary endpoint was recommended phase II dose (RP2D) and efficacy in terms of objective response rate (ORR, RECIST 1.1 criteria). Secondary endpoints included safety and a translational study of molecular biomarkers in serum and exosomes from peripheral blood samples at three-time points: baseline, 8 weeks of treatment, and progression of the disease. Results: Between July 2011 and July 2017, 53 eligible patients were treated and followed up (I, n = 20; II, n = 33). Pazopanib 800 mg + INF-2A 3 MIUs showed a manageable safety profile; therefore, it was selected for dose expansion. Overall, grade 3/4 toxicities were reported in 24 (72.7%) patients. The ORR was 27.2%. The 12-month OS rate was 83.6% (median not reached), and after 30.9 months of follow-up, 24 (72.7%) patients were still alive. CCL2, IL8, TNF-¿, and PD-L1 were significantly overexpressed after treatment initiation, while TGF-ß1 and CCL5 were significantly decreased. TNF-¿, endoglin, and PD-L1 expression are correlated with the response after treatment initiation. Conclusion: The trial did not reach its pre-specified target ORR. However, OS was longer than expected with pazopanib monotherapy. Changes in the molecular profile suggest a crucial role of vascular remodeling and inflammatory-mediated immune cell infiltration in optimal response to pazopanib plus INF-2A.
  • Autores: Szabados, B.; Ponz Sarvisé, Mariano; Machado, R.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.40 N° 6 2022
  • Autores: Sandua Condado, Amaia; Alegre Martínez, Estíbaliz; González Hernández, Álvaro (Autor de correspondencia)
    Revista: CANCERS
    ISSN 2072-6694 Vol.13 N° 17 2021 págs. 4330
    Resumen
    Simple Summary Lung cancer is a leading cause of cancer-related death worldwide and in most cases, detection is usually late and treatment resistance is frequent. For that reason, it is necessary to find biomarkers that could improve the diagnosis and disease management. Exosomes are a type of microvesicles secreted by tumor cells to the medium, with important functions in tumor development. Their analysis can be of utility in diagnosis, including early diagnosis, prognosis, treatment election or follow-up. However, isolation and analysis are cumbersome and can affect the subsequent data information. In this review, we will discuss the recent advances in the role of exosomes in lung cancer and their utility as liquid biopsy, with special attention to isolating methods. Lung cancer is a leading cause of cancer-related death worldwide and in most cases, diagnosis is reached when the tumor has already spread and prognosis is quite poor. For that reason, the research for new biomarkers that could improve early diagnosis and its management is essential. Exosomes are microvesicles actively secreted by cells, especially by tumor cells, hauling molecules that mimic molecules of the producing cells. There are multiple methods for exosome isolation and analysis, although not standardized, and cancer exosomes from biological fluids are especially difficult to study. Exosomes' cargo proteins, RNA, and DNA participate in the communication between cells, favoring lung cancer development by delivering signals for growth, metastasis, epithelial mesenchymal transition, angiogenesis, immunosuppression and even drug resistance. Exosome analysis can be useful as a type of liquid biopsy in the diagnosis, prognosis and follow-up of lung cancer. In this review, we will discuss recent advances in the role of exosomes in lung cancer and their utility as liquid biopsy, with special attention to isolating methods.
  • Autores: Narayanan, S.; Vicent Cambra, Silvestre (Autor de correspondencia); Ponz Sarvisé, Mariano (Autor de correspondencia)
    Revista: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
    ISSN 2296-634X Vol.9 2021 págs. 787249
    Resumen
    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a high mortality rate. The presence of a dense desmoplastic stroma rich in fibroblasts, extracellular matrix, and immune cells plays a critical role in disease progression, therapy response and is a distinguishing feature of PDAC. PDAC is currently treated with a combination of surgery, chemotherapy and radiation therapy in selected cases which results in long-term survival only in a small percentage of patients. Cancer therapies that incorporate immunotherapy-based techniques have become increasingly common in recent years. While such a strategy has been shown to be effective for immunogenic, "hot" tumors like melanoma and lung cancer, thus far PDAC patients display poor responses to this therapeutic approach. Various factors, such as low tumor mutational burden, increased infiltration of immunosuppressive cells, like MDSCs and Treg cells promote tolerance and immune deviation, further aggravating adaptive immunity in PDAC. In this review we will elaborate on the ability of PDAC tumors to evade immune detection. We will also discuss various 3D model system that can be used as a platform in preclinical research to investigate rational combinations of immunotherapy with chemotherapy or targeted therapy, to prime the immune microenvironment to enhance antitumor activity.
  • Autores: Macias Conde, Monica; García Cortés, Ángel; Torres Roca, Marcos; et al.
    Revista: CYTOKINE
    ISSN 1043-4666 Vol.141 2021 págs. 155471
    Resumen
    Background: Myeloid-derived suppressor cells (MDSCs) are relevant in prostate cancer microenvironment collaborating in tumor development. The main tumor marker used in this disease, prostate-specific antigen (PSA), does not provide information related to this tumor microenvironment. Cancer cells secrete exosomes carrying bioactive molecules contributing to MDSCs recruitment and induction. The aim of this study was to characterize the perioperative changes of exosomal cytokines relevant in MDSCs recruitment induced by prostatectomy in prostate cancer patients. Methods: Blood was drawn from 26 early-stage prostate cancer patients before and after radical prostatectomy and from 16 healthy volunteers. Serum exosomes were separated by precipitation. Cytokines related with MDSC cell recruitment and activation CCL2, CXCL2, CXCL5, CXCL8, CXCL12, MIF, S100A9 and TGF-ß were measured in serum and serum-derived exosomes using immunometric assays. Results: All cytokines were detected both in serum and exosomes, except for CXCL12, which was detected only in serum. Exosomes were enriched specially in MIF, TGF-ß and CXCL2. Presurgical MIF levels in exosomes correlated negatively with serum PSA. Also, presurgical TGF-ß decreased both in serum and exosomes as Gleason score rises. Patient¿ presurgical exosomes had increased CCL2, CXCL5 and TGF-ß levels than exosomes from healthy controls. These differences were not observed when cytokines were analyzed in serum, except for TGF-ß. Cytokine ...
  • Autores: Bockorny, B. ; Macarulla, T.; Semenisty, V.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN 1078-0432 Vol.27 N° 18 2021 págs. 5020 - 5027
    Resumen
    Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. Patients and Methods: Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability. Results: A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen. Conclusions: Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.
  • Autores: Rodríguez Pérez, María; Ajona Martínez-Polo, Daniel; Seijo Maceiras, Luis Miguel; et al.
    Revista: TRANSLATIONAL LUNG CANCER RESEARCH
    ISSN 2218-6751 Vol.10 N° 2 2021 págs. 1165-1185
    Resumen
    Low dose computed tomography (LDCT) screening, together with the recent advances in targeted and immunotherapies, have shown to improve non-small cell lung cancer (NSCLC) survival. Furthermore, screening has increased the number of early stage-detected tumors, allowing for surgical resection and multimodality treatments when needed. The need for improved sensitivity and specificity of NSCLC screening has led to increased interest in combining clinical and radiological data with molecular data. The development of biomarkers is poised to refine inclusion criteria for LDCT screening programs. Biomarkers may also be useful to better characterize the risk of indeterminate nodules found in the course of screening or to refine prognosis and help in the management of screening detected tumors. The clinical implications of these biomarkers are still being investigated and whether or not biomarkers will be included in further decision-making algorithms in the context of screening and early lung cancer management still needs to be determined. However, it seems clear that there is much room for improvement even in early stage lung cancer disease-free survival (DFS) rates; thus, biomarkers may be the key to refine risk-stratification and treatment of these patients. Clinicians' capacity to register, integrate, and analyze all the available data in both high risk individuals and early stage NSCLC patients will lead to a better understanding of the disease's mechanisms, and will have a dire
  • Autores: Salas Benito, Diego; Conde Gallastegi, E.; Tamayo Uria, Ibon; et al.
    Revista: BRITISH JOURNAL OF CANCER
    ISSN 0007-0920 Vol.124 N° 6 2021 págs. 1138 - 1149
    Resumen
    Background Adoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those patients capable of rendering tumour-reactive TILs. We have investigated this in ovarian cancer (OC) patients as candidates for TIL therapy implementation. Methods PD-1(-) and PD-1(+) CD8 TILs were isolated from ovarian tumours and expanded cells were tested against autologous tumour cells. Baseline tumour samples were examined using flow cytometry, multiplexed immunofluorescence and Nanostring technology, for gene expression analyses, as well as a next-generation sequencing gene panel, for tumour mutational burden (TMB) calculation. Results Tumour-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1(+) fraction. Importantly, a high TIL density in the fresh tumour, the presence of CD137(+) cells within the PD-1(+)CD8(+) TIL subset and their location in the tumour epithelium, together with a baseline T-cell-inflamed genetic signature and/or a high TMB, are features that identify patients rendering tumour-reactive TIL products. Conclusion We have demonstrated that PD-1 identifies ovarian tumour-specific CD8 TILs and has uncovered predictive factors that identify OC patients who are likely to render tumour-specific cells from PD-1(+) TILs.
  • Autores: Ayala de la Pena, F. (Autor de correspondencia); Ortiz-Munoz, B.; Quintanar-Verduguez, T.; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN 1699-048X Vol.23 N° 7 2021 págs. 1272 - 1280
    Resumen
    The measurement of circulating tumour markers (TMs) for the diagnosis or monitoring of breast cancer has sometimes been considered of limited utility. In addition to the overinterpretation of irrelevant changes in marker levels, the characteristics of the patient, the disease or other pathologies that can modify them are often not considered in their evaluation. On the other hand, there are recent data on the relationship of TMs with molecular subtypes and on their prognostic value, the knowledge of which may improve their clinical utility. This consensus article arises from a collaboration between the Spanish Society of Laboratory Medicine (SEQC(ML)) and the Spanish Society of Medical Oncology (SEOM). It aims to improve the use and interpretation of circulating TMs in breast cancer. The text summarizes the current knowledge and available evidence on the subject and proposes a series of recommendations mainly focussed on the indication, the frequency of testing and the factors that should be considered for correctly interpreting changes in the levels of TMs.
  • Autores: Adkins, D. R. (Autor de correspondencia); Lin, J. C.; Sacco, A.; et al.
    Revista: ORAL ONCOLOGY
    ISSN 1368-8375 Vol.115 2021 págs. 105192
    Resumen
    Objectives: This study examined whether palbociclib and cetuximab prolonged overall survival (OS) versus placebo and cetuximab. Materials and methods: In this double-blind, randomized, phase 2 trial (PALATINUS), patients with platinumresistant, cetuximab-na?ve, human papillomavirus-unrelated recurrent/metastatic head and neck squamouscell carcinoma received cetuximab and either palbociclib (arm A) or placebo (arm B). The primary endpoint was OS; 120 patients were required to have ?80% power to detect a hazard ratio (HR) of 0.6 (median OS of 10 months in arm A and 6 months in arm B) using a one-sided, log-rank test (P = 0.10). Results: 125 patients were randomized (arm A: 65, arm B: 60). Median follow-up was 15.9 months (IQR, 11.3?22.7). Median OS was 9.7 months in arm A and 7.8 months in arm B (HR, 0.82; 95% CI, 0.54?1.25; P = 0.18). Median progression-free survival was 3.9 months in arm A and 4.6 months in arm B (HR, 1.00; 95% CI, 0.67?1.5; P = 0.50). The most common treatment-related adverse events in arm A were rash (39 patients, 60.9%) and neutropenia (26, 40.6%; three febrile) and in arm B was rash (32, 53.3%). Conclusion: There was no significant difference in median OS with palbociclib and cetuximab versus placebo and cetuximab. Funding: Pfizer Inc (NCT02499120).
  • Autores: Gil Bazo, Ignacio; Puyalto Calvo, Ander; Rodríguez Remírez, María; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.32 N° Supl. 5 2021 págs. S1216 - S1217
  • Autores: Narayanan, S.; Erice Azparren, Oihane; Feliu, I.; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.81 N° 22 2021 págs. 59 - 60
  • Autores: Hidalgo, M.; Macarulla, T.; Semenisty, V. ; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.81 N° 13 Supl. S 2021
  • Autores: Puyalto Calvo, Ander; Rodríguez Remírez, María; López, I.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN 1556-0864 Vol.16 N° 10 2021 págs. S1007 - S1007
  • Autores: Ponz Sarvisé, Mariano; de Carvajal, C.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.81 N° 13 Supl. S 2021
  • Autores: Ponz Sarvisé, Mariano; Elez, E. ; Munoz, A.; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.81 N° 13 Supl. S 2021
  • Autores: Rolfo, C.; Cardona, A. F.; Cristofanilli, M.; et al.
    Revista: CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
    ISSN 1040-8428 Vol.151 2020 págs. 102978
    Resumen
    Precision medicine was born with the development of new diagnostic techniques and targeted drugs, yielding better outcomes in cancer care. With the evolution and increasing sensitivity for detecting oncogenic drivers, liquid biopsies (LBs), specifically cell-free DNA (cfDNA) analysis, have been proposed as a minimally-invasive technique for genomic profiling. Ranging from sequencing techniques to PCR-based methods and other more complex strategies, this approach, currently applicable in some solid tumors with robust evidence, is showing promising opportunities in other cancers. However, difficulties in validating their clinical utility exist within limitation at different levels among several techniques, reporting of the results, lack of appropriate clinical trial designs, and unknown economic impact. One of the aims of the ISLB is to create recommendations to develop reliable and sustainable diagnostic, prognostic and predictive tools using LBs. This paper is addressing these objectives, helping the healthcare providers and scientific community to understand the potential of LB.
  • Autores: Baraibar Argota, Iosune; Mezquita, L. ; Gil Bazo, Ignacio; et al.
    Revista: CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
    ISSN 1040-8428 Vol.148 2020 págs. 102906
    Resumen
    Approximately 4% of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) present EGFR exon 20 in-frame insertions, accounting for 0.3 %-3.7 % of NSCLC. In addition, 2 %-4 % of patients with NSCLC harbor human epidermal growth factor receptor 2 gene (HER2) mutations, being the 90 % of them exon 20 insertions. These mutations confer intrinsic resistance to available EGFR tyrosine kinase inhibitors (TKIs) and anti-HER2 treatments, as they result in steric hindrance of the drug-binding pocket. Therefore, no targeted therapies have been approved for NSCLC patients with EGFR or HER2 exon 20- activating mutations to date and remain an unmet clinical need. Promising efforts to novel treatment development have been made. Early data provide encouraging activity of novel drugs targeting EGFR and HER2 mutations in metastatic NSCLC. In this review we will summarize all the data reported to date about these driver molecular alterations and potential targeted therapies.
  • Autores: Serrano, M. J. (Autor de correspondencia); Garrido-Navas, M. C.; Mochon, J. J. D.; et al.
    Revista: CANCER DISCOVERY
    ISSN 2159-8274 Vol.10 N° 11 2020 págs. 1635 - 1644
    Resumen
    Despite major therapeutic progress, most advanced solid tumors are still incurable. Cancer interception is the active way to combat cancer onset, and development of this approach within high-risk populations seems a logical first step. Until now, strategies for the identification of high-risk subjects have been based on low-sensitivity and low-specificity assays. However, new liquid biopsy assays, "the Rosetta Stone of the new biomedicine ere with the ability to identify circulating biomarkers with unprecedented sensitivity, promise to revolutionize cancer management. This review focuses on novel liquid biopsy approaches and the applications to cancer interception. Cancer interception involves the identification of biomarkers associated with developing cancer, and includes genetic and epigenetic alterations, as well as circulating tumor cells and circulating epithelial cells in individuals at risk, and the implementation of therapeutic strategies to prevent the beginning of cancer and to stop its development. Large prospective studies are needed to confirm the potential role of liquid biopsy for early detection of precancer lesions and tumors.
  • Autores: Rolfo, C.; Cardona, A. F.; Cristofanilli, M. ; et al.
    Revista: CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
    ISSN 1040-8428 Vol.154 2020
  • Autores: Gil Bazo, Ignacio (Autor de correspondencia)
    Revista: CANCERS
    ISSN 2072-6694 Vol.12 N° 11 2020 págs. 3373
  • Autores: Eguren Santamaría, Iñaki; Fernández de Sanmamed Gutiérrez, Miguel; Gil Bazo, Ignacio (Autor de correspondencia)
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN 1556-0864 Vol.15 N° 4 2020 págs. 489 - 492
  • Autores: Sendino, T.; Sandúa, A.; Calleja, S.; et al.
    Revista: ADVANCES IN LABORATORY MEDICINE / AVANCES EN MEDICINA DE LABORATORIO
    ISSN 2628-491X Vol.1 N° 4 2020 págs. 1 - 5
  • Autores: Macias Conde, Monica; Cañada Higueras, Eva María; Alegre Martínez, Estíbaliz; et al.
    Revista: CLINICAL CHEMISTRY AND LABORATORY MEDICINE
    ISSN 1434-6621 Vol.58 N° 8 2020 págs. 1341 - 1348
    Resumen
    Background: Genomic alterations studies in cell-free DNA (cfDNA) have increasing clinical use in oncology. Nextgeneration sequencing (NGS) technology provides the most complete mutational analysis, but nowadays limited data are available related to the comparison of results reported by different platforms. Here we compare two NGS panels for cfDNA: OncomineT Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific), suitable for clinical laboratories, and Guardant360 (R) (GuardantHealth), with more genes targeted but only available in an outsourcing laboratory. Methods: Peripheral blood was obtained from 16 advanced cancer patients in which Guardant360 (R) (G360) was requested as part of their clinical assistance. Blood samples were sent to be analyzed with G360 panel, and an additional blood sample was drawn to obtain and analyze cfDNA with OncomineT Pan-Cancer (OM) panel in an Ion GeneStudio S5T System. Results: cfDNA analysis globally rendered 101 mutations. Regarding the 55/101 mutations claimed to be included by manufacturers in both panels, 17 mutations were reported only by G360, 10 only by OM and 28 by both. In those coincident cases, there was a high correlation between the variant allele fractions (VAFs) calculated with each panel (r = 0.979, p < 0.01). Regarding the six actionable mutations with an FDA-approved therapy reported by G360, one was missed with OM. Also, 12 mutations with clinical trials available were reported by G360 but not by OM. Conclusions: In summary, G360 and OM can produce different mutational profile in the same sample, even in genes included in both panels, which is especially important if these mutations are potentially druggable.
  • Autores: Sandua Condado, Amaia; Macias Conde, Monica; Perdomo Zelaya, Carolina María; et al.
    Revista: ADVANCES IN LABORATORY MEDICINE / AVANCES EN MEDICINA DE LABORATORIO
    ISSN 2628-491X Vol.1 N° 1 2020 págs. 20190017
    Resumen
    Background: Thyroglobulin (Tg) is fundamental for differentiated thyroid cancer (DTC) monitoring. Tg detection can be enhanced using recombinant human thyroidstimulating hormone (TSH) (rhTSH). This study is aimed to evaluate the use of the rhTSH stimulation test when using a high-sensitivity Tg assay. Methods: We retrospectively studied 181 rhTSH tests from 114 patients with DTC and negative for antithyroglobulin antibodies (anti-TgAb). Image studies were performed in all cases. Serum Tg and anti-TgAb were measured using specific immunoassays. Results: rhTSH stimulation in patients with basal serum Tg (b-Tg) concentrations lower than 0.2 ng/mL always resulted in rhTSH-stimulated serum Tg (s-Tg) concentrations lower than 1.0 ng/mL and negative structural disease. In patients with bTg concentration between 0.2 and 1.0 ng/mL, s-Tg detected one patient (1/30) who showed biochemical incomplete response. Patients with negative images had lower s-Tg than
  • Autores: Bockorny, B.; Semenisty, V. ; Macarulla, T.; et al.
    Revista: NATURE MEDICINE
    ISSN 1078-8956 Vol.26 N° 6 2020 págs. 878 ¿ 885
    Resumen
    Results from the phase IIa COMBAT trial combining CXCR4 and PD-1 inhibition in patients with metastatic cancer show encouraging clinical responses in association with enhanced antitumor immune activation. Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8(+) effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
  • Autores: Castañón Álvarez, Eduardo; Vidal Adroher, Cristina; Resano Eraul, Leyre; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Supl. 1 2020 págs. S4 - S4
  • Autores: Vilalta, A.; Urrizola Martínez, Amaia; Aldaz Pastor, Azucena; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 Supl 2020 págs. 4636
  • Autores: Hong, D.; Bazhenova, L. ; Cho, B. C.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN 0959-8049 Vol.138 N° Supl. 2 2020 págs. S1
  • Autores: Vilalta Lacarra, Anna; Urrizola Martínez, Amaia; Aldaz Pastor, Azucena; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 2020 págs. S946 - S947
  • Autores: Ceniceros Paredes, Lucía; Baixauli Fons, Jorge; Aldaz Pastor, Azucena; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 Supl. 2020 págs. 4104
  • Autores: Forner, A.; Vidili, G.; Rengo, M.; et al.
    Revista: LIVER INTERNATIONAL
    ISSN 1478-3223 Vol.39 N° Supl. 1 2019 págs. 98 - 107
    Resumen
    Cholangiocarcinoma (CCA) is a heterogeneous group of tumours, derived from cells of the biliary tree, which represent the second most frequent primary liver tumour. According to the most recent classifications, CCA can be subdivided into intrahepatic (iCCA) and extrahepatic (eCCA) which include perihilar (pCCA) and distal (dCCA) CCA. CCA are usually identified at advanced stages, when the primary tumour grows enough to produce a large liver mass or when jaundice has developed because of biliary tree obstruction. The ongoing challenges in the identification of risk factors and definition of a specific population at higher risk of developing CCA are the main challenges for the development of screening programs. Therefore, late diagnosis remains an unresolved issue in CCA. Imaging plays an important role in the detection and characterization of CCA, helping with radiological diagnosis, guiding biopsy procedures and allowing staging of the tumour. This review focuses on clinical presentations and diagnosis and staging techniques of CCA.
  • Autores: Forner, A.; Vidili, G.; Rengo, M.; et al.
    Revista: LIVER INTERNATIONAL
    ISSN 1478-3223 Vol.39 2019 págs. 98 - 107
  • Autores: Alegre Martínez, Estíbaliz; Fernández de Sanmamed Gutiérrez, Miguel; Sendino, Teresa; et al.
    Revista: ADVANCES IN LABORATORY MEDICINE / AVANCES EN MEDICINA DE LABORATORIO
    ISSN 2628-491X Vol.1 N° 2 2019 págs. 1 - 2
  • Autores: Macias Conde, Monica; Alegre Martínez, Estíbaliz; Alkorta Aranburu, Gorka; et al.
    Revista: DISEASE MARKERS
    ISSN 0278-0240 Vol.2019 N° 7954921 2019 págs. 1 - 7
    Resumen
    Epidermal growth factor receptor (EGFR) mutational testing in advanced non-small-cell lung cancer (NSCLC) is usually performed in tumor tissue, although cfDNA (cell-free DNA) could be an alternative. We evaluated EGFR mutations in cfDNA as a complementary tool in patients, who had already known EGFR mutations in tumor tissue and were treated with either EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy. We obtained plasma samples from 21 advanced NSCLC patients with known EGFR tumor mutations, before and during therapy with EGFR-TKIs and/or chemotherapy. cfDNA was isolated and EGFR mutations were analyzed with the multiple targeted cobas EGFR Mutation Test v2. EGFR mutations were detected at baseline in cfDNA from 57% of patients. The semiquantitative index (SQI) significantly decreased from the baseline (median = 11, IQR = 9.5-13) to the best response (median = 0, IQR = 0-0, p < 0.01), followed by a significant increase at progression (median = 11, IQR = 11-15, p < 0.01) in patients treated with either EGFR-TKIs or chemotherapy. The SQI obtained with the cobas EGFR Mutation Test v2 did not correlate with the concentration in copies/mL determined by droplet digital PCR. Resistance mutation p.T790M was observed at progression in patients with either type of treatment. In conclusion, cfDNA multiple targeted EGFR mutation analysis is useful for treatment monitoring in tissue of EGFR-positive NSCLC patients independently of the drug received.
  • Autores: Corral Jaime, Jesús (Autor de correspondencia); Majem, M.; Rodriguez-Abreu, D.; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN 1699-048X Vol.21 N° 9 2019 págs. 1270 - 1279
    Resumen
    PurposeBoth nintedanib/docetaxel and anti-PD-1/PD-L1 immunotherapies have demonstrated efficacy as second-line treatment of patients with advanced lung adenocarcinoma. This is the first report on the efficacy of the nintedanib/docetaxel combination following first-line platinum-based chemotherapy and subsequent immunotherapy in a real-world setting.Methods/patientsFrom May 2014 to December 2015, 390 patients in 108 Spanish centres enrolled in the nintedanib named patient use program. Inclusion criteria were advanced lung adenocarcinoma with progressive disease following at least one line of platinum-based doublet chemotherapy. The objective was to evaluate the efficacy of the nintedanib/docetaxel combination in patients who also received immunotherapy.ResultsEleven patients met the inclusion criteria; with a median age of 67years. PD-L1 expression was positive in six patients. Median progression-free survival (PFS) of first-line platinum-based chemotherapy was 3.3months (95% CI 1.9-4.6). Second-line immunotherapy was pembrolizumab (36.5%), atezolizumab (36.5%) or nivolumab (27%). Median PFS of second-line immunotherapy was 2.3months (95% CI 0-6.1). The overall response rate (ORR) to second-line immunotherapy was 18% with a disease-control rate (DCR) of 45%. Median PFS of nintedanib/docetaxel was 3.2months (95% CI 1.9-4.5). Best response was partial response in four patients (36%), stable disease in five patients (46%), and progressive disease in two patients (18%), for an ORR of 36% and a DCR of 82%.ConclusionOur experience suggests an encouraging efficacy of nintedanib/docetaxel in patients with adenocarcinoma NSCLC pretreated with platinum-based doublet chemotherapy and immunotherapy, reinforcing the importance of an optimal therapeutic sequence for managing advanced lung adenocarcinoma.
  • Autores: Roman, M.; López Erdozain, María Inés; Guruceaga Martínez, Elisabet; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.79 N° 3 2019 págs. 625 - 638
    Resumen
    Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G(2)-M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in down-regulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD. Significance: These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.
  • Autores: Jang, J. H.; Janker, F. ; De Meester, I. ; et al.
    Revista: CARCINOGENESIS
    ISSN 0143-3334 Vol.40 N° 2 2019 págs. 324 - 334
    Resumen
    CD26/dipeptidyl peptidase 4 (DPP4) is a transmembrane protein which is expressed by various malignant cells. We found that the expression of CD26/DPP4 was significantly higher in lung adenocarcinoma samples in our own patient cohort compared to normal lung tissue. We therefore hypothesize that the inhibition of CD26/DPP4 can potentially suppress lung cancer growth. The CD26/DPP4 inhibitor vildagliptin was employed on Lewis Lung Carcinoma (LLC) cell line and a human lung adenocarcinoma (H460) cell line. Two weeks after subcutaneous injection of tumor cells into C57BL/6 and CD1/nude mice, the size of LLC and H460 tumors was significantly reduced by vildagliptin. Immunohistochemically, the number of macrophages (F4/80(+)) and NK cells (NKp46(+)) was significantly increased in vildagliptin-treated tumor samples. Mechanistically, we found in vitro that lung cancer cell lines expressed increased levels of surfactant protein upon vildagliptin treatment thereby promoting the pro-inflammatory activity of macrophages. By the depletion of macrophages with clodronate and by using NK cell deficient (IL-15(-/-)) mice, tumors reversed to the size of controls, suggesting that indeed macrophages and NK cells were responsible for the observed tumor-suppressing effect upon vildagliptin treatment. FACS analysis showed tumor-infiltrating NK cells to express tumor necrosis-related apoptosis-inducing ligand (TRAIL) which induced the intra-cellular stress marker gamma H2AX. Accordingly, we found upregulated gamma H2AX in vildagliptin-treated tumors and TRAIL-treated cell lines. Moreover, the effect of vildagliptin-mediated enhanced NK cell cytotoxicity could be reversed by antagonizing the TRAIL receptor. Our data provide evidence that the CD26/DPP4-inhibitor vildagliptin reduces lung cancer growth. We could demonstrate that this effect is exerted by surfactant-activated macrophages and NK cells that act against the tumor via TRAIL-mediated cytotoxicity.
  • Autores: Macias Conde, Monica; Rebmann, V.; Mateos, B.; et al.
    Revista: CLINICAL CHEMISTRY AND LABORATORY MEDICINE
    ISSN 1434-6621 Vol.57 N° 10 2019 págs. 1539 - 1545
    Resumen
    Background: Exosomes are nanovesicles released by cells that can be detected in blood. Exosomes contain several molecules, such as cytokines that have potential utility as disease biomarkers. The aim of the present work is to compare six different commercial kits suitable for the clinical laboratory in relation to the efficiency and purity of exosome isolation, and their effect in subsequent cytokines analysis. Methods: Serum exosomes were obtained from 10 volunteers using six commercial kits: exoEasy, ExoQuick, Exo-spin, ME kit, ExoQuick Plus and Exo-Flow. Exosome concentrations and size distributions were quantified by nanoparticle tracking analysis. Exosome markers CD63, CD9 and TSG101 were determined by Western blot. ApoB and albumin were measured using nephelometry. S100A9, CXCL5 and CXCL12 were measured using a Luminex assay. Results: The concentration of particles obtained between different kits varied by a factor of 100. There was no correlation in particle concentrations extracted between different kits, except between ExoQuick and Exo-Flow. The highest exosome purity was achieved with ExoQuick Plus and exoEasy, while the lowest were achieved with ME and ExoQuick. Albumin was present in all exosome extracts analyzed and ApoB in all except those extracted with Exo-Flow and ME. Cytokine detection varied depending on the purification kit used and there was no correlation in cytokine concentrations between samples obtained with different kits. Conclusions: Both the sample and the type of commercial kit used affect the efficiency and purity of exosome isolation. In addition, the exosome purification method deeply affects the capability to detect and quantify cytokines.
  • Autores: Ponz Sarvisé, Mariano; Corbo, V.; Tiriac, H.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN 1078-0432 Vol.25 N° 22 2019 págs. 6742 - 6755
    Resumen
    Purpose: KRAS is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells. Experimental Design: We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. In addition, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignantspecific vulnerabilities. Results: Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies. Conclusions: Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models, pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT, and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both in vitro and in vivo.
  • Autores: Naumann, R. W. (Autor de correspondencia); Hollebecque, A. ; Meyer, T. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.37 N° 31 2019 págs. 2825 - 2864
    Resumen
    PURPOSE Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. PATIENTS AND METHODS Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. RESULTS Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. CONCLUSION The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population.
  • Autores: Gaspar-Blázquez, M. J. (Autor de correspondencia); Trapé-Pujol, J.; Augé-Fradera, J. M.; et al.
    Revista: REVISTA DEL LABORATORIO CLINICO
    ISSN 1888-4008 Vol.12 N° 1 2019 págs. 38 - 52
    Resumen
    Este documento describe las causas de error más frecuentes en la medición de marcadores tumorales séricos proteicos en sus diferentes fases: preanalítica, analítica y postanalítica y recomendaciones para detectar y solventar problemas, así como la interpretación de los resultados de los marcadores tumorales en la práctica clínica.
  • Autores: Reclusa, P. ; Laes, J. F. ; Malapelle, U. ; et al.
    Revista: TRANSLATIONAL CANCER RESEARCH
    ISSN 2218-676X Vol.8 N° Supl. 1 2019 págs. S76 - S78
    Resumen
    The introduction of druggable targets has significantly improved the outcomes of non-small cell lung cancer patients (NSCLC). EML4-ALK translocation represents 4-6% of the druggable alterations in NSCLC. With the approval of Crizotinib, first discovered drug for the EML4-ALK translocation, on first line treatment for patients with detected mutation meant a complete change on the treatment landscape. The current standard method for EML4-ALK identification is immunohistochemistry or FISH in a tumor biopsy. However, a big number of NSCLC patients have not tissue available for analysis and others are not suitable fir biopsy due to their physical condition or the location of the tumor. Liquid biopsy seems the best alternative for identification in these patients that have no tissue available. Circulating free RNA has not been validated for the identification of this mutation. As a complementary tool, exosomes might represent a good tool for predictive biomarkers study; and due to their stability; they preserve the genetic material contained in them. Our group has described for the first time the translocation EML4-ALK in RNA isolated from exosomes derived from NSCLC patients using next generation sequencing.
  • Autores: González Hernández, Álvaro (Autor de correspondencia); Pérez-Barrios, C.; Macher, H.; et al.
    Revista: REVISTA DEL LABORATORIO CLINICO
    ISSN 1888-4008 Vol.12 N° 3 2019 págs. e40 - e46
    Resumen
    El análisis de ADN circulante a partir de sangre periférica ha demostrado ser de utilidad en campos clínicos tan diferentes como la oncología, los trasplantes y el cribado prenatal. Para su incorporación al laboratorio clínico es necesario asegurar protocolos preanalíticos adecuados, reproducibles y estandarizados. En este documento se pretenden dar unas recomendaciones preanalíticas para la obtención de ADN circulante a partir de sangre periférica. Incluyen el tipo de espécimen, el tipo de tubo de extracción, el modo de centrifugación de la muestra, la extracción del ADN circulante y cuantificación, así como su conservación.
  • Autores: Naumann, R. W.; Oaknin, A. ; Meyer, T.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Supl. 5 2019 págs. 898 - +
  • Autores: Hidalgo, M. ; Semenisty, V.; Bockorny, B.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Supl. 11 2019
  • Autores: Jang, J.; Haberecker, M. ; Curioni, A. ; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN 1556-0864 Vol.14 N° 10 2019 págs. S965 - S965
  • Autores: Gil Bazo, Ignacio
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN 1556-0864 Vol.14 N° 11 2019 págs. S1165 - S1166
  • Autores: Macías Mojón, María; Sendino Miguel, Teresa; Sandua Condado, Amaia; et al.
    Revista: CLINICA CHIMICA ACTA
    ISSN 0009-8981 Vol.493 N° Supl. 1 2019 págs. S137
  • Autores: Cubero, J. H. ; Sanz, M. T. ; Bayonas, A. C. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Supl. 5 2019 págs. 759
  • Autores: Passiglia, F.; Caglevic, C.; Giovannetti, E.; et al.
    Revista: SEMINARS IN CANCER BIOLOGY
    ISSN 1044-579X Vol.52 2018 págs. 259 - 268
    Resumen
    Recent studies with immunomodulatory agents targeting both cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death 1 (PD1)/programmed cell death ligand 1 (PDL1) have shown to be very effective in several cancers revealing an unexpected great activity in patients with both primary and metastatic brain tumors. Combining anti-CTLA4 and anti-PD1 agents as upfront systemic therapy has revealed to further increase the clinical benefit observed with single agent, even at cost of higher toxicity. Since the brain is an immunological specialized area it's crucial to establish the specific composition of the brain tumors' micro environment in order to predict the potential activity of immunomodulatory agents. This review briefly summarizes the basis of the brain immunogenicity, providing the most updated clinical evidences in terms of immune-checkpoint inhibitors efficacy and toxicity in both primary and metastatic brain tumors with the final aim of defining potential biomarkers for immunomodulatory cancer treatment.
  • Autores: Macias Conde, Monica; Alegre Martínez, Estíbaliz; Díaz Lagares, Ángel; et al.
    Revista: ADVANCES IN CLINICAL CHEMISTRY
    ISSN 0065-2423 Vol.83 2018 págs. 73 - 119
    Resumen
    Liquid biopsy refers to the molecular analysis in biological fluids of nucleic acids, subcellular structures, especially exosomes, and, in the context of cancer, circulating tumor cells. In the last 10 years, there has been an intensive research in liquid biopsy to achieve a less invasive and more precise personalized medicine. Molecular assessment of these circulating biomarkers can complement or even surrogate tissue biopsy. Because of this research, liquid biopsy has been introduced in clinical practice, especially in oncology, prenatal screening, and transplantation. Here we review the biology, methodological approaches, and clinical applications of the main biomarkers involved in liquid biopsy.
  • Autores: Roman Moreno, Marta; Baraibar Argota, Iosune; López Erdozain, María Inés; et al.
    Revista: MOLECULAR CANCER
    ISSN 1476-4598 Vol.17 2018
    Resumen
    Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed. Moreover, the role of KRAS oncogene in NSCLC remains unclear and its predictive and prognostic impact remains controversial. The study of the underlying biology of KRAS in NSCLC patients could help to determine potential candidates to evaluate novel targeted agents and combinations that may allow a tailored treatment for these patients. The aim of this review is to update the current knowledge about KRAS-mutated lung adenocarcinoma, including a historical overview, the biology of the molecular pathways involved, the clinical relevance of KRAS mutations as a prognostic and predictive marker and the potential therapeutic approaches for a personalized treatment of KRAS-mutated NSCLC patients.
  • Autores: Eguren Santamaría, Iñaki; Sánchez Bayona, Rodrigo; Patiño García, Ana; et al.
    Revista: LUNG CANCER
    ISSN 0169-5002 Vol.122 2018 págs. 120 - 123
    Resumen
    BACKGROUND: The differential diagnosis between multiple primary lung cancer (MPLC) and advanced lung cancer has traditionally relied on conventional radiology and pathology. However, the outcomes of traditional diagnostic workup are often limited, and staging is uncertain. Increasing evidence suggests that next-generation sequencing (NGS) techniques offer the possibility of comparing multiple tumors on a genomic level. OBJECTIVES: The objective of this study is to assess the clinical impact utility of targeted sequencing in patients presenting with multiple synchronous or metachronous lung tumors. MATERIALS AND METHODS: We describe the diagnostic workup conducted in a patient with three lung tumors, where we used a targeted 50-gene DNA sequencing panel (Ion AmpliSeq TM Cancer Hotspot Panel v2) to assess clonality and establish an accurate lung adenocarcinoma stage. Positive results were confirmed by pyrosequencing or Sanger sequencing. RESULTS: Three surgically resected lung tumors were submitted for targeted sequencing. The tumor from the upper right lobe was positive for a TP53 c.659A¿>¿G mutation and native for KRAS. The tumor from the upper left lobe was positive for TP53 c.725G¿>¿T and KRAS c.35G¿>¿T mutations. The tumor from the lower left lobe was positive for TP53 c.1024C¿>¿T and KRAS C.34G¿>¿T mutations. Results and reviewed literature in the field support the diagnosis of MPLC instead of a single advanced lung cancer. CONCLUSION: Targeted DNA sequencing significantly increases diagnostic accuracy in patients with multiple lung tumors. NGS panels should be available for patients presenting with multiple lung tumors.
  • Autores: Rodriguez-Abreu, D.; Campillo, J.; Grau, F. ; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN 1556-0864 Vol.13 N° 10 2018 págs. S827
  • Autores: Izaguirre Ascargorta, Maitane ; Fernández Landázuri, Sara; Mugueta Uriaque, María del Carmen; et al.
    Libro: Principios de Bioquímica Clínica y Patología Molecular
    ISSN 978-84-9113-389-6 Vol.3 2019 págs. 33-40
  • Autores: Ramirez Ruiz, Maria Carla; González Hernández, Álvaro; Alegre Martínez, Estíbaliz; et al.
    Libro: Principios de bioquímica clínica y patología molecular
    ISSN 978-84-9113-386-6 2019 págs. 151 - 164
  • Autores: Martínez Espartosa, Débora; Ramirez Ruiz, Maria Carla; González Hernández, Álvaro; et al.
    Libro: Principios de bioquímica clínica y patología molecular
    ISSN 978-84-9113-389-6 Vol.3 2019 págs. 325-332
  • Autores: Ramirez Ruiz, Maria Carla; González Hernández, Álvaro; Alegre Martínez, Estíbaliz; et al.
    Libro: Principios de bioquímica clínica y patología molecular
    ISSN 978-84-9113-386-6 2019 págs. 69 - 78
  • Autores: Recalde Zamacona, Borja; Cano Rafart, David; Ezponda Casajús, Ana; et al.
    Libro: Guía de Inmunotoxicidad. Diagnóstico y manejo de los efectos secundarios asociados a inmunoterapia en oncología
    ISSN 9788431333003 N° 8 2019 págs. 108-113
  • Autores: Martínez Espartosa, Débora; González Hernández, Álvaro; Alegre Martínez, Estíbaliz; et al.
    Libro: Principios de Bioquímica Clínica y Patología Molecular
    ISSN 978-84-9113-389-6 Vol.3 2019 págs. 313-324
  • Autores: Martínez Espartosa, Débora; González Hernández, Álvaro; Alegre Martínez, Estíbaliz; et al.
    Libro: Principios de Bioquímica Clínica y patología molecular
    ISSN 978-84-9113-389-6 Vol.3 2019 págs. 143-152
  • Autores: Macias Conde, Monica; Alegre Martínez, Estíbaliz; Díaz-Lagares, A.; et al.
    Libro: Advances in Clinical Chemistry
    ISSN 978-0-12-815207-2 Vol.83 2018 págs. 73 - 119
    Resumen
    Liquid biopsy refers to the molecular analysis in biological fluids of nucleic acids, subcellular structures, especially exosomes, and, in the context of cancer, circulating tumor cells. In the last 10 years, there has been an intensive research in liquid biopsy to achieve a less invasive and more precise personalized medicine. Molecular assessment of these circulating biomarkers can complement or even surrogate tissue biopsy. Because of this research, liquid biopsy has been introduced in clinical practice, especially in oncology, prenatal screening, and transplantation. Here we review the biology, methodological approaches, and clinical applications of the main biomarkers involved in liquid biopsy.
  • Autores: Ponz Sarvisé, Mariano; de la Riva Onandía, Susana Rosa; Mora Moriana, Lorena
    Título: Digestivo
    Libro: Guia inmuno-toxicidad: diagnóstico y manejo de los efectos secundarios asociados a inmunoterapia en oncología
    ISSN 978-84-313-3300-3 2018 págs. 53 - 61
  • Autores: González Hernández, Álvaro (Editor)
    ISSN 9788491133896 2019
    Resumen
    Nueva edición de la obra en el campo de la bioquímica clínica que año tras año se está convirtiendo en una herramienta fundamental para la toma de decisiones del clínico, ya que gran parte de ellas se basan en los datos proporcionados por el laboratorio que necesitan por una interpretación adecuada teniendo en cuenta los diferentes factores preanalíticos y analíticos que puedan influir en ellos. Uno de las novedades más importantes de la bioquímica clínica es que ha ido incorporando progresivamente técnicas propias de la biología molecular y la proteómica.

Proyectos desde 2018

  • Título: GRANATE - GRUPO DE RADIOTERAPIA AVANZADA DE NAVARRA ¿ TERAPIA Y EFICACIA
    Código de expediente: 0011-1411-2022-000066
    Investigador principal: ANA PATIÑO GARCIA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2022 GN PROYECTOS ESTRATEGICOS DE I+D 2022-2025
    Fecha de inicio: 01-06-2022
    Fecha fin: 31-12-2024
    Importe concedido: 536.739,00 €
    Fondos FEDER: NO
  • Título: Nuevas opciones de imagen metabólica en la caracterización de la respuesta inducida por el bloqueo combinado de anti-PD-1 e Id1 y su correlación con la generación de neontígenos en un modelo de cáncer de pulmón
    Código de expediente: GNS_53-2021
    Investigador principal: IGNACIO GIL BAZO.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2021 GN Proyectos de Investigación en salud
    Fecha de inicio: 23-12-2021
    Fecha fin: 22-12-2024
    Importe concedido: 68.250,00 €
    Fondos FEDER: NO
  • Título: Aplicaciones del estudio multi-ómico de la microbiota al desarrollo de soluciones biotecnológicas innovadoras en el área de la salud (microBiomics)
    Código de expediente: 0011-1411-2021-000106
    Investigador principal: MARIA TERESA HERRAIZ BAYOD.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2021 GN PROYECTOS ESTRATEGICOS DE I+D 2021-2024
    Fecha de inicio: 15-04-2021
    Fecha fin: 30-11-2023
    Importe concedido: 366.577,17 €
    Fondos FEDER: NO
  • Título: Estudios funcionales, moleculares y clínicos del papel de la lámina C2 (LAMC2) en el cáncer de páncreas
    Código de expediente: PI20/01718
    Investigador principal: MARIANO PONZ SARVISE.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2020 AES Proyectos de investigación
    Fecha de inicio: 01-01-2021
    Fecha fin: 31-12-2023
    Importe concedido: 85.910,00 €
    Fondos FEDER: SI
  • Título: platafoRma de intElIgeNcia artiFicial para la predicción de tOxicidad y Recurrencia del CancE
    Código de expediente: 0011-1411-2020-000074
    Investigador principal: JAVIER RODRIGUEZ RODRIGUEZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 22-06-2020
    Fecha fin: 30-11-2023
    Importe concedido: 212.396,26 €
    Fondos FEDER: NO
  • Título: Nuevas combinaciones inmunomoduladoras frente al adenocarcinoma de pulmón según el estado mutacional del oncogen KRAS. Estudio de nuevos biomarcadores de respuesta a terapia anti-PD-1
    Código de expediente: PI19/00678
    Investigador principal: IGNACIO GIL BAZO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2022
    Importe concedido: 111.320,00 €
    Fondos FEDER: SI
  • Título: Desarrollo EStratégico de terapias CART para el tratamiento de Tumores Hematológicos y Sólidos (DESCARTHeS)
    Código de expediente: 0011-1411-2019-000072
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 GN PROYECTOS ESTRATEGICOS DE I+D 2019-2021
    Fecha de inicio: 01-04-2019
    Fecha fin: 30-11-2021
    Importe concedido: 164.695,50 €
    Fondos FEDER: NO
  • Título: Potenciación de la inmunoterapia frente al cáncer de pulmón mediante la modulación de la respuesta tumoral innata
    Código de expediente: PI17/00411
    Investigador principal: RUBEN PIO OSES, DANIEL AJONA MARTINEZ - POLO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2017 - PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-12-2020
    Importe concedido: 123.420,00 €
    Fondos FEDER: SI
  • Título: Nueva estrategia terapéutica para evitar el escape inmune en cáncer de pulmón metastásico mediante el bloqueo combinado de PD-1 e Id1
    Código de expediente: 74/2017
    Investigador principal: IGNACIO GIL BAZO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2017 GN SALUD
    Fecha de inicio: 01-01-2018
    Fecha fin: 15-12-2020
    Importe concedido: 90.000,00 €
    Fondos FEDER: SI
  • Título: Caracterización de la recíproca interacción oncogén/ remodeladores de cromatina en tumorogénesis y metástasis en el cáncer de pulmón
    Código de expediente: 77/2017
    Investigador principal: FERNANDO LECANDA CORDERO.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2017 PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 15-12-2017
    Fecha fin: 15-09-2021
    Importe concedido: 64.842,75 €
    Fondos FEDER: SI
  • Título: Tecnología de secuenciación de nueva generación (NGS) para optimizar la eficacia del diagnóstico y tratamiento en pacientes con tumores de alta mortalidad (DIANA: Diagnostico biomédico e Innovación Abierta en Navarra)
    Código de expediente: 0011-1411-2017-000030
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2017 GN ESTRATEGICOS
    Fecha de inicio: 01-04-2017
    Fecha fin: 30-11-2019
    Importe concedido: 37.315,72 €
    Fondos FEDER: NO
  • Título: Análisis molecular mediante plataformas de última generación del carcinoma no microcítico de pulmón para el desarrollo de perfiles pronósticos y nuevas herramientas terapéuticas
    Código de expediente: PI16/01821
    Investigador principal: LUIS MONTUENGA BADIA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2016 - PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2017
    Fecha fin: 31-12-2019
    Importe concedido: 128.865,00 €
    Fondos FEDER: SI
  • Título: Estudio pronóstico y predictivo de células tumorales circulantes (CTC) en adenocarcinoma de pulmón. Valoración invivo del papel de Id1 e Id3 en la capacidad metastásica de las CTC
    Código de expediente: PI15/02223
    Investigador principal: IGNACIO GIL BAZO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2015 AES PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2016
    Fecha fin: 30-11-2020
    Importe concedido: 92.565,00 €
    Fondos FEDER: NO
  • Título: Estudio de coste-efectividad y factibilidad del cribado de cáncer de pulmón en España
    Código de expediente: PI15/02157
    Investigador principal: JAVIER JOSEPH ZULUETA FRANCES.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2015 AES PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2016
    Fecha fin: 31-12-2018
    Importe concedido: 62.315,00 €
    Fondos FEDER: NO
  • Título: Estudio de exosomas tumorales como inductores de células mieloides supresoras y mensajeros transportadores de moléculas inmunosupresoras.
    Código de expediente: PI14/00274
    Investigador principal: ALVARO GONZALEZ HERNANDEZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2014 ISCIII Proyectos de I+D
    Fecha de inicio: 01-01-2015
    Fecha fin: 31-12-2018
    Importe concedido: 55.055,00 €
    Fondos FEDER: NO
  • Título: PancREatic Cancer OrganoiDs rEsearch Network
    Código de expediente:
    Investigador principal: MARIANO PONZ SARVISE
    Financiador: COMISIÓN EUROPEA
    Convocatoria: MSCA-ITN-2019 H2020
    Fecha de inicio: 01-10-2019
    Fecha fin: 30-09-2023
    Importe concedido: 250.904,88 €
    Fondos FEDER: NO