Lopez, I. (Inés)
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- Identification of colorectal cancer metastasis markers by an angiogenesis-related cytokine-antibody array(MDPI AG, 2012) Boni, V. (Valentina); Bitarte, N. (Nerea); Zarate, R. (Ruth); Rodriguez, J. (Javier); Gonzalez-Huarriz, M. (Marisol); Bandres, E. (Eva); Garcia-Foncillas, J. (Jesús); Abajo, A. (Ana); Lopez, I. (Inés)AIM: To investigate the angiogenesis-related protein expression profile characterizing metastatic colorectal cancer (mCRC) with the aim of identifying prognostic markers. METHODS: The expression of 44 angiogenesis-secreted factors was measured by a novel cytokine antibody array methodology. The study evaluated vascular endothelial growth factor (VEGF) and its soluble vascular endothelial growth factor receptor (sVEGFR)-1 protein levels by enzyme immunoassay (EIA) in a panel of 16 CRC cell lines. mRNA VEGF and VEGF-A isoforms were quantified by quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR) and vascular endothelial growth factor receptor (VEGFR)-2 expression was analyzed by flow cytometry. RESULTS: Metastasis-derived CRC cell lines expressed a distinctive molecular profile as compared with those isolated from a primary tumor site. Metastatic CRC cell lines were characterized by higher expression of angiogenin-2 (Ang-2), macrophage chemoattractant proteins-3/4 (MCP-3/4), matrix metalloproteinase-1 (MMP-1), and the chemokines interferon γ inducible T cell α chemoattractant protein (I-TAC), monocyte chemoattractant protein I-309, and interleukins interleukin (IL)-2 and IL-1α, as compared to primary tumor cell lines. In contrast, primary CRC cell lines expressed higher levels of interferon γ (IFN-γ), insulin-like growth factor-1 (IGF-1), IL-6, leptin, epidermal growth factor (EGF), placental growth factor (PlGF), thrombopoietin, transforming growth factor β1 (TGF-β1) and VEGF-D, as compared with the metastatic cell lines. VEGF expression does not significantly differ according to the CRC cellular origin in normoxia. Severe hypoxia induced VEGF expression up-regulation but contrary to expectations, metastatic CRC cell lines did not respond as much as primary cell lines to the hypoxic stimulus. In CRC primary-derived cell lines, we observed a two-fold increase in VEGF expression between normoxia and hypoxia as compared to metastatic cell lines. CRC cell lines express a similar pattern of VEGF isoforms (VEGF₁₂₁, VEGF₁₆₅ and VEGF₁₈₉) despite variability in VEGF expression, where the major transcript was VEGF₁₂₁. No relevant expression of VEGFR-2 was found in CRC cell lines, as compared to that of human umbilical vein endothelial cells and sVEGFR-1 expression did not depend on the CRC cellular origin. CONCLUSION: A distinct angiogenesis-related expression pattern characterizes metastatic CRC cell lines. Factors other than VEGF appear as prognostic markers and intervention targets in the metastatic CRC setting.
- KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target(BMC, 2018) Gil-Bazo, I. (Ignacio); Román, M. (Marta); Vicent, S. (Silvestre); Nadal, E. (Ernest); Rolfo, C. (Christian); Baraibar-Argota, I. (Iosune); Lopez, I. (Inés)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.
- A novel [89Zr]-anti-PD-1-PET-CT to assess response to PD-1/PD-L1 blockade in lung cancer(2023) Gil-Bazo, I. (Ignacio); Francisco-Cruz, A. (Alejandro); Ecay-Ilzarbe, M. (Margarita); Sandiego, S. (Sergio); Puyalto, A. (Ander); Peñuelas-Sanchez, I. (Ivan); Simón-Martínez, J.A. (Jon Ander); Ajona-Martínez-Polo, D. (Daniel); Collantes-Martínez, M. (María); Vilalta-Lacarra, A. (Anna); Rodríguez-Remírez, M. (M.); Solórzano-Rendón, J.L. (José Luis); Iribarren, F. (Fabiola); Lopez, I. (Inés); Calvo-González, A. (Alfonso)Background: Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [89Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC. Materials and methods: A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [89Zr]-labeled anti-PD-1 antibody and measured as 89Zr tumor uptake. Results: Conventional [18F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [89Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [89Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found (Cor = 0.8; p = 0.001). Conclusion: Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC.
- Id1 and Id3 co-expression correlates with clinical outcome in stage III-N2 non-small cell lung cancer patients treated with definitive chemoradiotherapy(BioMed Central, 2013) Gil-Bazo, I. (Ignacio); Lozano, M.D. (María Dolores); Arbea-Moreno, L. (Leire); Moreno, M. (Marta); Castañon, E. (Eduardo); Lopez-Picazo, J.M. (José M.); Lopez, I. (Inés); Bosch-Barrera, J. (Joaquim); Collado, V. (Víctor)A correlation between Id1 and Id3 protein expression is observed. Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy.
- Thymidylate synthase polymorphisms in genomic DNA as clinical outcome predictors in a European population of advanced non-small cell lung cancer patients receiving pemetrexed(BioMed Central, 2014) Gil-Bazo, I. (Ignacio); Patiño-García, A. (Ana); Arevalo, E. (Estefanía); Rodriguez-Ruiz, M.E. (María Esperanza); Castañon, E. (Eduardo); Santisteban, M. (Marta); Rolfo, C. (Christian); Zubiri, L. (Leire); Lopez, I. (Inés); Salgado, J. (Josefa); Martin, P. (Patricia); Collado, V. (Víctor)BACKGROUND: We studied whether thymidylate synthase (TS) genotype has an independent prognostic/predictive impact on a European population of advanced non-small cell lung cancer (NSCLC) patients receiving pemetrexed. METHODS: Twenty-five patients treated with pemetrexed-based regimens were included. Genomic DNA was isolated prior to treatment. The variable number of tandem repeat (VNTR) polymorphisms, the G > C single nucleotide polymorphisms (SNP) and the TS 6-bp insertion/deletion (6/6) in the 3' untranslated region (UTR) polymorphisms were analyzed and correlated with overall response rate (ORR), progression-free survival (PFS), overall-survival (OS) and toxicity. RESULTS: The genotype +6/+6 predicted a higher ORR among active/former smokers compared to +6/-6 genotype (100% vs. 50%; p = 0.085). Overall, the 3R/3R genotype predicted a higher ORR (100%) over the rest VNTR polymorphisms (p = 0.055). The presence of 3R/3R genotype significantly correlated with a superior ORR in patients without EGFR activating mutations (100%) compared to 2R/2R, 2R/3R and 3R/4R genotype (77.8%, 33.3% and 0% respectively; p = 0.017). After a median follow-up of 21 months, a trend towards a better PFS, although not significant, was found among subjects showing 3R/3R polymorphisms (p = 0.089). A significantly superior OS was found in patients showing 3R/3R genotype rather than other VNTR polymorphisms (p = 0.019). No significant correlation with the toxicity was observed. CONCLUSION: In our series, 3R/3R polymorphism correlated with a superior OS. Also, this polymorphism, when associated to wild type EGFR, was related to a higher ORR to pemetrexed. Toxicity was not significantly correlated with a specific TS genotype.
- Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells(2020) Gil-Bazo, I. (Ignacio); Pio, R. (Rubén); Román, M. (Marta); Puyalto, A. (Ander); Collantes, M. (María); Lozano-Moreda, T. (Teresa); Vicent, S. (Silvestre); Garcia-Ros, D. (David); Villalba-Esparza, M. (María); Caglevic, C. (Christian); Ecay, M. (Margarita); Rodríguez-Remírez, M. (M.); Alignani, D. (Diego); Rolfo, C. (Christian); Guruceaga, E. (Elizabeth); Moreno, H. (Haritz); Andrea, C.E. (Carlos Eduardo) de; Ortiz-Espinosa, S. (Sergio); Vilalta, A. (Anna); Torregrosa, M.S. (María Soledad); Baraibar-Argota, I. (Iosune); Lopez, I. (Inés); Calvo-González, A. (Alfonso); Ajona, D. (Daniel); Oliver, A. (Ana); Lasarte, J.J. (Juan José)The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.
- The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer(2023) Halberg, N. (Nils); Vicent, S. (Silvestre); Vallejo-Blanco, A. (Adrián); Cueto-Ureña, C. (Cristina); Entrialgo-Cadierno, R. (Rodrigo); Vera, L. (Laura); Ambrogio, C. (Chiara); Vietti-Michelina, S. (Sandra); Cortés-Dominguez, I. (Iván); Scaparone, P. (Pietro); Lara-Astiaso, D. (David); Erice, O. (Oihane); Macaya, I. (Irati); Darbo, E. (Elodie); Feliu, I. (Iker); Morales-Urteaga, X. (Xabier); Guruceaga, E. (Elizabeth); Moreno, H. (Haritz); Goñi-Salaverri, A. (Ainhoa); Lecanda, F. (Fernando); Welch, C. (Connor); Lopez, I. (Inés)BackgroundThe discovery of functionally relevant KRAS effectors in lung and pancreatic ductal adenocarcinoma (LUAD and PDAC) may yield novel molecular targets or mechanisms amenable to inhibition strategies. Phospholipids availability has been appreciated as a mechanism to modulate KRAS oncogenic potential. Thus, phospholipid transporters may play a functional role in KRAS-driven oncogenesis. Here, we identified and systematically studied the phospholipid transporter PITPNC1 and its controlled network in LUAD and PDAC.MethodsGenetic modulation of KRAS expression as well as pharmacological inhibition of canonical effectors was completed. PITPNC1 genetic depletion was performed in in vitro and in vivo LUAD and PDAC models. PITPNC1-deficient cells were RNA sequenced, and Gene Ontology and enrichment analyses were applied to the output data. Protein-based biochemical and subcellular localization assays were run to investigate PITPNC1-regulated pathways. A drug repurposing approach was used to predict surrogate PITPNC1 inhibitors that were tested in combination with KRASG12C inhibitors in 2D, 3D, and in vivo models.ResultsPITPNC1 was increased in human LUAD and PDAC, and associated with poor patients' survival. PITPNC1 was regulated by KRAS through MEK1/2 and JNK1/2. Functional experiments showed PITPNC1 requirement for cell proliferation, cell cycle progression and tumour growth. Furthermore, PITPNC1 overexpression enhanced lung colonization and liver metastasis. PITPNC1 regulated a transcriptional signature which highly overlapped with that of KRAS, and controlled mTOR localization via enhanced MYC protein stability to prevent autophagy. JAK2 inhibitors were predicted as putative PITPNC1 inhibitors with antiproliferative effect and their combination with KRASG12C inhibitors elicited a substantial anti-tumour effect in LUAD and PDAC.ConclusionsOur data highlight the functional and clinical relevance of PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new mechanism linking KRAS to MYC, and controls a druggable transcriptional network for combinatorial treatments.
- Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer(2023) Gil-Bazo, I. (Ignacio); Drosten, M. (Mathias); Barbacid, M. (Mariano); Kovalski, J. (Joanna); Pineda-Lucena, A. (Antonio); Román, M. (Marta); Jantus-Lewintre, E. (Eloisa); Calabuig-Fariñas, S. (Silvia); Vicent, S. (Silvestre); Ludwig, I.A. (Iziar Amaia); Entrialgo-Cadierno, R. (Rodrigo); Palomino-Echeverría, S. (Sara); Salmon, M. (Marina); Fernandez-Irigoyen, J. (Joaquín); Ruggero, D. (Davide); Lara-Astiaso, D. (David); Santos, A. (Alba); Ponz-Sarvise, M. (Mariano); Macaya, I. (Irati); Feliu, I. (Iker); Rodríguez-Remírez, M. (M.); Guruceaga, E. (Elizabeth); Paz-Ares, L. (Luis); Ferrer, I. (Irene); Narayanan, S. (Shruthi); Ferrero, M. (Macarena); Lecanda, F. (Fernando); Welch, C. (Connor); Lopez, I. (Inés); Lonfgren, S.M. (Shane M.); Santamaria, E. (Enrique); Khatri, P. (Purvesh)Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
- Identification of predictive circulating biomarkers of bevacizumab-containing regimen efficacy in pre-treated metastatic colorectal cancer patients(Nature, 2012-07-10) Boni, V. (Valentina); Bitarte, N. (Nerea); Zarate, R. (Ruth); Rodriguez, J. (Javier); Gonzalez-Huarriz, M. (Marisol); Bandres, E. (Eva); Garcia-Foncillas, J. (Jesús); Abajo, A. (Ana); Lopez, I. (Inés)BACKGROUND: To identify whether circulating levels of angiogenesis-related factors may be predictive of bevacizumab efficacy in pre-treated metastatic colorectal cancer (mCRC) patients. METHODS: Pre-treatment serum levels of 24 cytokines were measured using a multiplex bead assay (MBA) in 32 pre-treated mCRC patients treated with irinotecan plus bevacizumab-based salvage therapy. Macrophage-derived chemokine (MDC), interleukins (ILs) 8 and 6 levels were also validated by enzyme-linked immunosorbent assay (ELISA) at different time points during therapy. RESULTS: Higher epidermal growth factor (EGF) and MDC baseline levels (2.2- and 1.4-fold, respectively) and lower IL-10, IL-6 and IL-8 levels (0.2-, 0.6-, and 0.6-fold, respectively, P<0.05) were observed in patients responding to therapy. Baseline levels of these five serum factors compose a risk signature that may define the subset of patients most likely to benefit from bevacizumab-based therapy in terms of response rate and survival times. A positive correlation was found between MBA and ELISA results (P<0.01). Treatment exposure increased MDC and had opposite effects on IL-8 levels, which were decreased (P<0.05). CONCLUSION: This study suggests that a set of inflammatory and angiogenesis-related serum markers may be associated with the efficacy of bevacizumab-containing regimen.
- Correction: The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer(2023) Halberg, N. (Nils); Vicent, S. (Silvestre); Vallejo-Blanco, A. (Adrián); Cueto-Ureña, C. (Cristina); Entrialgo-Cadierno, R. (Rodrigo); Vera, L. (Laura); Ambrogio, C. (Chiara); Vietti-Michelina, S. (Sandra); Cortés-Dominguez, I. (Iván); Scaparone, P. (Pietro); Lara-Astiaso, D. (David); Erice, O. (Oihane); Macaya, I. (Irati); Darbo, E. (Elodie); Feliu, I. (Iker); Morales-Urteaga, X. (Xabier); Guruceaga, E. (Elizabeth); Moreno, H. (Haritz); Goñi-Salaverri, A. (Ainhoa); Lecanda, F. (Fernando); Welch, C. (Connor); Lopez, I. (Inés)