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Your search keyword '"Álvaro Otero"' showing total 13 results
Start Over Author "Álvaro Otero" Publisher american association for cancer research (aacr)
13 results on '"Álvaro Otero"'

1. Legends supplementary Figures 1-6 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Legends for Supplementary Figures 1-6

Published
2023

2. Table S3 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Table S3: Treatment regimens of the Avatar patient derived xenograft models carrying the VEGFR2 WT and L840F genotypes.

Published
2023

3. Figure S2 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Figure S2: Read alignments from WES-cfDNA, showing somatic mutations in APC and TP53 genes.

Published
2023

4. Table S4 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Table S4: Primers used for site-directed mutagenesis. The mutated nucleotides are indicated in bold and underlined in each mutant.

Published
2023

5. Table S2 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Table S2: Custom primers and probes designed based on the Thermofisher online design tool for TaqManÃ,® genotyping assay for KDR c.2518C>T (VEGFR2 p.L840L). TaqManÃ,® MGB (minor groove binder) probes incorporate a 5' reporter (VIC or FAM) and a 3' nonfluorescent quencher (NFQ).

Published
2023

6. Online Methods from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Detailed methods

Published
2023

7. Figure S4 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Figure S4: A) Molecular dynamics simulations with L840F VEGFR2 indicates that most of the adopted F840 conformations during the simulation are not compatible with inhibitor binding. Clashes between VEGFR2 and the sorafenib area are shown as red discs. B) Kinase assays showing impaired kinase activities of VEGFR2 L840F and R1032Q compared to wild-type. C) Effects of the L840F mutation on Y1175 VEGFR2 phosphorylation. HEK293 cells were transiently transfected with increasing levels of a plasmid encoding for WT or L840F VEGFR2. Cells at 70% confluence were starved in 1% BSA/DMEM for 4 h, and then incubated in the absence or presence of 60 ng/ml VEGF165 for 10 min at 37 {degree sign}C. Whole cell lysates were analyzed by western blotting, using antibodies against phosphoY1175 and total VEGFR2. Representative results are shown. D) PAE cells stably expressing WT or L840F VEGFR2 were generated from a PAE cell line that does not normally express VEGFR2 (empty). Cells at 70% confluence were starved in 1% BSA/DMEM for 4h, and then incubated in the absence or presence of 60 ng/ml VEGF165 for 10 min at 37 {degree sign}C. Whole cell lysates were then analyzed by western blotting, using antibodies against phosphoY1175 and total VEGFR2. Representative results are shown, highlighting the significant decrease in VEGF-induced Y1175 VEGFR2 phosphorylation in the presence of the L840F mutation.

Published
2023

8. Figure S3 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Figure S3: Analyses of interactions between tyrosine kinase receptors and kinase inhibitors, performed with LigProt.

Published
2023

9. Figure S1 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Figure S1: Read alignments from WES-cfDNA, showing somatic mutations in APC and TP53 genes.

Published
2023

10. Figure S5 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Figure S5: A) Levels of phosphorylated ERK following treatment of the MDST8 colorectal cell line, expressing R1032Q VEGFR2, with different kinase inhibitors in the presence. B) Proliferation assays of Colo320 cell lines, stably expressing WT and R1032Q VEGFR2, upon treatment with TKIs. The expression of the VEGFR2 R1032Q hot-spot mutant in Colo320 cell lines (WT to KRAS/NRAS/BRAF/PIK3CA and mutated to TP53 and APC) increased sensitivity to cabozantinib.

Published
2023

11. Figure S6 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Figure S6: Assessment of the expression of phosphorylated ERK (p-ERK) in the WT and L840F VEGFR2 PDX Avatar models by immunohistochemistry (A), confocal microscopy (B), and immunoblotting (C). The MAPK pathway was activated in the L840F VEGFR2 mutant model and was not decreased following treatment with TKIs.

Published
2023

12. Table S5 from Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Manuel Hidalgo, Jorge L. Martínez-Torrecuadrada, Orlando Domínguez, Antonio Cubillo, Carmen Blanco-Aparicio, Daniel Lietha, Alba De Martino, Rafael Álvarez, Sofia Perea, Tania Sanchez-Perez, Marta Camacho-Artacho, Francesca Sarno, Victoria Bonilla, Yolanda Durán, Natalia Baños, Maria I. Albarran, Álvaro Otero, Estela Vega, Jorge Monsech, Tirso Pons, Maria Mitsi, Elena Garralda, and Rodrigo A. Toledo

Abstract

Table S5: List of KDR/VEGFR2 somatic mutations from the Cosmic, TCGA, GENIE and PCA-WGS databases.

Published
2023

13. Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies

Author

Maria Mitsi, Estela Vega, Yolanda Duran, Rafael Álvarez, Elena Garralda, María Isabel Albarrán, Sofia Perea, Antonio Cubillo, Manuel Hidalgo, Marta Camacho-Artacho, T. Sánchez-Pérez, Orlando Domínguez, Carmen Blanco-Aparicio, Álvaro Otero, Natalia Baños, Jorge Monsech, Alba de Martino, Jorge L. Martínez-Torrecuadrada, Tirso Pons, Francesca Sarno, Rodrigo A. Toledo, Victoria Bonilla, and Daniel Lietha

Subjects
Vascular Endothelial Growth Factor A, 0301 basic medicine, Cancer Research, Class I Phosphatidylinositol 3-Kinases, Protein Conformation, Somatic cell, Colorectal cancer, Angiogenesis Inhibitors, Biology, medicine.disease_cause, Germline, Mice, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Cell Line, Tumor, Exome Sequencing, Biomarkers, Tumor, medicine, Animals, Humans, Anaplastic Lymphoma Kinase, Exome, Proto-Oncogene Proteins c-abl, Exome sequencing, Cell Proliferation, Mutation, Neovascularization, Pathologic, Kinase, Cancer, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, ErbB Receptors, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Heterografts, Female, Colorectal Neoplasms, Cell-Free Nucleic Acids
Abstract

Purpose: Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown. Experimental Design: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts. Results: WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the KDR/VEGFR2 L840F clonal, somatic mutation as the cause of therapy refractoriness in our patient. In addition, we found that 1% to 3% of samples from cancer sequencing projects harbor KDR somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our in vitro and in vivo functional assays confirmed that L840F causes strong resistance to antiangiogenic drugs, whereas the KDR hot-spot mutant R1032Q confers sensitivity to strong VEGFR2 inhibitors. Moreover, we showed that the D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2 mutants promote tumor growth in mice. Conclusions: Our study supports WES-cfDNA as a powerful platform for portraying the somatic mutation landscape of cancer and discovery of new resistance mechanisms to cancer therapies. Importantly, we discovered that VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs. Clin Cancer Res; 24(15); 3550–9. ©2018 AACR.

Published
2018

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