Examinando por Autor "Rojo, Federico"

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Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy
(Nature Publishing Group, 2014-05-27) del Puerto-Nevado, Laura; Rojo, Federico; Zazo, Sandra; Carames, Cristina; Rubio, Gustavo; Vega, Ricardo; Chamizo, Cristina; Casado, Victoria; Martinez-Useros, Javier; Rincón, Raul; Rodríguez-Remírez, Maria; Borrero-Palacios, Aurea; Cristobal, Ion; Madoz-Gúrpide, Juan; Aguilera, Oscar; García-Foncillas, Jesus
Background: Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients. Methods: Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out. Results: The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10–300); for KDR 258.5 (range, 150–300); for pKDRY1775 10.8 (range, 0–65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10–126). Statistical differences for PFS (P = 0.01) and OS (P = 0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDRY1775 expression remained significant after multivariate Cox analysis for PFS (P = 0.01; HR: 5.35, 95% CI, 1.49–19.13) and for OS (P = 0.02; HR: 5.13, 95% CI, 1.25–21.05). Conclusions: Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.
DEK is a potential marker for aggressive phenotype and irinotecan-based therapy response in metastatic colorectal cancer
(Springer-Nature, 2014-12-16) Martínez-Useros, Javier; Rodríguez-Remírez, Maria; Borrero-Palacios, Aurea; Moreno, Irene; Cebrian, Arancha; Gomez del Pulgar, Teresa; del Puerto-Nevado, Laura; Vega-Bravo, Ricardo; Puime-Otin, Alberto; Perez, Nuria; Zazo, Sandra; Senin, Clara; Fernández-Aceñero, María Jesús; Soengas, Marisol; Rojo, Federico; García-Foncillas, Jesus
Background: DEK is a transcription factor involved in stabilization of heterochromatin and cruciform structures. It plays an important role in development and progression of different types of cancer. This study aims to analyze the role of DEK in metastatic colorectal cancer. Methods: Baseline DEK expression was firstly quantified in 9 colorectal cell lines and normal mucosa by WB. SiRNA-mediated DEK inhibition was carried out for transient DEK silencing in DLD1 and SW620 to dissect its role in colorectal cancer aggressiveness. Irinotecan response assays were performed with SN38 over 24 hours and apoptosis was quantified by flow cytometry. Ex-vivo assay was carried out with 3 fresh tumour tissues taken from surgical resection and treated with SN38 for 24 hours. DEK expression was determined by immunohistochemistry in 67 formalin-fixed paraffin-embedded tumour samples from metastatic colorectal cancer patients treated with irinotecan-based therapy as first-line treatment. Results: The DEK oncogene is overexpressed in all colorectal cancer cell lines. Knock-down of DEK on DLD1 and SW620 cell lines decreased cell migration and increased irinotecan-induced apoptosis. In addition, low DEK expression level predicted irinotecan-based chemotherapy response in metastatic colorectal cancer patients with KRAS wild-type. Conclusions: These data suggest DEK overexpression as a crucial event for the emergence of an aggressive phenotype in colorectal cancer and its potential role as biomarker for irinotecan response in those patients with KRAS wild-type status.
PP2A Inhibition Is a Common Event in Colorectal Cancer and Its Restoration Using FTY720 Shows Promising Therapeutic Potential
(AACR Journals, 2014-04-01) Cristobal, Ion; Manso, Rebeca; Rincon, Raul; Carames, Cristina; Senin, Clara; Borrero, Aurea; Martínez-Useros, Javier; Rodriguez, Maria; Zazo, Sandra; Aguilera, Oscar; Madoz-Gurpide, Juan; Rojo, Federico; García-Foncillas, Jesus
Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates many signaling pathways crucial for cell transformation. In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colorectal cancer, indicating that PP2A represents a potential therapeutic target for this disease. We identified overexpression of the endogenous PP2A inhibitors SET and CIP2A, and downregulation of regulatory PP2A such as PPP2R2A and PPP2R5E, as contributing mechanisms to PP2A inhibition in colorectal cancer. Moreover, we observed that its restoration using FTY720 impairs proliferation and clonogenic potential of colorectal cancer cells, induces caspase-dependent apoptosis, and affects AKT and extracellular signal-regulated kinase-1/2 activation status. Interestingly, treatment with FTY720 showed an additive effect with 5- fluorouracil, SN-38, and oxaliplatin, drugs used in standard chemotherapy in patients with colorectal cancer. These results suggest that PP2A activity is commonly decreased in colorectal cancer cells, and that the use of PP2A activators, such as FTY720, might represent a potential novel therapeutic strategy in colorectal cancer. Mol Cancer Ther; 13(4); 938–47. 2014 AACR.