Browsing by Author "Melero, I."
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Item Identification of TNF-alpha and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array.(British Journal of Cancer, 2009) Pérez-Gracia, J. L.; Prior, C.; Guillén-Grima, F.; Segura, V.; González, A.; Panizo, A.; Melero, I.; Grande-Pulido, E.; Gurpide, A.; Gurpide, A.; Gil-Bazo, I.; Calvo, A.BACKGROUND: Several drugs are available to treat metastatic renal-cell carcinoma (MRCC), and predictive markers to identify the most adequate treatment for each patient are needed. Our objective was to identify potential predictive markers of sunitinib activity in MRCC. METHODS: We collected sequential serum samples from 31 patients treated with sunitinib. Sera of six patients with extreme phenotypes of either marked responses or clear progressions were analysed with a Human Cytokine Array which evaluates 174 cytokines before and after treatment. Variations in cytokine signal intensity were compared between both groups and the most relevant cytokines were assessed by ELISA in all the patients. RESULTS: Twenty-seven of the 174 cytokines varied significantly between both groups. Five of them (TNF-a, MMP-9, ICAM-1, BDNF and SDF-1) were assessed by ELISA in 21 evaluable patients. TNF-a and MMP-9 baseline levels were significantly increased in nonresponders and significantly associated with reduced overall survival and time-to-progression, respectively. The area under the ROC curves for TNF-a and MMP-9 as predictive markers of sunitinib activity were 0.83 and 0.77. CONCLUSION: Baseline levels of TNF-a and MMP-9 warrant further study as predictive markers of sunitinib activity in MRCC. Selection of patients with extreme phenotypes seems a valid method to identify potential predictive factors of response.Item Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes.(British Journal of Cancer, 2009) Alfaro, C.; Suárez, N.; González, A.; Solano, S.; Erro, L.; Dubrot, J.; Palazón, A.; Hervas-Stubbs, S.; Gurpide, A.; López-Picazo, J.M.; Grande-Pulido, E.; Melero, I.; Pérez-Gracia, J. L.Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.