Grande-Pulido, E. (E.)

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    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
    (Nature Publishing Group, 2009) Gil-Bazo, I. (Ignacio); Prior, C. (Celia); Perez-Gracia, J.L. (Jose Luis); Gonzalez-Hernandez, A. (Alvaro); Gurpide, A. (Alfonso); Guillen-Grima, F. (Francisco); Melero, I. (Ignacio); Panizo, A. (Ángel); Grande-Pulido, E. (E.); Segura, V. (Víctor); Calvo-González, A. (Alfonso)
    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-alpha, MMP-9, ICAM-1, BDNF and SDF-1) were assessed by ELISA in 21 evaluable patients. TNF-alpha and MMP-9 baseline levels were significantly increased in non-responders and significantly associated with reduced overall survival and time-to-progression, respectively. The area under the ROC curves for TNF-alpha and MMP-9 as predictive markers of sunitinib activity were 0.83 and 0.77. CONCLUSION: Baseline levels of TNF-alpha 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.
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    Patient-reported outcomes in a phase III, randomized study of sunitinib versus interferon-{alpha} as first-line systemic therapy for patients with metastatic renal cell carcinoma in a European population
    (Oxford University Press, 2009-11) Gonzalez-Larriba, J.L. (José Luis); Perez-Gracia, J.L. (Jose Luis); Pardo, A. (A.); Garcia-del-Muro, X. (X.); Diaz-Cerezo, S. (S.); Ruiz, M.A. (M. A.); Abrio, M.V. (M. V.); Castellano, D. (Daniel); Guzman, C. (C.); Grande-Pulido, E. (E.)
    BACKGROUND: The purpose of this study is to evaluate the impact on the health-related quality of life (HRQoL) of sunitinib versus interferon-alpha (IFN-alpha) treatment in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In all, 304 mRCC patients (European cohort) were randomized 1 : 1 to receive sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off) or IFN-alpha (9 million units s.c. injection three times/week). The following questionnaires were completed (days 1 and 28 per cycle): Functional Assessment of Cancer Therapy-General (FACT-G), the FACT-Kidney Symptom Index and the EuroQol Group's EQ-5D self-report questionnaire (EQ-5D). Results correspond to an ongoing trial with progression-free survival time as primary end point, and patients were still being followed up. Data were analyzed using repeated measures mixed effects models (MEMs) that allow the inclusion of initial differences and uncompleted repeated measures, with the assumption of data missing at random. Six-cycle results were included. RESULTS: Results consistently showed that patients in sunitinib group experienced statistically significantly milder kidney-related symptoms, better cancer-specific HRQoL and general health status (in social utility scores) during the study period as measured by these patient-reported outcome end points. No statistical differences between groups were found on the FACT-G physical well-being subscale or the EQ-5D VAS values. CONCLUSIONS: Results from MEM showed the sunitinib's benefit on HRQoL compared with IFN-alpha.
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    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
    (Cancer Research UK, 2009) Dubrot, J. (Juan); Alfaro, C. (Carlos); Solano, S. (Sarai); Perez-Gracia, J.L. (Jose Luis); Lopez-Picazo, J.M. (José M.); Gonzalez-Hernandez, A. (Alvaro); Gurpide, A. (Alfonso); Hervas-Stubbs, S. (Sandra); Erro, L. (Lorena); Melero, I. (Ignacio); Palazon, A. (Asís); Suarez, N. (Natalia); Grande-Pulido, E. (E.)
    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.