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Métodos Terapéuticos y Terapias MTCI
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Lancet Oncol ; 15(3): 286-96, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24556040


BACKGROUND: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. METHODS: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with, number NCT01223027. FINDINGS: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). INTERPRETATION: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. FUNDING: Novartis Pharmaceuticals Corporation.

Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolonas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bencimidazoles/efectos adversos , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Femenino , Humanos , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Quinolonas/efectos adversos , Sorafenib , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores
Mol Cancer Ther ; 10(9): 1542-52, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21764904


We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role.

Antineoplásicos/farmacología , Factores de Crecimiento de Fibroblastos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/genética , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
Br J Haematol ; 150(1): 46-57, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20507304


Constitutive activation of Janus kinase (Jak) 2 is the most prevalent pathogenic event observed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove valuable in their management. Inhibition of the Aurora kinases has also proven to be an effective therapeutic strategy in a number of haematological malignancies. AT9283 is a multi-targeted kinase inhibitor with potent activity against Jak2 and Aurora kinases A and B, and is currently being evaluated in clinical trials. To investigate the therapeutic potential of AT9283 in the MPD we studied its activity in a number of Jak2-dependent systems. AT9283 potently inhibited proliferation and Jak2-related signalling in Jak2-dependent cell lines as well as inhibiting the formation of erythroid colonies from haematopoietic progenitors isolated from MPD patients with Jak2 mutations. The compound also demonstrated significant therapeutic potential in vivo in an ETV6-JAK2 (TEL-JAK2) murine leukaemia model. Inhibition of both Jak2 and Aurora B was observed in the model systems used, indicating a dual mechanism of action. Our results suggest that AT9283 may be a valuable therapy in patients with MPD and that the dual inhibition of Jak2 and the Aurora kinases may potentially offer combinatorial efficacy in the treatment of these diseases.

Antineoplásicos/farmacología , Bencimidazoles/farmacología , Janus Quinasa 2/antagonistas & inhibidores , Trastornos Mieloproliferativos/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Antineoplásicos/uso terapéutico , Aurora Quinasa B , Aurora Quinasas , Bencimidazoles/uso terapéutico , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Células Precursoras Eritroides/efectos de los fármacos , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/fisiología , Leucemia Experimental/tratamiento farmacológico , Leucemia Experimental/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Urea/farmacología , Urea/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto