RESUMEN
It is becoming increasingly evident that cancers are dependent on a number of altered molecular pathways and can develop diverse mechanisms of resistance to therapy with single agents. Therefore, combination regimens may provide the best hope for effective therapies with durable effects. Despite preclinical data to support this notion, there are many challenges to the development of targeted combinations including scientific, economic, legal, and regulatory barriers. A discussion of these challenges and identification of models and best practices are presented with intent of aiding the research community in addressing real and perceived barriers to the development of combination therapies for cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos como Asunto/métodos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto/normas , Ensayos Clínicos como Asunto/tendencias , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Industria Farmacéutica/legislación & jurisprudencia , Sinergismo Farmacológico , Humanos , Propiedad Intelectual , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , National Cancer Institute (U.S.) , Proyectos de Investigación , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 32 patients with smoldering, chronic, lymphoma and acute leukemia using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared with normal lymphocytes. Several unique genes were identified that were overexpressed in leukemic cells, including TNFSF11, RGS13, MAFb, CSPG2, C/EBP-alpha, and TCF4; 200 of the most highly overexpressed ATL genes were analyzed by the Pathway Studio, version 4.0 program. ATL leukemia cells were characterized by an increase in genes linked to "central" genes CDC2/cyclin B1, SYK/LYN, proliferating cell nuclear antigen, and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells with BIRC5 shRNA decreased BIRC5 expression and cell viability 80%. Clinical treatment of ATL patients with Zenapax or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Factores de Transcripción/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Ácidos Borónicos/uso terapéutico , Bortezomib , Linfocitos T CD4-Positivos/metabolismo , Supervivencia Celular , Proteínas de Unión al ADN/genética , Daclizumab , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoglobulina G/uso terapéutico , Proteínas Inhibidoras de la Apoptosis , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/genética , Masculino , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Pirazinas/uso terapéutico , Interferencia de ARN , Survivin , Factor de Transcripción 4 , Factores de Transcripción/genética , Células Tumorales CultivadasAsunto(s)
Becas , Investigadores , Enseñanza , Academias e Institutos , Femenino , Humanos , Masculino , Prejuicio , Investigadores/psicología , Recursos HumanosRESUMEN
The p53 tumor suppressor protein plays a critical role in mediating cellular response to stress. Upon DNA damage, post-translational modifications stabilize and activate this nuclear phosphoprotein. To determine the effect of phosphorylation site mutants in the context of the whole p53 protein, we performed reporter assays in p53 and MDM2 knockout mouse embryonic fibroblasts transfected with full-length p53 constructs. We show that mutation of S37 causes a decrease in p53 transcriptional activity compared to wild-type p53. Our data further suggest that the dephosphorylation of p53 at S37 is a regulated event involving protein phosphatase 2A (PP2A). Coimmunoprecipitation and immunofluorescence microscopy studies demonstrate that PP2A and p53 associate with one another in vivo following gamma-irradiation. Consistent with these observations, phosphorylated S37 accumulates in cell extracts prepared from gamma-irradiated Molt-4 cells in the presence of okadaic acid. Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37. These results suggest that dephosphorylation of p53 at S37 plays a role in the transcriptional regulation of the p53 protein in response to DNA damage.