RESUMEN

Overexpression of the Bcl-2 family of genes results in increased transcription of anti-apoptotic proteins. In vitro data suggest that this may enhance acquired chemoresistance and correlate with extramedullary invasion. This has led to pursuing the Bcl-2 family of proteins as therapeutic targets in several malignant disorders, including multiple myeloma (MM). The impact of novel therapeutic agents such as bortezomib on these molecular markers is not known. We investigated the association between the expression of anti-apoptotic members of the Bcl-2 family and the efficacy of bortezomib in patients with relapsed/refractory MM. Gene expression data generated prospectively from large clinical trials were utilized. Hypothesis testing using a multisample test for equivalence was performed. The association between Bcl-2 expression levels and clinical response was negated in bortezomib-treated patients (p = 0.014), while not so in dexamethasone-treated patients (p = 0.92). Similar results were noted for variant 2 of the Mcl-1 gene (p = 0.003). Results for Bcl-xl did not meet the level of significance. Thus, the importance of the Bcl-2 family of proteins as prognostic markers in MM should be reassessed in the novel therapeutic agent era. Our data suggest that bortezomib may overcome the prognostic effect conferred by overexpression of some of the anti-apoptotic Bcl-2 family of genes in patients with relapsed/refractory MM.

Asunto(s)

Ácidos Borónicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Genes bcl-2/genética , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Ácidos Borónicos/farmacología , Bortezomib , Ensayos Clínicos como Asunto/estadística & datos numéricos , Análisis por Conglomerados , Resistencia a Antineoplásicos/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes bcl-2/efectos de los fármacos , Humanos , Análisis por Micromatrices , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Pronóstico , Pirazinas/farmacología , Recurrencia , Insuficiencia del Tratamiento , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética

RESUMEN

Immunohistochemical analyses of archival tumor specimens were used for pre-planned exploratory analyses of protocol-specified candidate biomarkers of bortezomib activity in 73 patients with relapsed/refractory mantle cell lymphoma in the phase 2 PINNACLE study. Consistent with other studies, elevated Ki-67 was a marker of poor prognosis, demonstrating significant associations with shorter time to progression and overall survival. Elevated NF-kappaB p65 and low PSMA5 expression demonstrated a trend for better response and were significantly associated with longer time to progression; elevated NF-kappaB p65 demonstrated a trend toward longer overall survival. This is consistent with myeloma clinical genomics research, suggesting biomarker relevance across tumor types. Elevated p27 was significantly associated with longer overall survival. Overall survival analyses by International Prognostic Index and Mantle Cell Lymphoma International Prognostic Index confirmed differential prognosis by both scores. These biomarkers data begin to illuminate bortezomib's mechanism of action in lymphoma.

Asunto(s)

Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Ácidos Borónicos/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/metabolismo , Pirazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Bortezomib , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento

Asunto(s)

Antineoplásicos/administración & dosificación , Ácidos Borónicos/administración & dosificación , Dexametasona/administración & dosificación , Regulación Neoplásica de la Expresión Génica , Modelos Biológicos , Mieloma Múltiple , Proteínas de Neoplasias/biosíntesis , Pirazinas/administración & dosificación , Bortezomib , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Masculino , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/mortalidad , Valor Predictivo de las Pruebas , Factores de Riesgo , Factores de Tiempo

RESUMEN

Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/genética , Mutación/genética , FN-kappa B/genética , Proteínas de Neoplasias/metabolismo , Adenoviridae , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Antígenos CD40/genética , Antígenos CD40/metabolismo , Células Cultivadas , Enzima Desubiquitinante CYLD , Activación Enzimática , Técnica del Anticuerpo Fluorescente , Eliminación de Gen , Perfilación de la Expresión Génica , Humanos , Immunoblotting , Técnicas para Inmunoenzimas , Hibridación Fluorescente in Situ , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , FN-kappa B/metabolismo , Subunidad p50 de NF-kappa B/genética , Subunidad p50 de NF-kappa B/metabolismo , Subunidad p52 de NF-kappa B/genética , Subunidad p52 de NF-kappa B/metabolismo , Proteínas de Neoplasias/genética , Hibridación de Ácido Nucleico , Plásmidos , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Factor 2 Asociado a Receptor de TNF/genética , Factor 2 Asociado a Receptor de TNF/metabolismo , Factor 3 Asociado a Receptor de TNF/genética , Factor 3 Asociado a Receptor de TNF/metabolismo , Transfección , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas , Quinasa de Factor Nuclear kappa B

RESUMEN

The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents.

Asunto(s)

Ácidos Borónicos/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Modelos Biológicos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Inhibidores de Proteasas/administración & dosificación , Pirazinas/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Bortezomib , Dexametasona/administración & dosificación , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Farmacogenética , Valor Predictivo de las Pruebas , Estudios Prospectivos , Inhibidores de Proteasoma , Recurrencia , Resultado del Tratamiento

RESUMEN

The Pap test has effectively reduced the incidence and mortality of cervical cancer. However, because of the morphological basis of this test, sensitivity and specificity are less than ideal, a situation that complicates the clinical management of women diagnosed with low-grade cervical abnormalities. In an attempt to understand the molecular basis of cervical tumorigenesis and to discover molecular markers for accurate cervical cancer screening, we used cDNA microarrays containing >30,000 Unigene clones to examine the gene expression patterns of 34 cervical tissues from different clinically defined stages. It was found that global gene expression patterns separated normal cervical tissues and low-grade squamous intraepithelial lesions from cervical cancers and most of the high-grade squamous intraepithelial lesions (HSILs). Among the top 62 genes/(expressed sequence tags) that were overexpressed in tumors and HSIL tissues, 35 were confirmed using in situ hybridization on cervical tissue micorarrays. Many of these genes were overexpressed in high-grade dysplastic and malignant cervical epithelium or in stroma adjacent to the diseased tissues, with cellular proliferation and extracellular matrix-associated genes being the most common. In general, the extent of gene overexpression increased as the lesions progressed from low-grade squamous intraepithelial lesions to HSILs and finally to cancer. It is hoped that with additional development, some of these markers will improve the interpretation of cervical screening tests and provide useful information for patient management decisions.

Asunto(s)

Neoplasias del Cuello Uterino/genética , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , División Celular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/fisiología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Marcadores Genéticos/genética , Humanos , Hibridación in Situ , Análisis de Secuencia por Matrices de Oligonucleótidos , Activación Transcripcional , Neoplasias del Cuello Uterino/metabolismo , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/metabolismo