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1.
Cancer Rep (Hoboken) ; 7(4): e2065, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38627902

RESUMEN

BACKGROUND: Extrapleural pneumonectomy (EPP) is a complex surgical procedure involving en-bloc resection of the parietal and visceral pleura, lung, pericardium, and ipsilateral diaphragm. Small case series of pleural-based sarcoma of predominantly pediatric patients suggest EPP may be a life-prolonging surgical option. We aimed to describe the characteristics and outcomes of adults who underwent EPP at a specialized sarcoma center. METHODS: Clinicopathologic variables, surgical details, and follow-up information were extracted for patients undergoing EPP for pleural-based sarcoma between August 2017 and December 2020. Primary outcomes were event-free survival (EFS) and overall survival (OS) from the date of EPP. Secondary outcomes were disease-free interval (DFI) prior to EPP, and early and late postoperative complications. RESULTS: Eight patients were identified, seven with soft tissue sarcoma and one with bone sarcoma. Patients had either localized disease with a primary thoracic sarcoma, sarcoma recurrent to the thorax, or de novo metastatic disease. All patients underwent resection of their pleural-based sarcoma by an experienced cardiothoracic surgeon, and some patients had pre or postoperative treatment. The perioperative morbidity was comparable with previously published reports of EPP performed in mesothelioma patients. At median follow-up of 22.5 months, median EFS was 6.0 months and OS was 20.7 months. Six patients (75%) had disease recurrence; five (62.5%) died of progressive disease. Two patients (25%) had not recurred: one died of a radiation-related esophageal rupture, and one was alive with no evidence of disease at 37.0 months. Characteristics of those with the longest EFS included low-grade histology and achieving a metabolic response to preoperative chemotherapy. CONCLUSIONS: In adults with pleural-based sarcoma, EPP is rarely curative but appears to be a feasible salvage procedure when performed at specialized centers. Patient selection is critical with strong consideration given to multimodal therapy to optimize patient outcomes. In the absence of a confirmed response to neoadjuvant treatment, long term survival is poor and EPP should not be recommended.


Asunto(s)
Mesotelioma , Neoplasias Pleurales , Sarcoma , Adulto , Humanos , Niño , Neumonectomía/efectos adversos , Neumonectomía/métodos , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/cirugía , Recurrencia Local de Neoplasia , Mesotelioma/patología , Mesotelioma/cirugía , Sarcoma/diagnóstico , Sarcoma/cirugía
2.
Cancer Treat Rev ; 124: 102694, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38325070

RESUMEN

INTRODUCTION: Patients with high-risk or metastatic Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) have a guarded prognosis. High-dose chemotherapy (HDT) with autologous stem cell transplant (ASCT) has been evaluated as a treatment option to improve outcomes. However, survival benefits remain unclear, and treatment is associated with severe toxicities. METHODS: A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether utilization of HDT/ASCT impacts the outcome of patients with ES and RMS compared to standard chemotherapy alone, as part of first line treatment or in the relapse setting. Medline, Embase and Cochrane Central were queried for publications from 1990 to October 2022 that evaluated event-free survival (EFS), overall survival (OS), and toxicities. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed. RESULTS: Of 1,172 unique studies screened, 41 studies were eligible for inclusion with 29 studies considering ES, 10 studies considering RMS and 2 studies considering both. In ES patients with high-risk localised disease who received HDT/ASCT after VIDE chemotherapy, consolidation with melphalan-based HDT/ASCT as first line therapy conveyed an EFS and OS benefit over standard chemotherapy consolidation. Efficacy of HDT/ASCT using a VDC/IE backbone, which is now standard care, has not been established. Survival benefits are not confirmed for ES patients with metastatic disease at initial diagnosis. For relapsed/refractory ES, four retrospective studies report improvement in outcomes with HDT/ASCT with the greatest evidence in patients who demonstrate a treatment response before HDT, and in patients under the age of 14. In RMS, there is no proven survival benefit of HDT/ASCT in primary localised, metastatic or relapsed disease. CONCLUSION: Prospective randomised trials are required to determine the utility of HDT/ASCT in ES and RMS. Selected patients with relapsed ES could be considered for HDT/ASCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Rabdomiosarcoma , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/secundario , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Estudios Prospectivos , Nueva Zelanda , Recurrencia Local de Neoplasia/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico , Trasplante Autólogo , Resultado del Tratamiento , Trasplante de Células Madre Hematopoyéticas/métodos
3.
Clin Cancer Res ; 29(24): 5057-5068, 2023 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-37843857

RESUMEN

PURPOSE: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS). PATIENTS AND METHODS: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller-Schäfer method. RESULTS: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43-1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%-90.8%) for ZOL vs. 81.7% (95% CI, 75.2%-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%-97.5%) for ZOL and 94.6% (95% CI, 90.9%-98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003). CONCLUSIONS: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.


Asunto(s)
Neoplasias Óseas , Sarcoma de Ewing , Humanos , Masculino , Femenino , Sarcoma de Ewing/patología , Ácido Zoledrónico/uso terapéutico , Estudios Prospectivos , Supervivencia sin Progresión , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/patología
4.
Cancer Med ; 12(1): 368-378, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35603739

RESUMEN

BACKGROUND: Mesenchymal chondrosarcoma (MCS) is an ultra-rare sarcoma that follows a more aggressive course than conventional chondrosarcoma. This study evaluates prognostic factors, treatments (surgery, chemotherapy, and radiation), and outcomes in an Australian setting. METHODS: We collected demographics, clinicopathological variables, treatment characteristics, and survival status from patients with MCS registered on the national ACCORD sarcoma database. Outcomes include overall survival (OS) and progression-free survival (PFS). RESULTS: We identified 22 patients with MCS between 2001-2022. Median age was 28 (range 10-59) years, 19 (86%) had localised disease at diagnosis of whom 16 had surgery (84%), 11 received radiation (58%), and 10 chemotherapy (53%). Ten (52%) developed recurrence and/or metastases on follow-up and three patients with initial metastatic disease received surgery, radiation, and chemotherapy. At a median follow-up of 50.9  (range 0.4-210) months nine patients had died. The median OS was 104.1 months (95% CI 25.8-182.3). There was improved OS for patients with localised disease who had surgical resection of the primary (p = 0.003) and those with ECOG 0-1 compared to 2-3 (p = 0.023) on univariate analysis. CONCLUSIONS: This study demonstrates contemporary Australian treatment patterns of MCS. The role of chemotherapy for localised disease remains uncertain. Understanding treatment patterns and outcomes help support treatment decisions and design of trials for novel therapeutic strategies.


Asunto(s)
Neoplasias Óseas , Condrosarcoma Mesenquimal , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Condrosarcoma Mesenquimal/cirugía , Neoplasias Óseas/patología , Australia/epidemiología , Estudios de Cohortes , Estudios Retrospectivos
5.
Cancer Med ; 11(8): 1805-1816, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35178869

RESUMEN

CIC-rearranged sarcoma is a recently established, ultra-rare, molecularly defined sarcoma subtype. We aimed to further characterise clinical features of CIC-rearranged sarcomas and explore clinical management including systemic treatments and outcomes. METHODS: A multi-centre retrospective cohort study of patients diagnosed between 2014-2019. RESULTS: Eighteen patients were identified. The median age was 27 years (range 13-56), 10 patients were male (56%), 11 patients (61%) had localised disease and 7 patients had advanced (metastatic or unresectable) disease at diagnosis. Of 11 patients with localised disease at diagnosis, median overall survival (OS) was 40.6 months and the 1-, 2- and 5-year OS estimates were 82%, 64% and 34% respectively. Nine patients (82%) underwent surgery (all had R0 resections), 8 (73%) patients received radiotherapy to the primary site (median dose 57Gy in 28 fractions), and 8 (73%) patients received chemotherapy (predominantly Ewing-based regimens). Metastases developed in 55% with a median time to recurrence of 10.5 months. In patients with advanced disease at diagnosis, median OS was 12.6 months (95% CI 5.1-20.1), 1-year OS was 57%. Median progression-free survival was 5.8 months (95% CI 4.5-7.2). Durable systemic therapy responses occurred infrequently with a median duration of systemic treatment response of 2.1 months. One durable complete response of metastatic disease to VDC/IE chemotherapy was seen. Responses to pazopanib (n = 1) and pembrolizumab (n = 1) were not seen. CONCLUSION: In this series, CIC-rearranged sarcomas affected young adults and had a high incidence of presenting with, or developing, metastatic disease. The prognosis overall was poor. In advanced disease, durable systemic therapy responses were infrequent.


Asunto(s)
Sarcoma de Células Pequeñas , Sarcoma , Neoplasias de los Tejidos Blandos , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Sarcoma/genética , Sarcoma/patología , Sarcoma/terapia , Sarcoma de Células Pequeñas/patología , Adulto Joven
6.
Cancer Rep (Hoboken) ; 4(2): e1327, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33314769

RESUMEN

BACKGROUND: Sarcomas represent 10%-15% of cancers in adolescent and young adult (AYA) patients, and survival for those with metastatic disease or relapse is poor. Immunotherapy with checkpoint inhibition has improved outcomes in multiple tumor types, but data in advanced sarcomas, particularly within the AYA population, are limited. AIM: We aim to evaluate response and toxicity for AYA patients with sarcoma treated with pembrolizumab. METHODS AND RESULTS: We retrospectively reviewed AYA patients with advanced bone and soft tissue sarcoma who received self-funded pembrolizumab between May 2015 and January 2019. Eighteen patients were identified. One patient with Ewing sarcoma had a sustained complete response to therapy. Two patients with alveolar soft part sarcoma received a clinical benefit from pembrolizumab: one had a radiological partial response with an excellent clinical response and one patient achieved stable disease. Four patients died of disease prior to first scheduled assessment and thus were not evaluable. The remaining eleven patients had progressive disease. CONCLUSION: The role of immunotherapy in AYA sarcoma warrants further investigation. Biomarkers of response need to be further evaluated in order to guide patient selection.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adolescente , Adulto , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Clasificación del Tumor , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios Retrospectivos , Sarcoma/diagnóstico , Sarcoma/patología , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/patología , Resultado del Tratamiento , Adulto Joven
7.
Histopathology ; 69(6): 1000-1011, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27385661

RESUMEN

AIMS: Recurrent Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangements characterize a select group of bone and soft tissue tumours. In our routine diagnostic practice with fluorescence in-situ hybridization (FISH), we have occasionally observed EWSR1 gene rearrangements in tumours not associated classically with EWSR1 translocations. This study aimed to review our institutional experience of this phenomenon and also to highlight the occurrence of unusual EWSR1 FISH signals (i.e. 5' centromeric region or 3' telomeric region signals) that do not fulfil the published diagnostic criteria for rearrangements. METHODS AND RESULTS: Using an EWSR1 break-apart probe, we performed FISH assays on formalin-fixed paraffin-embedded tissue sections from 135 bone and soft tissue specimens as part of their routine diagnostic work-up. EWSR1 gene rearrangements were identified in 51% of cases, 56% of which also showed an abnormal FISH signal pattern (in addition to classically rearranged signals). However, atypical FISH signals were present in 45% of the non-rearranged cases. In addition, we observed tumours unrelated to those described classically as EWSR1-associated that were technically EWSR1-rearranged in 6% of cases. Borderline levels of rearrangement (affecting 10-30% of lesional cells) were present in an additional 17% of these cases. CONCLUSIONS: While our study confirmed that FISH is a sensitive and specific tool in the diagnosis of EWSR1-associated tumours, atypical FISH signals and classical rearrangement in entities other than EWSR1-associated tumours can occur. Therefore, it is essential that the FISH result not be used as an isolated test, but must be evaluated in the context of clinical features, imaging, pathological and immunohistochemical findings.


Asunto(s)
Neoplasias Óseas/genética , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión al ARN/genética , Neoplasias de los Tejidos Blandos/genética , Reordenamiento Génico , Humanos , Hibridación Fluorescente in Situ , Proteína EWS de Unión a ARN
8.
J Hematol Oncol ; 9(1): 48, 2016 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-27259563

RESUMEN

BACKGROUND: Ewing sarcoma (EWS) is a malignant tumour of bone and soft tissue, and although many patients are cured with conventional multimodal therapy, those with recurrent or metastatic disease have a poor prognosis. Genomic instability and programmed cell death ligand-1 (PD-L1) expression have been identified in EWS, providing a rationale for treatment with agents that block the programmed cell death-1 (PD-1) receptor. CASE PRESENTATION: In this report, we describe a heavily pre-treated patient with recurrent metastatic EWS who achieved a clinical and radiological remission with PD-1 blockade. CONCLUSIONS: To our knowledge, this is the first reported case demonstrating efficacy of PD-1 blockade in EWS. This warrants further investigation in particular given the poor prognosis in patients with recurrent or metastatic disease.


Asunto(s)
Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Sarcoma de Ewing/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/farmacología , Humanos , Masculino , Metástasis de la Neoplasia , Recurrencia , Sarcoma de Ewing/diagnóstico por imagen , Sarcoma de Ewing/patología , Sarcoma de Ewing/radioterapia , Resultado del Tratamiento , Adulto Joven
9.
Blood ; 125(2): 273-83, 2015 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-25336632

RESUMEN

Glucocorticoids are critical components of combination chemotherapy regimens in pediatric acute lymphoblastic leukemia (ALL). The proapoptotic BIM protein is an important mediator of glucocorticoid-induced apoptosis in normal and malignant lymphocytes, whereas the antiapoptotic BCL2 confers resistance. The signaling pathways regulating BIM and BCL2 expression in glucocorticoid-treated lymphoid cells remain unclear. In this study, pediatric ALL patient-derived xenografts (PDXs) inherently sensitive or resistant to glucocorticoids were exposed to dexamethasone in vivo. Microarray analysis showed that KLF13 and MYB gene expression changes were significantly greater in dexamethasone-sensitive than -resistant PDXs. Chromatin immunoprecipitation (ChIP) analysis detected glucocorticoid receptor (GR) binding at the KLF13 promoter to trigger KLF13 expression only in sensitive PDXs. Next, KLF13 bound to the MYB promoter, deactivating MYB expression only in sensitive PDXs. Sustained MYB expression in resistant PDXs resulted in maintenance of BCL2 expression and inhibition of apoptosis. ChIP sequencing analysis revealed a novel GR binding site in a BIM intronic region (IGR) that was engaged only in dexamethasone-sensitive PDXs. The absence of GR binding at the BIM IGR was associated with BIM silencing and dexamethasone resistance. This study has identified novel mechanisms of opposing BCL2 and BIM gene regulation that control glucocorticoid-induced apoptosis in pediatric ALL cells in vivo.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Apoptosis/genética , Proteínas de la Membrana/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Glucocorticoides/genética , Animales , Antineoplásicos Hormonales/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteína 11 Similar a Bcl2 , Western Blotting , Inmunoprecipitación de Cromatina , Dexametasona/farmacología , Resistencia a Antineoplásicos/genética , Ensayo de Inmunoadsorción Enzimática , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Proteínas de la Membrana/biosíntesis , Ratones , Ratones Endogámicos NOD , Ratones SCID , Análisis de Secuencia por Matrices de Oligonucleótidos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Glucocorticoides/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
10.
BMC Genomics ; 15: 416, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-24885906

RESUMEN

BACKGROUND: Patient-derived tumour xenografts are an attractive model for preclinical testing of anti-cancer drugs. Insights into tumour biology and biomarkers predictive of responses to chemotherapeutic drugs can also be gained from investigating xenograft models. As a first step towards examining the equivalence of epigenetic profiles between xenografts and primary tumours in paediatric leukaemia, we performed genome-scale DNA methylation and gene expression profiling on a panel of 10 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) tumours that were stratified by prednisolone response. RESULTS: We found high correlations in DNA methylation and gene expression profiles between matching primary and xenograft tumour samples with Pearson's correlation coefficients ranging between 0.85 and 0.98. In order to demonstrate the potential utility of epigenetic analyses in BCP-ALL xenografts, we identified DNA methylation biomarkers that correlated with prednisolone responsiveness of the original tumour samples. Differential methylation of CAPS2, ARHGAP21, ARX and HOXB6 were confirmed by locus specific analysis. We identified 20 genes showing an inverse relationship between DNA methylation and gene expression in association with prednisolone response. Pathway analysis of these genes implicated apoptosis, cell signalling and cell structure networks in prednisolone responsiveness. CONCLUSIONS: The findings of this study confirm the stability of epigenetic and gene expression profiles of paediatric BCP-ALL propagated in mouse xenograft models. Further, our preliminary investigation of prednisolone sensitivity highlights the utility of mouse xenograft models for preclinical development of novel drug regimens with parallel investigation of underlying gene expression and epigenetic responses associated with novel drug responses.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Metilación de ADN/efectos de los fármacos , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Prednisolona/farmacología , Adolescente , Animales , Antineoplásicos Hormonales/uso terapéutico , Niño , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Humanos , Lactante , Masculino , Ratones Endogámicos NOD , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Prednisolona/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
12.
J Paediatr Child Health ; 48(8): 634-40, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22050419

RESUMEN

Glucocorticoids (GCs), such as prednisolone and dexamethasone, are key components in multi-agent chemotherapy protocols used for the treatment of acute lymphoblastic leukaemia (ALL). Approximately 10% of children with ALL will respond poorly to GCs, and GC resistance is associated with a significantly inferior outcome. This review summarises the current knowledge of GC resistance in ALL, including the roles of the GC receptor and its co-chaperone molecules, the pro-apoptotic and pro-survival B-cell lymphoma 2 family members and alternative non-apoptotic mechanisms of cell death. It concludes with a discussion on therapeutic attempts to overcome GC resistance.


Asunto(s)
Resistencia a Antineoplásicos , Glucocorticoides/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Niño , Glucocorticoides/farmacología , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo
13.
BMC Genomics ; 12: 565, 2011 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-22093874

RESUMEN

BACKGROUND: Glucocorticoids such as prednisolone and dexamethasone are critical drugs used in multi-agent chemotherapy protocols used to treat acute lymphoblastic leukemia (ALL), and response to glucocorticoids is highly predictive of outcome. The NOD/SCID xenograft mouse model of ALL is a clinically relevant model in which the mice develop a systemic leukemia which retains the fundamental biological characteristics of the original disease. Here we report a study evaluating the NOD/SCID xenograft mouse model to investigate glucocorticoid-induced gene expression. Cells from a glucocorticoid-sensitive xenograft derived from a child with B-cell precursor ALL were inoculated into NOD/SCID mice. When highly engrafted the mice were randomized into groups of 4 to receive dexamethasone 15 mg/kg by intraperitoneal injection or vehicle control. Leukemia cells were harvested from mice spleens at 0, 8, 24 or 48 hours thereafter, and gene expression analyzed on Illumina WG-6_V3 chips, comparing all groups to time 0 hours. RESULTS: The 8 hour dexamethasone-treated timepoint had the highest number of significantly differentially expressed genes, with fewer observed at the 24 and 48 hour timepoints, and with minimal changes seen across the time-matched controls. When compared to publicly available datasets of glucocorticoid-induced gene expression from an in vitro cell line study and from an in vivo study of patients with ALL, at the level of pathways, expression changes in the 8 hour xenograft samples showed a similar response to patients treated with glucocorticoids. Replicate analysis revealed that at the 8 hour timepoint, a dataset with high signal and differential expression, using data from 3 replicates instead of 4 resulted in excellent recovery scores of > 0.9. However at other timepoints with less signal very poor recovery scores were obtained with 3 replicates. CONCLUSIONS: The NOD/SCID xenograft mouse model provides a reproducible experimental system in which to investigate clinically-relevant mechanisms of drug-induced gene regulation in ALL; the 8 hour timepoint provides the highest number of significantly differentially expressed genes; time-matched controls are redundant and excellent recovery scores can be obtained with 3 replicates.


Asunto(s)
Dexametasona/farmacología , Modelos Animales de Enfermedad , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Glucocorticoides/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Animales , Femenino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trasplante de Neoplasias , Factores de Tiempo , Transcriptoma
15.
Blood ; 116(16): 3013-22, 2010 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-20647567

RESUMEN

Glucocorticoids play a critical role in the therapy of lymphoid malignancies, including pediatric acute lymphoblastic leukemia (ALL), although the mechanisms underlying cellular resistance remain unclear. We report glucocorticoid resistance attributable to epigenetic silencing of the BIM gene in pediatric ALL biopsies and xenografts established in immune-deficient mice from direct patient explants as well as a therapeutic approach to reverse resistance in vivo. Glucocorticoid resistance in ALL xenografts was consistently associated with failure to up-regulate BIM expression after dexamethasone exposure despite confirmation of a functional glucocorticoid receptor. Although a comprehensive assessment of BIM CpG island methylation revealed no consistent changes, glucocorticoid resistance in xenografts and patient biopsies significantly correlated with decreased histone H3 acetylation. Moreover, the histone deacetylase inhibitor vorinostat relieved BIM repression and exerted synergistic antileukemic efficacy with dexamethasone in vitro and in vivo. These findings provide a novel therapeutic strategy to reverse glucocorticoid resistance and improve outcome for high-risk pediatric ALL.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas Reguladoras de la Apoptosis/genética , Resistencia a Antineoplásicos , Silenciador del Gen , Glucocorticoides/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Proteínas de la Membrana/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Proteína 11 Similar a Bcl2 , Niño , Dexametasona/farmacología , Dexametasona/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Sitios Genéticos , Glucocorticoides/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Ratones , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Vorinostat
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