Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cancer Res ; 79(21): 5652-5667, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31501192

RESUMO

MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN-PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN-PA2G4 protein-protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. SIGNIFICANCE: Competitive chemical inhibition of the PA2G4-MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

3.
Sci Transl Med ; 11(477)2019 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-30700572

RESUMO

Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.

4.
Am J Hum Genet ; 104(2): 213-228, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639323

RESUMO

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

6.
Mol Cancer Ther ; 17(5): 1012-1023, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29491149

RESUMO

Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug-resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC Dream Vector (EDVTM) is a nanocell, which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase I trials in adults with refractory tumors have shown an acceptable safety profile. Herein we investigated the activity of EGFR-targeted and doxorubicin-loaded EDVTM (EGFREDVTMDox) for the treatment of neuroblastoma. Two independent neuroblastoma cell lines with variable expression of EGFR protein [SK-N-BE(2), high; SH-SY-5Y, low] were used. EGFREDVTMDox induced apoptosis in these cells compared to control, doxorubicin, or non-doxorubicin loaded EGFREDVTM In three-dimensional tumor spheroids, imaging and fluorescence life-time microscopy revealed that EGFREDVTMDox had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR-targeted EDVTMDox, with enhanced spheroid penetration leading to increased apoptosis. In two independent orthotopic human neuroblastoma xenograft models, short-term studies (28 days) of tumor-bearing mice led to a significant decrease in tumor size in EGFREDVTMDox-treated animals compared to control, doxorubicin, or non-EGFR EDVTMDox There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDVTMDox Moreover, overall survival was increased in neuroblastoma mice treated with EGFREDVTMDox (P < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVsTM offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma. Mol Cancer Ther; 17(5); 1012-23. ©2018 AACR.

7.
Pediatr Dev Pathol ; 21(5): 461-466, 2018 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29426276

RESUMO

Background Although MYCN (aka N-myc) amplification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN amplification nor MYCN protein overexpression. Both of these tumors exhibited "large cell neuroblastoma" histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with "aberrant" desmin expression. Conclusions MYC-amplified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features.

8.
Eur J Cancer ; 83: 132-141, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28735070

RESUMO

The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumour formation; however, Abcc4-null neuroblastomas were strongly sensitised to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitise tumours to ABCC4 chemotherapeutic substrates.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Proteínas Associadas à Resistência a Múltiplos Medicamentos/deficiência , Neuroblastoma/tratamento farmacológico , Animais , Western Blotting , Camptotecina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Doxiciclina/farmacologia , Xenoenxertos/efeitos dos fármacos , Irinotecano , Camundongos , Camundongos Knockout , Proteínas Associadas à Resistência a Múltiplos Medicamentos/fisiologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Clin Case Rep ; 5(5): 559-566, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28469849

RESUMO

Alveolar capillary dysplasia (ACD) is a rare condition with variable presentation and clinical course. Clinicians should consider this diagnosis in neonates presenting with nonlethal congenital gastrointestinal malformation, a period of well-being after birth then unremitting hypoxemia and refractory pulmonary hypertension. Lung biopsy and FOXF1 gene testing may help in diagnosis.

10.
PLoS One ; 12(1): e0169485, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28052119

RESUMO

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. METHODS: A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. RESULTS: In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. CONCLUSION: Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.


Assuntos
Neoplasias do Tronco Encefálico/tratamento farmacológico , Engenharia Genética , Glioma/tratamento farmacológico , Ácidos Hidroxâmicos/uso terapêutico , Indóis/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Acetilação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Células Clonais , Glioma/patologia , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Concentração Inibidora 50 , Camundongos Endogâmicos C57BL , Panobinostat , Resultado do Tratamento
12.
Sci Transl Med ; 7(312): 312ra176, 2015 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-26537256

RESUMO

Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT (facilitates chromatin transcription) as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small-molecule curaxin compound CBL0137 markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma.


Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Grupo de Alta Mobilidade/antagonistas & inibidores , Neoplasias do Sistema Nervoso/tratamento farmacológico , Neoplasias do Sistema Nervoso/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Elongação da Transcrição/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Carbazóis/uso terapêutico , Reparo do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Fatores de Elongação da Transcrição/metabolismo
13.
ANZ J Surg ; 82(11): 803-8, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22924988

RESUMO

BACKGROUND: Intraoperative sentinel lymph node (SLN) examination during breast cancer surgery guides the need for immediate axillary clearance. This may be difficult to implement when surgery is performed distant to the centres where pathological examination is undertaken. We aimed to implement and validate a telepathology service for the remote examination of breast SLN by frozen section (FS). METHODS: We tested an Internet-based remote microscopy system to report intraoperative FS in real time from two district hospitals without on-site anatomical pathology services. RESULTS: FS was performed remotely on 52 patients. Seventeen out of 52 patients had metastases, of which there were six false-negative diagnoses comprising four of micrometastatic disease and two of isolated tumour cells (ITCs). There were no false-negative diagnoses for macrometastatic disease and no false-positive diagnoses. As a control, we audited our experience with 239 consecutive SLN FS examined by on-site pathologists. Sixty out of 239 patients had metastases, of which there were 24 false-negative diagnoses comprising 12 cases of ITC, 5 of micrometastases and 7 of macrometastases. The accuracy of remote FS was equivalent to that of in-house FS (88.2% versus 89.9%). CONCLUSION: Remote FS for breast SLN is an accurate procedure ,which is not inferior to FS performed on site.


Assuntos
Neoplasias da Mama/patologia , Secções Congeladas , Cuidados Intraoperatórios , Biópsia de Linfonodo Sentinela , Telepatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
14.
Am J Surg ; 197(6): e61-3, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19497405

RESUMO

A patient with a pancreatic mass noted on a computed tomography scan was suspected of having a nonfunctioning pancreatic neuroendocrine neoplasm. The eventual diagnosis of intrapancreatic accessory spleen was made by noninvasive means, thus avoiding unnecessary surgery.


Assuntos
Neoplasias Pancreáticas/diagnóstico , Baço/anormalidades , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade
15.
Am J Surg ; 194(1): 75-6, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17560913

RESUMO

Intrapancreatic accessory spleens are uncommon, however, the recognition and appropriate confirmatory diagnostic imaging of an intrapancreatic splenunculus is important to avoid an unnecessary surgery for a suspected pancreatic tumor. We present a patient who underwent a distal pancreatectomy for a suspected pancreatic neuroendocrine tumor based on clinical history, radiologic imaging, and a positive labeled octreotide scan. A brief review of intrapancreatic splenunculi and confirmatory diagnostic imaging is discussed.


Assuntos
Coristoma/cirurgia , Pancreatopatias/cirurgia , Baço , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatectomia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA