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1.
Am J Pathol ; 181(1): 303-12, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22658485

RESUMO

New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)-II acts as an autocrine factor in several tumor types by binding to IGF receptor type 1 (IGF-1R) and/or the insulin receptor (IR) isoform A. The aim of the present study was to investigate the putative role of unprocessed pro-IGF-II, called 'big'-IGF-II, in GISTs. The imatinib-sensitive GIST882 and imatinib-resistant GIST48 cell lines secrete high levels of big-IGF-II as demonstrated by ELISA and Western blotting analyses. IR isoform A mRNA and protein expression, but not that of IGF-1R, was found in these KIT mutant cell lines and in KIT and platelet-derived growth factor receptor α-mutant GIST specimens. Down-regulation of either big-IGF-II or IR affected AKT and MAPK signaling and reduced survival in both cell lines. Disruption of big-IGF-II signaling in combination with imatinib had additive cytotoxic effects on GIST882 cells. IGF-II mRNA as determined by in situ hybridization was present in 91% of 60 primary GISTs. Immunohistochemical analysis of big-IGF-II protein expression was associated with moderate- to high-risk tumors compared with tumors with a lower risk classification (P < 0.028). Our data put forth the big-IGF-II/IR isoform A axis as an autocrine survival pathway and potential therapeutic target in GISTs.


Assuntos
Tumores do Estroma Gastrointestinal/fisiopatologia , Fator de Crescimento Insulin-Like II/fisiologia , Precursores de Proteínas/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/fisiologia , Benzamidas , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Sobrevivência Celular/fisiologia , Regulação para Baixo/fisiologia , Feminino , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Piperazinas/farmacologia , Precursores de Proteínas/metabolismo , Pirimidinas/farmacologia , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Células Tumorais Cultivadas , Adulto Jovem
2.
Eur J Cancer ; 144: 151-161, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33341447

RESUMO

BACKGROUND: The androgen receptor (AR) is a potential target in metastatic breast cancer (MBC), and 16ß-[18F]-fluoro-5α-dihydrotestosterone positron emission tomography ([18F]-FDHT-PET) can be used for noninvasive visualisation of AR. [18F]-FDHT uptake reduction during AR-targeting therapy reflects AR occupancy and might be predictive for treatment response. We assessed the feasibility of [18F]-FDHT-PET to detect changes in AR availability during bicalutamide treatment and correlated these changes with treatment response. PATIENTS AND METHODS: Patients with AR + MBC, regardless of oestrogen receptor status, received an [18F]-FDHT-PET at baseline and after 4-6 weeks bicalutamide treatment. Baseline [18F]-FDHT uptake was expressed as maximum standardised uptake value. Percentage change in tracer uptake, corrected for background activity (SUVcor), between baseline and follow-up PET scan (% reduction), was assessed per-patient and lesion. Clinical benefit was determined in accordance with Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 or clinical evaluation (absence of disease progression for ≥24 weeks). RESULTS: Baseline [18F]-FDHT-PET in 21 patients detected 341 of 515 lesions found with standard imaging and 21 new lesions. Follow-up [18F]-FDHT-PET was evaluable in 17 patients with 349 lesions, showing a decrease in median SUVcor from 1.3 to 0.7 per-patient and lesion (P < 0.001). Median % reduction per-patient was -45% and per-lesion -39%. In patients with progressive disease (n = 11), median % reduction was -30% versus -53% for patients who showed clinical benefit (in accordance with RECIST (n = 3) or clinical evaluation (n = 3); P = 0.338). CONCLUSION: In this feasibility study, a bicalutamide-induced reduction in [18F]-FDHT uptake could be detected by follow-up [18F]-FDHT-PET in patients with AR + MBC. However, this change could not predict bicalutamide response. CLINICAL TRIAL INFORMATION: NCT02697032.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Neoplasias da Mama/patologia , Di-Hidrotestosterona/metabolismo , Radioisótopos de Flúor/metabolismo , Nitrilas/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Receptores Androgênicos/química , Compostos de Tosil/uso terapêutico , Idoso , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Seguimentos , Humanos , Metástase Neoplásica , Prognóstico , Estudos Prospectivos , Compostos Radiofarmacêuticos/metabolismo
3.
J Pathol ; 217(4): 469-82, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19148905

RESUMO

Sarcomas are a diverse group of malignant mesenchymal tumours arising from bone and soft tissues. The identification of critical cellular signalling pathways in sarcomas is an important issue for the development of new targeted therapies. This review highlights the experimental and clinical evidence supporting the role of the insulin-like growth factor (IGF) signalling system in the cellular transformation and progression of several types of sarcoma, including rhabdomyosarcoma, synovial sarcoma, leiomyosarcoma, Ewing's sarcoma and osteosarcoma. Preclinical data suggest that the IGF system could be a promising target for therapy in these sarcomas. Currently, therapies interrupting IGF signalling have been or are being developed. In recent phase 1 clinical studies with humanized monoclonal antibodies directed against IGF receptor type 1 (IGF-1R), objective tumour responses were observed in several patients with Ewing's sarcoma, encouraging further clinical testing in Ewing's sarcoma and other sarcoma (sub)types. Moreover, the occasional occurrence of paraneoplastic hypoglycaemia as a result of the secretion of incompletely processed forms of pro-IGF-II by sarcomas is discussed.


Assuntos
Insulina/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Somatomedina/metabolismo , Sarcoma/metabolismo , Transdução de Sinais/fisiologia , Somatomedinas/metabolismo , Anticorpos Monoclonais/uso terapêutico , Humanos , Hipoglicemia/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Somatomedina/imunologia
4.
Endocr Relat Cancer ; 14(4): 979-93, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18045950

RESUMO

This review focuses on the tumour types and symptoms associated with non-islet cell tumour-induced hypoglycaemia (NICTH) as well as the pathogenesis, diagnosis and treatment of this rare paraneoplastic phenomenon. In addition, we report two illustrative cases of patients suffering from NICTH caused by a solid fibrous tumour and a haemangiopericytoma respectively. In the first case, NICTH resolved following complete resection of the tumour, but in the second case the patient needed long-term treatment aimed at controlling hypoglycaemia because of non-resectable metastases. Many tumour types have been associated with NICTH. The crucial event in the development of NICTH seems to be overexpression of the IGF-II gene by the tumour. NICTH is characterised by recurrent fasting hypoglycaemia and is associated with the secretion of incompletely processed precursors of IGF-II ('big'-IGF-II) by the tumour. This induces dramatic secondary changes in the circulating levels of insulin, GH, IGF-I and IGF-binding proteins, resulting in an insulin-like hypoglycaemic activity of 'big'-IGF-II.


Assuntos
Hipoglicemia/etiologia , Neoplasias Pancreáticas/complicações , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Feminino , Humanos , Fator de Crescimento Insulin-Like II/genética , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , RNA Mensageiro/genética
5.
Cancer Biol Ther ; 2(6): 707-12, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14688482

RESUMO

p53 plays a central role in the cellular response to stressful stimuli, including DNA damage, aberrant growth signals, and hypoxia. Upon activation, it binds to a specific DNA binding motif and functions to transcriptionally activate or repress different groups of genes. The biologic outcome of these events can lead to cell-cycle arrest, DNA repair, or apoptosis. While many downstream targets of p53 have been identified, the factors that determine which of these outcomes will occur in an individual cell are less clear. In this study, we show that caspase 10, an initiator caspase, is induced in response to DNA damaging chemotherapeutic agents in a p53-dependent manner. Following treatment with etoposide or adriamycin, induction of caspase 10 occurred at both the mRNA and protein levels. In contrast, DNA damage did not affect levels of caspase 8, another initiator caspase with significant structural and functional homology to caspase 10. By chromatin immunoprecipitation assay, p53 bound in vivo to multiple p53-specific binding sites located within the caspase 10 gene locus, suggesting that caspase 10 is a direct transcriptional target of p53. Upregulation of caspase 10 may represent one factor that determines how p53 activation leads to cellular apoptosis following DNA damage.


Assuntos
Caspases/biossíntese , Dano ao DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Proteína Supressora de Tumor p53/metabolismo , Adenoviridae/genética , Western Blotting , Caspase 10 , Caspases/genética , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Etoposídeo/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Osteossarcoma/patologia , Neoplasias Ovarianas/patologia , Testes de Precipitina , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , Regulação para Cima
6.
Anticancer Res ; 32(10): 4485-97, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23060577

RESUMO

BACKGROUND: The prognosis of rhabdomyosarcoma (RMS) in children and adolescents has improved since the introduction of multi-agent chemotherapy. However, outcome data of adults with RMS are scarce. This multicenter retrospective study investigated the effect of age on outcome of RMS. PATIENTS AND METHODS: Data were collected from three Dutch University Medical Centers between 1977-2009. The effect of age and clinical prognostic factors on relapse-free and disease-specific survival (DSS) were analyzed. RESULTS: Age as a continuous variable predicted poor survival in multivariate analysis. Five-year DSS was highest for non-metastatic embryonal RMS, followed by non-metastatic alveolar RMS and was poor in metastatic disease. Higher age correlated with unfavorable histological subtype (alveolar RMS) and with metastatic disease at presentation in embryonal RMS. In non-metastatic embryonal RMS and in all alveolar RMS, higher age was an adverse prognostic factor of outcome. CONCLUSION: This study indicates that age is a negative predictor of survival in patients with embryonal and alveolar RMS.


Assuntos
Rabdomiossarcoma Alveolar/mortalidade , Rabdomiossarcoma Embrionário/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma Alveolar/secundário , Rabdomiossarcoma Embrionário/secundário , Resultado do Tratamento , Adulto Jovem
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