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1.
Invest New Drugs ; 38(6): 1677-1686, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32436058

RESUMO

Children with aggressive pediatric solid tumors have poor outcomes and novel treatments are needed. Pediatric solid tumors demonstrate aberrant expression and activity of the fibroblast growth factor receptor (FGFR) family, suggesting FGFR inhibitors may be effective therapeutic agents. AZD4547 is a multikinase inhibitor of the FGFR1-3 kinases, and we hypothesized that AZD4547 would be effective in pediatric solid tumor preclinical models. We evaluated the effects of AZD4547 on neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma cells alone and in combination with STAT3 inhibition. Continuous live cell imaging was used to measure induction of apoptosis and effects on migration. Receptor inhibition and intracellular signaling were examined by western blotting. AZD4547 treatment resulted in decreased cell confluence, increased apoptosis and reduced cell migration in all tested cell lines. AZD4547 treatment led to decreased phosphorylation of signaling proteins involved in cell survival and apoptotic pathways and increased phosphorylation of STAT3, and treatment of cell lines with AZD4547 combined with STAT3 inhibition demonstrated increased efficacy. Sensitivity to AZD4547 appears to be mediated by effects on the Ras/MAPK and JAK/STAT pathways, and AZD4547 represents a potential novel therapeutic agent for children with solid tumors.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Neoplasias/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Criança , Óxidos S-Cíclicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
2.
Br J Cancer ; 123(4): 568-579, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32457362

RESUMO

BACKGROUND: Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis. METHODS: We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13-cis-retinoic acid on intracellular signalling. RESULTS: Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRß and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13-cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone. CONCLUSIONS: The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13-cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.


Assuntos
Isotretinoína/administração & dosagem , Neuroblastoma/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isotretinoína/farmacologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Compostos de Fenilureia/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Piridinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismo
3.
Oncotarget ; 10(59): 6323-6333, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31695841

RESUMO

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 15% of all pediatric cancer-related deaths. New therapies are needed to improve outcomes for children with high-risk and relapsed tumors. Inhibitors of the RET kinase and the RAS-MAPK pathway have previously been shown to be effective against neuroblastoma, suggesting that combined inhibition may have increased efficacy. RXDX-105 is a small molecule inhibitor of multiple kinases, including the RET and BRAF kinases. We found that treatment of neuroblastoma cells with RXDX-105 resulted in a significant decrease in cell viability and proliferation in vitro and in tumor growth and tumor vascularity in vivo. Treatment with RXDX-105 inhibited RET phosphorylation and phosphorylation of the MEK and ERK kinases in neuroblastoma cells and xenograft tumors, and RXDX-105 treatment induced both apoptosis and cell cycle arrest. RXDX-105 also showed enhanced efficacy in combination with 13-cis-retinoic acid, which is currently a component of maintenance therapy for children with high-risk neuroblastoma. Our results demonstrate that RXDX-105 shows promise as a novel therapeutic agent for children with high-risk and relapsed neuroblastoma.

4.
Vaccine ; 37(7): 903-909, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30661837

RESUMO

The New Zealand White rabbit is a highly accessible animal model which is regularly employed in biomedical research. However, the paucity of rabbit-specific reagents available limits its use in certain fields. Specifically, the lack of a reliable T cell assay has limited its employment in immune prophylactic and therapeutic studies. To address this inadequacy, we have developed an ELISpot assay to detect cellular immune responses (IFN-γ production) after antigenic stimulation. We have applied this assay to model the T cell responses elicited by a DNA vaccine. Immunization with an influenza nucleoprotein (NP) DNA vaccine revealed strong antigen-specific T cell responses in the peripheral blood mononuclear cell population. We believe this is the first report of such an assay in rabbit species, and it will become a useful tool to monitor in vivo responses to vaccines and permit the wider adoption of this model to measure immunological responses.


Assuntos
Antivirais/metabolismo , ELISPOT/métodos , Vacinas contra Influenza/imunologia , Interferon gama/metabolismo , Proteínas de Ligação a RNA/imunologia , Linfócitos T/imunologia , Vacinas de DNA/imunologia , Proteínas do Core Viral/imunologia , Animais , Feminino , Vacinas contra Influenza/administração & dosagem , Leucócitos Mononucleares/imunologia , Proteínas do Nucleocapsídeo , Coelhos , Vacinas de DNA/administração & dosagem
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