Assuntos
Aprovação de Drogas/legislação & jurisprudência , Indústria Farmacêutica/legislação & jurisprudência , Órgãos Governamentais/legislação & jurisprudência , Encaminhamento e Consulta/legislação & jurisprudência , Avaliação da Tecnologia Biomédica/legislação & jurisprudência , Desenvolvimento de Medicamentos/legislação & jurisprudência , Europa (Continente) , HumanosRESUMO
PURPOSE: Inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer due to its rapid onset and highly invasive nature. IBC carries 5- and 10-year disease-free survival rates of ~45% and <20%, respectively. Multiple studies demonstrate that in comparison with conventional breast cancer, IBC has a unique molecular identity. Here, we have identified platelet-derived growth factor receptor alpha (PDGFRA) as being uniquely expressed and active in IBC patient tumor cells. EXPERIMENTAL DESIGN: Here we focus on characterizing and targeting PDGFRA in IBC. Using gene expression, we analyzed IBC patient samples and compared them with non-IBC patient samples. Further, using IBC cells in culture, we determined the effect of small molecules inhibitors in both in vitro and in vivo assays. RESULTS: In IBC patients, we show more frequent PDGFRA activation signature than non-IBC samples. In addition, the PDGFRA activation signature is associated with shorter metastasis-free survival in both uni- and multivariate analyses. We also demonstrate that IBC cells express active PDGFRA. Finally, we show that PDGFRA targeting by crenolanib (CP-868-596), but not imatinib (STI571), two small molecule inhibitors, interferes with IBC cell growth and emboli formation in vitro and tumor growth in vivo. CONCLUSIONS: Our data suggest that PDGFRA may be a promising target for therapy in IBC.
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Neoplasias Inflamatórias Mamárias/metabolismo , Piperidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Adulto , Idoso , Animais , Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Modelos Animais de Doenças , Feminino , Seguimentos , Expressão Gênica , Humanos , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/patologia , Camundongos , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Piperidinas/uso terapêutico , Fator de Crescimento Derivado de Plaquetas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The development of an organism depends on individual cells receiving and executing their specific fates, although how this process is regulated remains largely unknown. Here, we identify a mechanism by which a specific cell fate, apoptosis, is determined through the cooperative efforts of Hox and E2F proteins. E2F transcription factors are critical, conserved regulators of the cell cycle and apoptosis. However, little is known about the two most recently discovered mammalian E2Fs-E2F7 and E2F8. In the nematode Caenorhabditis elegans, we identify a novel E2F7/8 homolog, EFL-3, and show that EFL-3 functions cooperatively with LIN-39, providing the first example in which these two major developmental pathways-E2F and Hox-are able to directly regulate the same target gene. Our studies demonstrate that LIN-39 and EFL-3 function in a cell type-specific context to regulate transcription of the egl-1 BH3-only cell death gene and to determine cell fate during development.