RESUMO
Niraparib (NIRA) is a highly selective inhibitor of poly (adenosine diphosphate-ribose) polymerase, PARP1 and PARP2, which play a role in DNA repair. The phase II QUEST study evaluated NIRA combinations in patients with metastatic castration-resistant prostate cancer who were positive for homologous recombination repair gene alterations and had progressed on 1 prior line of novel androgen receptor-targeted therapy. Results from the combination of NIRA with abiraterone acetate plus prednisone, which disrupts androgen axis signaling through inhibition of CYP17, showed promising efficacy and a manageable safety profile in this patient population.
Assuntos
Acetato de Abiraterona , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Acetato de Abiraterona/efeitos adversos , Prednisona/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
We recently discovered a novel gene and named it endothelial-derived gene 1 (EG-1). Previously, we have shown that the expression of EG-1 is significantly elevated in the epithelial cells of breast cancer, colorectal cancer, and prostate cancer. Here, we report that EG-1 can stimulate cellular proliferation. Transfection experiments which overexpressed the full-length EG-1 gene in human embryonic kidney HEK-293 cells or human breast cancer cell lines resulted in significantly increased in vitro proliferation, in comparison with transfection with empty vectors. On the other hand, small interfering RNA cotransfection resulted in inhibition of proliferation. S.c. xenograft assays were carried out in a severe combined immunodeficient mouse model. We found that injection of high EG-1 expressing HEK-293 clones resulted in significantly larger tumors, in comparison with clones carrying the empty vectors. To further clarify the function of this gene, we investigated its interaction with Src and members of the mitogen-activated protein kinase (MAPK) family. Immunoprecipitation with anti-Src antibody, followed by immunoblotting with anti-EG-1 antibody, showed an association between these two molecules. Overexpression of EG-1 was correlated with activation of the following kinases: extracellular signal-regulated kinases 1 and 2, c-jun-NH2-kinase, and p38. These observations collectively support the hypothesis that the novel gene EG-1 is a positive stimulator of cellular proliferation, and may possibly be involved in signaling pathways involving Src and MAPK activation.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas/fisiologia , Sequência de Aminoácidos , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Proteína Tirosina Quinase CSK , Processos de Crescimento Celular/genética , Linhagem Celular Tumoral , Ativação Enzimática , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Complexo Mediador , Camundongos , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Dados de Sequência Molecular , Transplante de Neoplasias , Fragmentos de Peptídeos/genética , Fosfotransferases/metabolismo , Proteínas Tirosina Quinases , Proteínas/antagonistas & inibidores , Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transplante Heterólogo , Quinases da Família srcRESUMO
PURPOSE: We recently discovered a novel gene responsive to tumor-conditioned media: endothelial-derived gene 1 (EG-1). Its transcript has been shown to be present in epithelial cells, as well as in endothelial cells. In this study, we examined the levels of EG-1 protein expression in breast, colon, prostate, and lung cancers, which constitute the four most common solid malignancies in the United States. EXPERIMENTAL DESIGN: Polyclonal antibodies were generated that recognize the EG-1 peptide. These antibodies were used in immunoblot analysis, as well as immunohistochemistry of multiple human clinical specimens of cancer. RESULTS: In immunoblots of whole cell lysates, EG-1 antibodies revealed the presence of a 22-kDa peptide. Immunohistochemistry of breast, colon, and prostate specimens showed higher levels of EG-1 peptides in cancer tissues, in comparison with their benign counterparts. However, EG-1 expression was minimal in both benign and malignant lung tissues. CONCLUSIONS: Here, we demonstrated that the expression of EG-1 is elevated in cancerous in comparison to benign epithelial cells, as seen in immunohistochemistry of human pathological specimens. These observations collectively support the hypothesis that the novel gene EG-1 is associated with the malignant phenotype of the common epithelial-derived cancers of the breast, colon, and prostate.