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1.
Cancer Cell ; 41(6): 1073-1090.e12, 2023 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-37236195

RESUMO

Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.


Assuntos
Antígeno CD11b , Neoplasias , Humanos , Antígeno CD11b/agonistas , Imunoterapia , Interferons , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/imunologia , NF-kappa B/metabolismo , Transdução de Sinais , Macrófagos Associados a Tumor/imunologia
2.
PLoS One ; 6(10): e25807, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22016777

RESUMO

We analyzed the gene expression patterns of 138 Non-Small Cell Lung Cancer (NSCLC) samples and developed a new algorithm called Coverage Analysis with Fisher's Exact Test (CAFET) to identify molecular pathways that are differentially activated in squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes. Analysis of the lung cancer samples demonstrated hierarchical clustering according to the histological subtype and revealed a strong enrichment for the Wnt signaling pathway components in the cluster consisting predominantly of SCC samples. The specific gene expression pattern observed correlated with enhanced activation of the Wnt Planar Cell Polarity (PCP) pathway and inhibition of the canonical Wnt signaling branch. Further real time RT-PCR follow-up with additional primary tumor samples and lung cancer cell lines confirmed enrichment of Wnt/PCP pathway associated genes in the SCC subtype. Dysregulation of the canonical Wnt pathway, characterized by increased levels of ß-catenin and epigenetic silencing of negative regulators, has been reported in adenocarcinoma of the lung. Our results suggest that SCC and AC utilize different branches of the Wnt pathway during oncogenesis.


Assuntos
Algoritmos , Carcinoma de Células Escamosas/patologia , Polaridade Celular/genética , Biologia Computacional/métodos , Neoplasias Pulmonares/patologia , Transcriptoma , Proteínas Wnt/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Sobrevivência Celular/genética , Análise por Conglomerados , Humanos , Neoplasias Pulmonares/genética , Transdução de Sinais/genética , Proteínas Wnt/metabolismo
3.
Proc Natl Acad Sci U S A ; 104(1): 270-5, 2007 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-17185414

RESUMO

Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC(50) values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.


Assuntos
Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Antígeno Ki-1/análise , Camundongos , Camundongos SCID , Fosforilação , Pirimidinas/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
BJU Int ; 97(4): 691-7, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16536755

RESUMO

OBJECTIVES: To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER-beta and induces apoptosis in vitro in androgen-independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene. PATIENTS, MATERIALS AND METHODS: Tumour proliferation rate in response to raloxifene treatment, and molecular markers of cell cycle and apoptosis, were evaluated in established ER-beta-positive androgen-dependent (AD) CWR22 and AI CWRSA9 human xenograft prostate cancer models. Twenty-one patients with AIPC and evidence of disease progression were enrolled into the clinical trial and given daily oral raloxifene. RESULTS: There was significant growth inhibition by raloxifene in the ADPC and AIPC xenograft models (CWR22 68%, P < 0.010; CWRSA9 64%, P < 0.001), with no tumour regression. There was evidence of G1 arrest by increased p27kip1 expression in the raloxifene-treated group. Eighteen patients comprised the efficacy analysis, as three withdrew before the first evaluation. At the first evaluation, five men had stable disease and continued on the study for a median of five cycles. The longest response was 17 cycles. Drug related toxicity was minimal. CONCLUSION: Raloxifene has activity in xenograft models, slowing disease progression. This translated to possible disease stabilization in patients with AIPC. Further studies are warranted.


Assuntos
Neoplasias da Próstata/tratamento farmacológico , Cloridrato de Raloxifeno/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Animais , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Projetos Piloto , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Resultado do Tratamento
5.
Prostate ; 61(3): 228-35, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15368474

RESUMO

BACKGROUND: Matriptase, a type-II transmembrane serine protease, is expressed by cancers of epithelial origin including breast, colon, and prostate carcinomas and has been implicated in tumor growth and progression. We studied the effects of CVS-3983, a selective small molecule matriptase inhibitor, on the growth of the androgen independent (AI) CWR22R and CWRSA6 human prostate cancer xenograft models. METHODS: CVS-3983 was administered i.p. twice-daily 7-days per week for 2-3 weeks to mice with established tumors. Measurements of tumor volume were made twice weekly. The effect of CVS-3983 on CWR22RV1 cell invasion through a reconstituted basement membrane matrix of proteins was also evaluated. Matriptase expression across the tumor lines was assessed by RT-PCR and Western blotting. RESULTS: CVS-3983 inhibited final mean tumor volume by 65.5% (n = 10, P = 0.0002) in the CWR22R model and by 56.2% (n = 8, P = 0.0017) in the CWRSA6 tumor model compared with vehicle-treated tumors. CVS-3983 did not inhibit the proliferation of CWR22RV1 cells in vitro; however, the small molecule did significantly reduce by 30.2% the invasion of these cells in vitro through a reconstituted basement membrane matrix. Molecular analysis of the xenograft tumors demonstrated high expression levels of matriptase at the RNA and protein levels, which were not affected by CVS-3983 treatment. CONCLUSIONS: These results identify CVS-3983 as a potent inhibitor of AI prostate cancer cell invasion in vitro and established xenograft tumor growth in vivo.


Assuntos
Oligopeptídeos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/farmacologia , Androgênios/metabolismo , Animais , Matriz Extracelular/enzimologia , Feminino , Masculino , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oligopeptídeos/química , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Inibidores de Serina Proteinase/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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