Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
Oncologist ; 20(10): 1140-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26306901

RESUMO

BACKGROUND: We evaluated the significance of hypertension developing during vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR-TKI) treatment and a group of cytokines and angiogenic factors (CAFs) in advanced non-clear cell renal cell carcinoma (nccRCC) patients treated with sunitinib in a phase II study. MATERIALS AND METHODS: Using multiplex assays, we analyzed the levels of 38 CAFs in plasma at baseline and after 4 weeks of sunitinib therapy. Sunitinib benefit was defined as a partial response or stable disease using the Response Evaluation Criteria in Solid Tumors lasting ≥4 months. Cox proportional hazards regression models were used to assess the associations among hypertension, CAFs, and progression-free (PFS) and overall survival (OS). RESULTS: Fifty-seven patients were evaluable; 53 had baseline CAF levels available. The median PFS and OS were 2.9 months (95% confidence interval [CI], 1.4-5.5) and 16.8 months (95% CI, 10.7-27.4), respectively. Sunitinib benefit was observed in 21 patients (37%). However, 33 patients (60%) developed hypertension during treatment, although no association was found with survival or response. Elevated baseline soluble tumor necrosis factor (TNF) receptor I, interleukin-8, growth-regulated oncogene, transforming growth factor-α, and VEGFR-2 levels were associated with an increased risk of death on multivariate analysis. CONCLUSION: We found no association between the development of hypertension and survival or sunitinib benefit in advanced nccRCC. TNF and angiogenic/immunomodulatory mediators were identified for evaluation as markers of prognosis and VEGFR-TKI benefit in future studies.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Citocinas/sangue , Hipertensão/induzido quimicamente , Indóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Pirróis/efeitos adversos , Adulto , Carcinoma de Células Renais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Sunitinibe , Resultado do Tratamento , Disfunção Ventricular Esquerda/induzido quimicamente
2.
Cancer Immunol Res ; 7(10): 1633-1646, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31431433

RESUMO

Elotuzumab (Elo) is an IgG1 monoclonal antibody targeting SLAMF7 (CS1, CRACC, and CD319), which is highly expressed on multiple myeloma (MM) cells, natural killer (NK) cells, and subsets of other leukocytes. By engaging with FcγRIIIA (CD16), Elo promotes potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) toward SLAMF7+ MM tumor cells. Relapsed/refractory MM patients treated with the combination of Elo, lenalidomide, and dexamethasone have improved progression-free survival. We previously showed that Elo enhances NK cell activity via a costimulation mechanism, independent of CD16 binding. Here, we further studied the effect of Elo on cytotoxicity of CD16-negative NK-92 cells. Elo, but not other SLAMF7 antibodies, uniquely enhanced cytotoxicity mediated by CD16-negative NK-92 cells toward SLAMF7+ target cells. Furthermore, this CD16-independent enhancement of cytotoxicity required expression of SLAMF7 containing the full cytoplasmic domain in the NK cells, implicating costimulatory signaling. The CD16-independent costimulation by Elo was associated with increased expression of NKG2D, ICAM-1, and activated LFA-1 on NK cells, and enhanced cytotoxicity was partially reduced by NKG2D blocking antibodies. In addition, an Fc mutant form of Elo that cannot bind CD16 promoted cytotoxicity of SLAMF7+ target cells by NK cells from most healthy donors, especially if previously cultured in IL2. We conclude that in addition to promoting NK cell-mediated ADCC (CD16-dependent) responses, Elo promoted SLAMF7-SLAMF7 interactions in a CD16-independent manner to enhance NK cytotoxicity toward MM cells.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Mieloma Múltiplo/tratamento farmacológico , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia
3.
Blood Adv ; 1(12): 753-765, 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29296719

RESUMO

Elotuzumab, a humanized monoclonal antibody that binds human signaling lymphocytic activation molecule F7 (hSLAMF7) on myeloma cells, was developed to treat patients with multiple myeloma (MM). Elotuzumab has a dual mechanism of action that includes the direct activation of natural killer (NK) cells and the induction of NK cell-mediated antibody-dependent cellular cytotoxicity. This study aimed to characterize the effects of elotuzumab on NK cells in vitro and in patients with MM and to determine whether elotuzumab antitumor activity was improved by programmed death receptor-1 (PD-1) blockade. Elotuzumab promoted NK cell activation when added to a coculture of human NK cells and SLAMF7-expressing myeloma cells. An increased frequency of activated NK cells was observed in bone marrow aspirates from elotuzumab-treated patients. In mouse tumor models expressing hSLAMF7, maximal antitumor efficacy of a murine immunoglobulin G2a version of elotuzumab (elotuzumab-g2a) required both Fcγ receptor-expressing NK cells and CD8+ T cells and was significantly enhanced by coadministration of anti-PD-1 antibody. In these mouse models, elotuzumab-g2a and anti-PD-1 combination treatment promoted tumor-infiltrating NK and CD8+ T-cell activation, as well as increased intratumoral cytokine and chemokine release. These observations support the rationale for clinical investigation of elotuzumab/anti-PD-1 combination therapy in patients with MM.

4.
Aging (Albany NY) ; 7(9): 613-5, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26412380

RESUMO

We have found evidence suggesting that ARF and p53 are essential for tumor regression upon MYC inactivation through distinct mechanisms ARF through p53-independent affect, is required to for MYC to regulate the expression of genes that are required for both the induction of cellular senescence as well as recruitment of innate immune activation. Our observations have possible implications for mechanisms of therapeutic resistance to targeted oncogene inactivation.


Assuntos
Fator 1 de Ribosilação do ADP/genética , Envelhecimento/genética , Imunidade Inata/genética , Animais , Genes p53 , Humanos , Oncogenes/genética
5.
PLoS One ; 10(8): e0135962, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26313261

RESUMO

The adenosine analog 8-chloroadenosine has been shown to deplete ATP and inhibit tumor growth in hematological malignancies as well as in lung and breast cancer cell lines. We investigated effects of 8-chloroadenosine on clear cell (cc) renal cell carcinoma (RCC) cell lines. 8-chloroadenosine was effective against ccRCC cell viability in vitro, with IC50 ranging from 2 µM in the most sensitive CAKI-1 to 36 µM in the most resistant RXF-393. Proteomic analysis by reverse-phase protein array revealed that 8-chloroadenosine treatment leads to inhibition of the mTOR pathway. In time-course experiments, 8-chloroadenosine treatment rapidly activated AMPK, measured by AMPK and ACC phosphorylation, and subsequently caused dephosphorylation of p70S6K and ribosomal protein RPS6 in the sensitive cell lines. However, in the resistant cell lines, AMPK activity and the mTOR pathway were unaffected by the treatment. We also noted that the resistant cell lines had elevated basal levels of phospho RPS6 and AKT. Inhibition of PI3K pathway enhanced the efficacy of 8-chloroadenosine across all cell lines. Our observations indicate that 8-chloroadenosine activity is associated with inhibition of the mTOR pathway, and that phospho RPS6 and PI3K pathway activation status may determine resistance. Among solid tumors, RCC is one of the few susceptible to mTOR inhibition. We thus infer that 8-chloroadenosine may be effective in RCC by activating AMPK and inhibiting the mTOR pathway.


Assuntos
2-Cloroadenosina/análogos & derivados , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma de Células Renais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Renais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , 2-Cloroadenosina/farmacologia , Western Blotting , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação/efeitos dos fármacos , Análise Serial de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Proteômica/métodos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA