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1.
Invest New Drugs ; 36(4): 629-637, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29196957

RESUMO

Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalation), LY3007113 was administered orally every 12 h (Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-day cycle until the maximum tolerated dose (MTD) was reached. In part B (dose confirmation), patients received MTD. Safety, pharmacokinetics, pharmacodynamics, and tumor response data were evaluated. Results MTD was 30 mg Q12H. The most frequent treatment-related adverse events (>10%) were tremor, rash, stomatitis, increased blood creatine phosphokinase, and fatigue. Grade ≥ 3 treatment-related adverse events included upper gastrointestinal haemorrhage and increased hepatic enzyme, both occurring at 40 mg Q12H and considered dose-limiting toxicities. LY3007113 exhibited an approximately dose-proportional increase in exposure and time-independent pharmacokinetics after repeated dosing. Maximal inhibition (80%) of primary biomarker MAPK-activated protein kinase 2 in peripheral blood mononuclear cells was not reached, and sustained minimal inhibition (60%) was not maintained for 6 h after dosing to achieve a biologically effective dose (BED). The best overall response in part B was stable disease in 3 of 27 patients. Conclusions The recommended phase 2 dosage of LY3007113 was 30 mg Q12H. Three patients continued treatment after the first radiographic assessment, and the BED was not achieved. Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Resultado do Tratamento
2.
Invest New Drugs ; 32(5): 825-37, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24919854

RESUMO

The G1 restriction point is critical for regulating the cell cycle and is controlled by the Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This pathway is important because of its inactivation in a majority of human tumors. Transition through the restriction point requires phosphorylation of retinoblastoma protein (Rb) by CDK4/6, which are highly validated cancer drug targets. We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different histologies in tumor-bearing mice. LY2835219 is effective and well tolerated when administered up to 56 days in immunodeficient mice without significant loss of body weight or tumor outgrowth. In calu-6 xenografts, LY2835219 in combination with gemcitabine enhanced in vivo antitumor activity without a G1 cell cycle arrest, but was associated with a reduction of ribonucleotide reductase expression. These results suggest LY2835219 may be used alone or in combination with standard-of-care cytotoxic therapy. In summary, we have identified a potent, orally active small-molecule inhibitor of CDK4/6 that is active in xenograft tumors. LY2835219 is currently in clinical development.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Aminopiridinas/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Quimioterapia Combinada , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteína do Retinoblastoma/antagonistas & inibidores , Proteína do Retinoblastoma/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
3.
Nat Med ; 29(10): 2570-2576, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37783970

RESUMO

Multiple myeloma (MM) is a plasma cell malignancy expressing B cell maturation antigen (BCMA). Elranatamab, a bispecific antibody, engages BCMA on MM and CD3 on T cells. The MagnetisMM-1 trial evaluated its safety, pharmacokinetics and efficacy. Primary endpoints, including the incidence of dose-limiting toxicities as well as objective response rate (ORR) and duration of response (DOR), were met. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Eighty-eight patients with relapsed or refractory MM received elranatamab monotherapy, and 55 patients received elranatamab at efficacious doses. Patients had received a median of five prior regimens; 90.9% were triple-class refractory, 29.1% had high cytogenetic risk and 23.6% received prior BCMA-directed therapy. No dose-limiting toxicities were observed during dose escalation. Adverse events included cytopenias and cytokine release syndrome. Exposure was dose proportional. With a median follow-up of 12.0 months, the ORR was 63.6% and 38.2% of patients achieving complete response or better. For responders, the median DOR was 17.1 months. All 13 patients evaluable for minimal residual disease achieved negativity. Even after prior BCMA-directed therapy, 53.8% achieved response. For all 55 patients, median PFS was 11.8 months, and median OS was 21.2 months. Elranatamab achieved durable responses, manageable safety and promising survival for patients with MM. ClinicalTrials.gov Identifier: NCT03269136 .


Assuntos
Anemia , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/patologia , Antígeno de Maturação de Linfócitos B , Linfócitos T/patologia , Intervalo Livre de Progressão , Anemia/etiologia , Imunoterapia Adotiva/efeitos adversos
4.
Exp Hematol ; 35(12): 1782-92, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17920756

RESUMO

OBJECTIVE: Monocytic zinc finger (MOZ) maintains hematopoietic stem cells and, upon fusion to the coactivator CREB-binding protein (CBP), induces acute myeloid leukemia (AML). Leukemic stem cells in AML often exhibit excessive signal-dependent activity of the transcription factor nuclear factor (NF)-kappaB. Because aberrant interaction between NF-kappaB and coactivators represents an alternative mechanism for enhancing NF-kappaB activity, we evaluated whether MOZ and MOZ-CBP cooperate with NF-kappaB to activate transcription from NF-kappaB-dependent promoters. METHODS: The ability of MOZ, MOZ mutants, and MOZ-CBP to enhance expression of NF-kappaB-dependent promoters was tested in reporter studies. The interaction between MOZ and NF-kappaB was evaluated by both coimmunoprecipitation and glutathione S-transferase pulldown assays. RESULTS: MOZ activates transcription from the NF-kappaB-dependent interleukin-8 promoter; interestingly, this effect is markedly enhanced by CBP. Although MOZ has less potent transcriptional activity than MOZ-CBP, both proteins cooperate with steroid receptor coactivator-1 to activate transcription. MOZ also induces multiple NF-kappaB-dependent viral promoters. Importantly, MOZ associates in a protein complex with the p65 subunit of NF-kappaB and interacts directly with p65 in vitro. Transcriptional activity of MOZ requires its C-terminal domain, which is absent from MOZ-CBP, indicating that the transcriptional activity of MOZ-CBP derives from its CBP sequence. CONCLUSIONS: MOZ interacts with the p65 subunit of NF-kappaB and enhances expression of NF-kappaB-dependent promoters. The more potent transcriptional activity of MOZ-CBP derives from its CBP sequence. Thus, interaction between NF-kappaB and MOZ-CBP may play an important role in the pathogenesis of certain acute myeloid leukemias.


Assuntos
NF-kappa B/metabolismo , Proteínas de Fusão Oncogênica/fisiologia , Regiões Promotoras Genéticas , Transcrição Gênica , Sequência de Bases , Linhagem Celular , Primers do DNA , Humanos , Imunoprecipitação , Interleucina-8/genética
5.
Clin Pharmacokinet ; 57(3): 335-344, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28540640

RESUMO

BACKGROUND AND OBJECTIVES: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels. METHODS: A phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib. Data were analyzed by popPK modeling, and patient demographics contributing to pharmacokinetic variability were explored. Target engagement was evaluated by combining the clinical popPK model with a previously developed pre-clinical pharmacokinetic/pharmacodynamic model. RESULTS: The pharmacokinetic analysis incorporated 4012 plasma concentrations from 224 patients treated with abemaciclib at doses ranging from 50 to 225 mg every 24 h and 75 to 275 mg every 12 h. A linear one-compartment model with time- and dose-dependent relative bioavailability (F rel) adequately described the pharmacokinetics of abemaciclib. Serum albumin and alkaline phosphatase were the only significant covariates identified in the model, the inclusion of which reduced inter-individual variability in F rel by 10.3 percentage points. By combining the clinical popPK model with the previously developed pre-clinical pharmacokinetic/pharmacodynamic model, the extent of target engagement in skin in cancer patients was successfully predicted. CONCLUSION: The proportion of abemaciclib pharmacokinetic variability that can be attributed to patient demographics is negligible, and as such there are currently no dose adjustments recommended for adult patients of different sex, age, or body weight. TRIAL REGISTRATION: NCT01394016 (ClinicalTrials.gov).


Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos/administração & dosagem , Benzimidazóis/administração & dosagem , Modelos Biológicos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Peso Corporal , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Fatores Sexuais , Adulto Jovem
6.
Eur J Cancer ; 56: 1-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26798966

RESUMO

BACKGROUND: Notch signalling regulates stem cell development and survival and is deregulated in multiple malignancies. LY900009 is a small molecule inhibitor of Notch signalling via selective inhibition of the γ-secretase protein. We report the first-in-human phase I trial of LY900009. METHODS: Dose escalation (Part A) was performed in cohorts of three advanced cancer patients using a modified continual reassessment method and dose confirmation (Part B) was performed in ovarian cancer patients. LY900009 was taken orally thrice weekly (every Monday, Wednesday, and Friday) during a 28-d cycle. The primary objective determined the maximum tolerated dose (MTD); secondary end-points included toxicity, pharmacokinetics, pharmacodynamics, and antitumour activity. RESULTS: Thirty-five patients received LY900009 at dose levels ranging from 2-60 mg. Study drug-related adverse events were diarrhoea (46%), vomiting (34%), anorexia (31%), nausea (31%), and fatigue (23%). At 30 mg, a dose-limiting toxicity (grade III mucosal inflammation) was observed. LY900009 absorption was rapid, with median tmax at 1-4 h post-dose. LY900009 inhibited plasma levels of amyloid-ß peptide in a dose-dependent manner with 80-90% inhibition observed in the 30- to 60-mg cohorts. No responses were seen, but five patients had stable disease. Two patients (5.7%) with leiomyosarcoma and ovarian cancer received four cycles of therapy. One patient (15 mg) showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway. CONCLUSIONS: The recommended MTD schedule for future studies was 30 mg thrice weekly, which exceeds the target inhibition level observed in preclinical models to promote tumour regression in humans.


Assuntos
Alanina/análogos & derivados , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Dibenzazepinas/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Proteases/administração & dosagem , Receptores Notch/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/farmacocinética , Secretases da Proteína Precursora do Amiloide/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Dibenzazepinas/efeitos adversos , Dibenzazepinas/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacocinética , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Estados Unidos , Adulto Jovem
7.
Clin Cancer Res ; 22(5): 1095-102, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26581242

RESUMO

PURPOSE: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. EXPERIMENTAL DESIGN: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor-positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. RESULTS: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK-induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥ 6 cycles. CONCLUSIONS: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Humanos , Imidazóis/farmacocinética , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , Piridinas/farmacocinética , Microambiente Tumoral/efeitos dos fármacos
8.
Cancer Discov ; 6(7): 740-53, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27217383

RESUMO

UNLABELLED: We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months. SIGNIFICANCE: Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53. ©2016 AACR.See related commentary by Lim et al., p. 697This article is highlighted in the In This Issue feature, p. 681.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Modelos Animais de Doenças , Monitoramento de Medicamentos , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/mortalidade , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Clin Cancer Res ; 20(14): 3763-74, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24850847

RESUMO

PURPOSE: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. EXPERIMENTAL DESIGN: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell-cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α, and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by: (i) relating the rate of tumor growth to mitotic cell density, and (ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated antitumor effect in A375 human melanoma xenografts. RESULTS: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. CONCLUSIONS: Our model provides mechanistic insight into the quantitative pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.


Assuntos
Aminopiridinas/farmacocinética , Antineoplásicos/farmacocinética , Benzimidazóis/farmacocinética , Administração Oral , Aminopiridinas/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Mol Cancer Ther ; 13(10): 2253-63, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25122067

RESUMO

B-RAF selective inhibitors, including vemurafenib, were recently developed as effective therapies for melanoma patients with B-RAF V600E mutation. However, most patients treated with vemurafenib eventually develop resistance largely due to reactivation of MAPK signaling. Inhibitors of MAPK signaling, including MEK1/2 inhibitor trametinib, failed to show significant clinical benefit in patients with acquired resistance to vemurafenib. Here, we describe that cell lines with acquired resistance to vemurafenib show reactivation of MAPK signaling and upregulation of cyclin D1 and are sensitive to inhibition of LY2835219, a selective inhibitor of cyclin-dependent kinase (CDK) 4/6. LY2835219 was demonstrated to inhibit growth of melanoma A375 tumor xenografts and delay tumor recurrence in combination with vemurafenib. Furthermore, we developed an in vivo vemurafenib-resistant model by continuous administration of vemurafenib in A375 xenografts. Consistently, we found that MAPK is reactivated and cyclin D1 is elevated in vemurafenib-resistant tumors, as well as in the resistant cell lines derived from these tumors. Importantly, LY2835219 exhibited tumor growth regression in a vemurafenib-resistant model. Mechanistic analysis revealed that LY2835219 induced apoptotic cell death in a concentration-dependent manner in vemurafenib-resistant cells whereas it primarily mediated cell-cycle G1 arrest in the parental cells. Similarly, RNAi-mediated knockdown of cyclin D1 induced significantly higher rate of apoptosis in the resistant cells than in parental cells, suggesting that elevated cyclin D1 activity is important for the survival of vemurafenib-resistant cells. Altogether, we propose that targeting cyclin D1-CDK4/6 signaling by LY2835219 is an effective strategy to overcome MAPK-mediated resistance to B-RAF inhibitors in B-RAF V600E melanoma.


Assuntos
Aminopiridinas/farmacologia , Benzimidazóis/farmacologia , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Transfecção , Regulação para Cima/efeitos dos fármacos , Vemurafenib , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Mol Cancer Ther ; 13(2): 364-74, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24356814

RESUMO

p38α mitogen-activated protein kinase (MAPK) is activated in cancer cells in response to environmental factors, oncogenic stress, radiation, and chemotherapy. p38α MAPK phosphorylates a number of substrates, including MAPKAP-K2 (MK2), and regulates the production of cytokines in the tumor microenvironment, such as TNF-α, interleukin-1ß (IL-1ß), IL-6, and CXCL8 (IL-8). p38α MAPK is highly expressed in human cancers and may play a role in tumor growth, invasion, metastasis, and drug resistance. LY2228820 dimesylate (hereafter LY2228820), a trisubstituted imidazole derivative, is a potent and selective, ATP-competitive inhibitor of the α- and ß-isoforms of p38 MAPK in vitro (IC(50) = 5.3 and 3.2 nmol/L, respectively). In cell-based assays, LY2228820 potently and selectively inhibited phosphorylation of MK2 (Thr334) in anisomycin-stimulated HeLa cells (at 9.8 nmol/L by Western blot analysis) and anisomycin-induced mouse RAW264.7 macrophages (IC(50) = 35.3 nmol/L) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc ≤ 10 µmol/L. LY2228820 also reduced TNF-α secretion by lipopolysaccharide/IFN-γ-stimulated macrophages (IC(50) = 6.3 nmol/L). In mice transplanted with B16-F10 melanoma, tumor phospho-MK2 (p-MK2) was inhibited by LY2228820 in a dose-dependent manner [threshold effective dose (TED)(70) = 11.2 mg/kg]. Significant target inhibition (>40% reduction in p-MK2) was maintained for 4 to 8 hours following a single 10 mg/kg oral dose. LY2228820 produced significant tumor growth delay in multiple in vivo cancer models (melanoma, non-small cell lung cancer, ovarian, glioma, myeloma, breast). In summary, LY2228820 is a p38 MAPK inhibitor, which has been optimized for potency, selectivity, drug-like properties (such as oral bioavailability), and efficacy in animal models of human cancer.


Assuntos
Imidazóis/farmacologia , Neoplasias/tratamento farmacológico , Piridinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Anisomicina/farmacologia , Sítios de Ligação , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Imidazóis/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Estrutura Molecular , Neoplasias/genética , Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Piridinas/química , Interferência de RNA , Resultado do Tratamento , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Leuk Res ; 35(8): 1108-10, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21420732

RESUMO

Prolonged administration of methyl transferase inhibitors may increase response rates in myelodysplastic syndromes (MDS). Fourteen MDS patients with anemia and less than 10% marrow blasts received azacitidine 50 mg/m(2) thrice weekly for 2 weeks every 4 weeks; 7 also received weekly erythropoietin. The response rate of 43% did not improve the rates reported with other azacitidine administration schedules, so the study was closed. A decreased apoptosis of primitive erythroid progenitors and increased expression of BclX(L) was observed with treatment in responding patients compared to non-responders. Azacitidine may modulate BclX(L) and improve erythropoiesis through reduction of apoptosis in primitive erythroid progenitor population in MDS.


Assuntos
Anemia/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Células Precursoras Eritroides/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Síndromes Mielodisplásicas/complicações , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Apoptose/efeitos dos fármacos , Eritropoetina/uso terapêutico , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Prognóstico , Proteína bcl-X/metabolismo
13.
Mol Cell Biol ; 29(16): 4376-93, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19528235

RESUMO

Juvenile myelomonocytic leukemia (JMML) is characterized by myelomonocytic cell overproduction and commonly bears activating mutations in PTPN11. Murine hematopoietic progenitors expressing activating Shp2 undergo myelomonocytic differentiation, despite being subjected to conditions that normally support only mast cells. Evaluation of hematopoietic-specific transcription factor expression indicates reduced GATA2 and elevated c-Jun in mutant Shp2-expressing progenitors. We hypothesized that mutant Shp2-induced Ras hyperactivation promotes c-Jun phosphorylation and constitutive c-Jun expression, permitting, as a coactivator of PU.1, excessive monocytic differentiation and reduced GATA2. Hematopoietic progenitors expressing activating Shp2 demonstrate enhanced macrophage CFU (CFU-M) compared to that of wild-type Shp2-expressing cells. Treatment with the JNK inhibitor SP600125 or cotransduction with GATA2 normalizes activating Shp2-generated CFU-M. However, cotransduction of DeltaGATA2 (lacking the C-terminal zinc finger, needed to bind PU.1) fails to normalize CFU-M. NIH 3T3 cells expressing Shp2E76K produce higher levels of luciferase expression directed by the macrophage colony-stimulating factor receptor (MCSFR) promoter, which utilizes c-Jun as a coactivator of PU.1. Coimmunoprecipitation demonstrates increased c-Jun-PU.1 complexes in mutant Shp2-expressing hematopoietic progenitors, while chromatin immunoprecipitation demonstrates increased c-Jun binding to the c-Jun promoter and an increased c-Jun-PU.1 complex at the Mcsfr promoter. Furthermore, JMML progenitors express higher levels of c-JUN than healthy controls, substantiating the disease relevance of these mechanistic findings.


Assuntos
Diferenciação Celular/fisiologia , Fator de Transcrição GATA2/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Monócitos/fisiologia , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Animais , Antracenos/metabolismo , Criança , Ativação Enzimática , Fator de Transcrição GATA2/genética , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Lactente , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Leucemia Mielomonocítica Juvenil/genética , Mastócitos/citologia , Mastócitos/fisiologia , Camundongos , Monócitos/citologia , Células NIH 3T3 , Regiões Promotoras Genéticas , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
14.
Blood ; 105(11): 4523-6, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15705784

RESUMO

Core binding factor (CBF) participates in specification of the hematopoietic stem cell and functions as a critical regulator of hematopoiesis. Translocation or point mutation of acute myeloid leukemia 1 (AML1)/RUNX1, which encodes the DNA-binding subunit of CBF, plays a central role in the pathogenesis of acute myeloid leukemia and myelodysplasia. We characterized the t(X;21)(p22.3;q22.1) in a patient with myelodysplasia that fuses AML1 in-frame to the novel partner gene FOG2/ZFPM2. The reciprocal gene fusions AML1-FOG2 and FOG2-AML1 are both expressed. AML1-FOG2, which fuses the DNA-binding domain of AML1 to most of FOG2, represses the transcriptional activity of both CBF and GATA1. AML1-FOG2 retains a motif that recruits the corepressor C-terminal binding protein (CtBP) and these proteins associate in a protein complex. These results suggest a central role for CtBP in AML1-FOG2 transcriptional repression and implicate coordinated disruption of the AML1 and GATAdevelopmental programs in the pathogenesis of myelodysplasia.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Síndromes Mielodisplásicas/genética , Proteínas de Fusão Oncogênica/genética , Fosfoproteínas/metabolismo , Oxirredutases do Álcool , Fator de Ligação a CCAAT/genética , Cromossomos Humanos Par 21 , Cromossomos Humanos X , Subunidade alfa 2 de Fator de Ligação ao Core , Proteínas de Ligação a DNA/genética , Fatores de Ligação de DNA Eritroide Específicos , Fator de Transcrição GATA1 , Humanos , Síndromes Mielodisplásicas/etiologia , Proteínas de Fusão Oncogênica/metabolismo , Ligação Proteica , Proteínas Repressoras , Fatores de Transcrição/genética , Transcrição Gênica , Translocação Genética
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