Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 221
Filtrar
1.
Cancer Epidemiol Biomarkers Prev ; 29(2): 509-519, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31871106

RESUMO

BACKGROUND: Recent efforts to improve outcomes for high-grade serous ovarian cancer, a leading cause of cancer death in women, have focused on identifying molecular subtypes and prognostic gene signatures, but existing subtypes have poor cross-study robustness. We tested the contribution of cell admixture in published ovarian cancer molecular subtypes and prognostic gene signatures. METHODS: Gene signatures of tumor and stroma were developed using paired microdissected tissue from two independent studies. Stromal genes were investigated in two molecular subtype classifications and 61 published gene signatures. Prognostic performance of gene signatures of stromal admixture was evaluated in 2,527 ovarian tumors (16 studies). Computational simulations of increasing stromal cell proportion were performed by mixing gene-expression profiles of paired microdissected ovarian tumor and stroma. RESULTS: Recently described ovarian cancer molecular subtypes are strongly associated with the cell admixture. Tumors were classified as different molecular subtypes in simulations where the percentage of stromal cells increased. Stromal gene expression in bulk tumors was associated with overall survival (hazard ratio, 1.17; 95% confidence interval, 1.11-1.23), and in one data set, increased stroma was associated with anatomic sampling location. Five published prognostic gene signatures were no longer prognostic in a multivariate model that adjusted for stromal content. CONCLUSIONS: Cell admixture affects the interpretation and reproduction of ovarian cancer molecular subtypes and gene signatures derived from bulk tissue. Elucidating the role of stroma in the tumor microenvironment and in prognosis is important. IMPACT: Single-cell analyses may be required to refine the molecular subtypes of high-grade serous ovarian cancer.

2.
Expert Rev Proteomics ; 15(12): 1033-1052, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30427223

RESUMO

INTRODUCTION: Proteasome inhibitors (PIs) are therapeutic backbones of multiple myeloma treatment, with PI-based therapies being standards of care throughout the treatment algorithm. Proteasome inhibition affects multiple critical signaling pathways in myeloma cells and interacts synergistically with mechanisms of action of other conventional and novel agents, resulting in substantial anti-myeloma activity and at least additive effects. Areas covered: This review summarizes the biologic effects of proteasome inhibition in myeloma and provides an overview of the importance of proteasome inhibition to the current treatment algorithm. It reviews key clinical data on three PIs, specifically bortezomib, carfilzomib, and ixazomib; assesses ongoing phase 3 trials with these agents; and looks ahead to the increasingly broad role of both approved PIs and PIs under investigation in the frontline and relapsed settings. Expert commentary: Progress to date with PIs in multiple myeloma has been impressive, but there remain unmet needs and challenges, as well as increasing opportunities to optimize the use of these agents. Understanding discrepancies between PIs in terms of efficacy and safety profile is a key goal of ongoing research, along with proteomics-based efforts to identify potential biomarkers of sensitivity and resistance, thereby enabling increasingly personalized treatment approaches in the future.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Humanos , Inibidores de Proteassoma/efeitos adversos
3.
PLoS Genet ; 14(10): e1007688, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30325918

RESUMO

Oncogenic mutations in the small GTPase Ras contribute to ~30% of human cancers. However, Ras mutations alone are insufficient for tumorigenesis, therefore it is paramount to identify cooperating cancer-relevant signaling pathways. We devised an in vivo near genome-wide, functional screen in Drosophila and discovered multiple novel, evolutionarily-conserved pathways controlling Ras-driven epithelial tumorigenesis. Human gene orthologs of the fly hits were significantly downregulated in thousands of primary tumors, revealing novel prognostic markers for human epithelial tumors. Of the top 100 candidate tumor suppressor genes, 80 were validated in secondary Drosophila assays, identifying many known cancer genes and multiple novel candidate genes that cooperate with Ras-driven tumorigenesis. Low expression of the confirmed hits significantly correlated with the KRASG12 mutation status and poor prognosis in pancreatic cancer. Among the novel top 80 candidate cancer genes, we mechanistically characterized the function of the top hit, the Tetraspanin family member Tsp29Fb, revealing that Tsp29Fb regulates EGFR signaling, epithelial architecture and restrains tumor growth and invasion. Our functional Drosophila screen uncovers multiple novel and evolutionarily conserved epithelial cancer genes, and experimentally confirmed Tsp29Fb as a key regulator of EGFR/Ras induced epithelial tumor growth and invasion.


Assuntos
Proteínas de Drosophila/genética , IMP Desidrogenase/genética , Neoplasias/genética , Tetraspanina 29/genética , Animais , Animais Geneticamente Modificados , Carcinogênese/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Genes ras , Testes Genéticos/métodos , Humanos , IMP Desidrogenase/metabolismo , Masculino , Camundongos , Neoplasias/metabolismo , Neoplasias/patologia , Oncogenes , Transdução de Sinais , Tetraspanina 29/metabolismo , Proteínas Supressoras de Tumor/genética
4.
Blood Adv ; 2(19): 2443-2451, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30266819

RESUMO

Proteasome inhibitors bortezomib, carfilzomib and ixazomib (approved by the US Food and Drug Administration [FDA]) induce remissions in patients with multiple myeloma (MM), but most patients eventually become resistant. MM and other hematologic malignancies express ubiquitous constitutive proteasomes and lymphoid tissue-specific immunoproteasomes; immunoproteasome expression is increased in resistant patients. Immunoproteasomes contain 3 distinct pairs of active sites, ß5i, ß1i, and ß2i, which are different from their constitutive ß5c, ß1c, and ß2c counterparts. Bortezomib and carfilzomib block ß5c and ß5i sites. We report here that pharmacologically relevant concentrations of ß5i-specific inhibitor ONX-0914 show cytotoxicity in MM cell lines similar to that of carfilzomib and bortezomib. In addition, increasing immunoproteasome expression by interferon-γ increases sensitivity to ONX-0914 but not to carfilzomib. LU-102, an inhibitor of ß2 sites, dramatically sensitizes MM cell lines and primary cells to ONX-0914. ONX-0914 synergizes with all FDA-approved proteasome inhibitors in MM in vitro and in vivo. Thus, immunoproteasome inhibitors, currently in clinical trials for the treatment of autoimmune diseases, should also be considered for the treatment of MM.


Assuntos
Antineoplásicos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Biomarcadores , Bortezomib/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Mieloma Múltiplo/metabolismo , Oligopeptídeos/farmacologia
5.
Haematologica ; 103(7): 1218-1228, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29622655

RESUMO

The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor Food and Drug Administration (FDA) approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Herein, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in coculture with bone marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. Transcriptome analysis and unbiased phosphoproteomics revealed that bone marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.


Assuntos
Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Reposicionamento de Medicamentos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Animais , Comunicação Celular , Modelos Animais de Doenças , Humanos , Janus Quinases/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Mieloma Múltiplo/metabolismo , Fosfoproteínas/metabolismo , Piperidinas/administração & dosagem , Plasmócitos/metabolismo , Plasmócitos/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Proteoma , Proteômica/métodos , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Immunol Immunother ; 67(6): 861-872, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29500635

RESUMO

Natural killer (NK) cell-based immunotherapy is a promising novel approach to treat cancer. However, NK cell function has been shown to be potentially diminished by factors common in the tumor microenvironment (TME). In this study, we assessed the synergistic potential of antibody-dependent cell-mediated cytotoxicity (ADCC) and killer immunoglobin-like receptor (KIR)-ligand mismatched NK cells to potentiate NK cell antitumor reactivity in multiple myeloma (MM). Hypoxia, lactate, prostaglandin E2 (PGE2) or combinations were selected to mimic the TME. To investigate this, NK cells from healthy donors were isolated and NK cell ADCC capacity in response to MM cells was assessed in flow cytometry-based cytotoxicity and degranulation (CD107a) assays in the presence of TME factors. Hypoxia, lactate and PGE2 reduced cytotoxicity of NK cells against myeloma target cells. The addition of daratumumab (anti-CD38 antibody) augmented NK-cell cytotoxicity against target cells expressing high CD38, but not against CD38 low or negative target cells also in the presence of TME. Co-staining for inhibitory KIRs and NKG2A demonstrated that daratumumab enhanced degranulation of all NK cell subsets. Nevertheless, KIR-ligand mismatched NK cells were slightly better effector cells than KIR-ligand matched NK cells. In summary, our study shows that combination therapy using strategies to maximize activating NK cell signaling by triggering ADCC in combination with an approach to minimize inhibitory signaling through a selection of KIR-ligand mismatched donors, can help to overcome the NK-suppressive TME. This can serve as a platform to improve the clinical efficacy of NK cells.


Assuntos
ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/metabolismo , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Células Matadoras Naturais/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Microambiente Tumoral
7.
Br J Haematol ; 179(5): 756-771, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29048129

RESUMO

Multiple myeloma (MM), a B cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow, remains incurable despite the use of novel and conventional therapies. In this study, we demonstrated MM cell cytotoxicity triggered by realgar (REA; As4 S4 ) nanoparticles (NREA) versus Arsenic trioxide (ATO) against MM cell lines and patient cells. Both NREA and ATO showed in vivo anti-MM activity, resulting in significantly decreased tumour burden. The anti-MM activity of NREA and ATO is associated with apoptosis, evidenced by DNA fragmentation, depletion of mitochondrial membrane potential, cleavage of caspases and anti-apoptotic proteins. NREA induced G2 /M cell cycle arrest and modulation of cyclin B1, p53 (TP53), p21 (CDKN1A), Puma (BBC3) and Wee-1 (WEE1). Moreover, NREA induced modulation of key regulatory molecules in MM pathogenesis including JNK activation, c-Myc (MYC), BRD4, and histones. Importantly, NREA, but not ATO, significantly depleted the proportion and clonogenicity of the MM stem-like side population, even in the context of the bone marrow stromal cells. Finally, our study showed that both NREA and ATO triggered synergistic anti-MM activity when combined with lenalidomide or melphalan. Taken together, the anti-MM activity of NREA was more potent compared to ATO, providing the preclinical framework for clinical trials to improve patient outcome in MM.


Assuntos
Antineoplásicos/administração & dosagem , Arsenicais/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Óxidos/administração & dosagem , Sulfetos/administração & dosagem , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/farmacologia , Arsenicais/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/métodos , Humanos , Camundongos SCID , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/patologia , Nanopartículas , Células-Tronco Neoplásicas/efeitos dos fármacos , Óxidos/farmacologia , Óxidos/uso terapêutico , Sulfetos/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Mol Cancer Ther ; 16(11): 2375-2386, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28878026

RESUMO

Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375-86. ©2017 AACR.


Assuntos
Adenosina Trifosfatases/genética , Indóis/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Proteínas Nucleares/genética , Fator 1 Nuclear Respiratório/genética , Inibidores de Proteassoma/administração & dosagem , Pirimidinas/administração & dosagem , Adenosina Trifosfatases/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteínas Nucleares/antagonistas & inibidores , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Ubiquitina/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Semin Cancer Biol ; 39: 68-76, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27544796

RESUMO

The nuclear factor-κB (NF-κB) transcription factor family plays critical roles in the pathophysiology of hematologic neoplasias, including multiple myeloma. The current review examines the roles that this transcription factor system plays in multiple myeloma cells and the nonmalignant accessory cells of the local microenvironment; as well as the evidence indicating that a large proportion of myeloma patients harbor genomic lesions which perturb diverse genes regulating the activity of NF-κB. This article also discusses the therapeutic targeting of the NF-κB pathway using proteasome inhibitors, a pharmacological class that has become a cornerstone in the therapeutic management of myeloma; and reviews some of the future challenges and opportunities for NF-κB-related research in myeloma.


Assuntos
Mieloma Múltiplo/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Humanos , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Transdução de Sinais , Microambiente Tumoral
10.
Cancer Cell ; 29(5): 611-612, 2016 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-27165736

RESUMO

In this issue of Cancer Cell, Zhang et al. report that TJP1 suppresses EGFR/JAK1/STAT3-mediated signaling and increases the proteasome inhibitor sensitivity of myeloma cells by altering the cellular proteasome capacity versus proteasome load of undegraded intracellular proteins.


Assuntos
Inibidores de Proteassoma/farmacologia , Proteína da Zônula de Oclusão-1 , Ácidos Borônicos , Bortezomib , Linhagem Celular Tumoral , Humanos , Mieloma Múltiplo/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo
11.
Clin Cancer Res ; 22(16): 4206-4214, 2016 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-27006493

RESUMO

PURPOSE: Since the pioneering work of Salmon and Durie, quantitative measures of tumor burden in multiple myeloma have been used to make clinical predictions and model tumor growth. However, such quantitative analyses have not yet been performed on large datasets from trials using modern chemotherapy regimens. EXPERIMENTAL DESIGN: We analyzed a large set of tumor response data from three randomized controlled trials of bortezomib-based chemotherapy regimens (total sample size n = 1,469 patients) to establish and validate a novel mathematical model of multiple myeloma cell dynamics. RESULTS: Treatment dynamics in newly diagnosed patients were most consistent with a model postulating two tumor cell subpopulations, "progenitor cells" and "differentiated cells." Differential treatment responses were observed with significant tumoricidal effects on differentiated cells and less clear effects on progenitor cells. We validated this model using a second trial of newly diagnosed patients and a third trial of refractory patients. When applying our model to data of relapsed patients, we found that a hybrid model incorporating both a differentiation hierarchy and clonal evolution best explains the response patterns. CONCLUSIONS: The clinical data, together with mathematical modeling, suggest that bortezomib-based therapy exerts a selection pressure on myeloma cells that can shape the disease phenotype, thereby generating further inter-patient variability. This model may be a useful tool for improving our understanding of disease biology and the response to chemotherapy regimens. Clin Cancer Res; 22(16); 4206-14. ©2016 AACR.


Assuntos
Diferenciação Celular , Evolução Clonal , Modelos Teóricos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/patologia , Diferenciação Celular/genética , Ensaios Clínicos como Assunto , Evolução Clonal/genética , Humanos , Modelos Estatísticos , Mieloma Múltiplo/terapia , Reprodutibilidade dos Testes
12.
Br J Haematol ; 169(6): 843-50, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26032514

RESUMO

Proteasome inhibitors (PI) and immunomodulatory agents (IMIDs) have improved the overall survival (OS) of patients with multiple myeloma (MM), but concerns have been raised about increased incidence of extramedullary disease (EMD) after the combined use of PIs and IMIDs for upfront therapy. We evaluated whether the addition of lenalidomide to bortezomib-based front-line regimens precipitated earlier development of EMD. We reviewed the charts of 117 MM patients (median follow-up from diagnosis 6·1 years; range 0·1-10·2 years) enrolled in eight clinical trials of first-line treatment with bortezomib-based regimens, with or without lenalidomide. We assessed development of EMD as extraosseous (distant from bone) or osseous (originating from bone) plasmacytomas. The primary endpoint was time from diagnosis until development of EMD, based on imaging, biopsy and/or physical examination. Any form of EMD at progression was observed in 40 (34·2%) patients, including 21 (18%) osseous, 8 (7%) extraosseous and 11 (9%) both osseous and extraosseous. Median OS was 0·9 years (range 0·1-4·8 years) after extraosseous EMD development. Sensitivity analyses with follow-up times truncated at 5 years detected no statistically significant difference in rates of any EMD form between the two groups (P > 0·2 for each comparison). Therefore, we observed no evidence that bortezomib-lenalidomide-based front-line therapy precipitates earlier EMD.


Assuntos
Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/etiologia , Segunda Neoplasia Primária , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Ácidos Borônicos/administração & dosagem , Bortezomib , Feminino , Seguimentos , Humanos , Incidência , Lenalidomida , Masculino , Mieloma Múltiplo/epidemiologia , Estadiamento de Neoplasias , Plasmocitoma/diagnóstico , Plasmocitoma/tratamento farmacológico , Pirazinas/administração & dosagem , Indução de Remissão , Risco , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Resultado do Tratamento
13.
Nat Med ; 21(6): 572-80, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26005854

RESUMO

B cell malignancies frequently colonize the bone marrow. The mechanisms responsible for this preferential homing are incompletely understood. Here we studied multiple myeloma (MM) as a model of a terminally differentiated B cell malignancy that selectively colonizes the bone marrow. We found that extracellular CyPA (eCyPA), secreted by bone marrow endothelial cells (BMECs), promoted the colonization and proliferation of MM cells in an in vivo scaffold system via binding to its receptor, CD147, on MM cells. The expression and secretion of eCyPA by BMECs was enhanced by BCL9, a Wnt-ß-catenin transcriptional coactivator that is selectively expressed by these cells. eCyPA levels were higher in bone marrow serum than in peripheral blood in individuals with MM, and eCyPA-CD147 blockade suppressed MM colonization and tumor growth in the in vivo scaffold system. eCyPA also promoted the migration of chronic lymphocytic leukemia and lymphoplasmacytic lymphoma cells, two other B cell malignancies that colonize the bone marrow and express CD147. These findings suggest that eCyPA-CD147 signaling promotes the bone marrow homing of B cell malignancies and offer a compelling rationale for exploring this axis as a therapeutic target for these malignancies.


Assuntos
Basigina/metabolismo , Proliferação de Células/genética , Ciclofilina A/metabolismo , Mieloma Múltiplo/metabolismo , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Basigina/genética , Medula Óssea/metabolismo , Medula Óssea/patologia , Movimento Celular , Ciclofilina A/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Complexos Multiproteicos/genética , Proteínas de Neoplasias , Fatores de Transcrição , Via de Sinalização Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
14.
Br J Haematol ; 169(6): 851-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25833301

RESUMO

Extramedullary disease (EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty-three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy-proven EMD was identified, comprising 8·3% of the total study population. EMD was present at the time of diagnosis in 14·5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4·1 years (95% CI: 3·1, 5·1) and the median overall survival from time of EMD diagnosis was 1·3 years (95% CI: 0·8, 2·3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation.


Assuntos
Mieloma Múltiplo/epidemiologia , Biópsia , Sistema Nervoso Central/patologia , Feminino , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Imuno-Histoquímica , Incidência , Linfonodos/patologia , Masculino , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Tomografia por Emissão de Pósitrons , Resultado do Tratamento
16.
Leukemia ; 29(1): 27-37, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24791855

RESUMO

Direct targeting of rat sarcoma (RAS), which is frequently mutated, has proven to be challenging, and inhibition of individual downstream RAS mediators has resulted in limited clinical efficacy. We designed a chemical screen to identify compounds capable of potentiating mammalian target of rapamycin (mTOR) inhibition in mutant RAS-positive leukemia, and identified a Wee1 inhibitor. Synergy was observed in both mutant neuroblastoma RAS viral oncogene homolog (NRAS)- and mutant kirsten RAS viral oncogene homolog (KRAS)-positive acute myelogenous leukemia (AML) cell lines and primary patient samples. The observed synergy enhanced dephosphorylation of AKT, 4E-binding protein 1 and s6 kinase, and correlated with increased apoptosis. The specificity of Wee1 as the target of MK-1775 was validated by Wee1 knockdown, as well as partial reversal of drug combination-induced apoptosis by a cyclin-dependent kinase 1 (CDK1) inhibitor. Importantly, we also extended our findings to other mutant RAS-expressing malignancies, including mutant NRAS-positive melanoma, and mutant KRAS-positive colorectal cancer, pancreatic cancer and lung cancer. We observed favorable responses with combined Wee1/mTOR inhibition in human cancer cell lines from multiple malignancies, and inhibition of tumor growth in in vivo models of mutant KRAS lung cancer and leukemia. The present study introduces for the first time Wee1 inhibition combined with mTOR inhibition as a novel therapeutic strategy for the selective treatment of mutant RAS-positive leukemia and other mutant RAS-expressing malignancies.


Assuntos
Proteínas de Ciclo Celular/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Nucleares/efeitos dos fármacos , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sequência de Bases , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Proteínas Nucleares/genética , Proteínas Tirosina Quinases/genética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinonas , RNA Interferente Pequeno/genética
17.
Proc Natl Acad Sci U S A ; 111(51): 18261-6, 2014 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-25489091

RESUMO

The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both full-length and splice-variant AR. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a first-in-field approach to target AR expression and function and improve outcomes in CRPC.


Assuntos
Fator de Transcrição GATA2/fisiologia , Coativadores de Receptor Nuclear/metabolismo , Receptores Androgênicos/metabolismo , Proliferação de Células , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Prognóstico , Receptores Androgênicos/fisiologia , Transdução de Sinais , Transcrição Genética/fisiologia
18.
BMC Genomics ; 15: 904, 2014 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-25322877

RESUMO

BACKGROUND: Bone destruction is a feature of multiple myeloma, characterised by osteolytic bone destruction due to increased osteoclast activity and suppressed or absent osteoblast activity. Almost all multiple myeloma patients develop osteolytic bone lesions associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as increased mortality. Biomarkers of bone remodelling are used to identify disease characteristics that can help select the optimal management of patients. However, more accurate biomarkers are needed to effectively mirror the dynamics of bone disease activity. RESULTS: A label-free mass spectrometry-based strategy was employed for discovery phase analysis of fractionated patient serum samples associated with no or high bone disease. A number of proteins were identified which were statistically significantly correlated with bone disease, including enzymes, extracellular matrix glycoproteins, and components of the complement system. CONCLUSIONS: Enzyme-linked immunosorbent assay of complement C4 and serum paraoxonase/arylesterase 1 indicated that these proteins were associated with high bone disease in a larger independent cohort of patient samples. These biomolecules may therefore be clinically useful in assessing the extent of bone disease.


Assuntos
Doenças Ósseas/complicações , Mieloma Múltiplo/sangue , Mieloma Múltiplo/complicações , Proteoma/metabolismo , Proteômica , Área Sob a Curva , Humanos , Mieloma Múltiplo/metabolismo
19.
Clin Cancer Res ; 20(21): 5483-95, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25186968

RESUMO

PURPOSE: Activating mutations in the RAS oncogene occur frequently in human leukemias. Direct targeting of RAS has proven to be challenging, although targeting of downstream RAS mediators, such as MEK, is currently being tested clinically. Given the complexity of RAS signaling, it is likely that combinations of targeted agents will be more effective than single agents. EXPERIMENTAL DESIGN: A chemical screen using RAS-dependent leukemia cells was developed to identify compounds with unanticipated activity in the presence of an MEK inhibitor and led to identification of inhibitors of IGF1R. Results were validated using cell-based proliferation, apoptosis, cell-cycle, and gene knockdown assays; immunoprecipitation and immunoblotting; and a noninvasive in vivo bioluminescence model of acute myeloid leukemia (AML). RESULTS: Mechanistically, IGF1R protein expression/activity was substantially increased in mutant RAS-expressing cells, and suppression of RAS led to decreases in IGF1R. Synergy between MEK and IGF1R inhibitors correlated with induction of apoptosis, inhibition of cell-cycle progression, and decreased phospho-S6 and phospho-4E-BP1. In vivo, NSG mice tail veins injected with OCI-AML3-luc+ cells showed significantly lower tumor burden following 1 week of daily oral administration of 50 mg/kg NVP-AEW541 (IGF1R inhibitor) combined with 25 mg/kg AZD6244 (MEK inhibitor), as compared with mice treated with either agent alone. Drug combination effects observed in cell-based assays were generalized to additional mutant RAS-positive neoplasms. CONCLUSIONS: The finding that downstream inhibitors of RAS signaling and IGF1R inhibitors have synergistic activity warrants further clinical investigation of IGF1R and RAS signaling inhibition as a potential treatment strategy for RAS-driven malignancies.


Assuntos
Genes ras/genética , Leucemia Mieloide Aguda/genética , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação para Cima/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzimidazóis/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Pirimidinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais/genética
20.
Nature ; 511(7511): 616-20, 2014 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-25043025

RESUMO

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.


Assuntos
Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimologia , Pirimidinas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Cisteína/metabolismo , Humanos , Células Jurkat , Fosforilação/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA