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1.
Br J Haematol ; 186(4): 549-560, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31124580

RESUMO

Selinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non-clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose-escalation trial of twice-weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib-refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose-limiting toxicity (cardiac failure). The RP2D of twice-weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment-emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual-class refractory (PI and immunomodulatory drug)/quad-exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression-free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re-established disease control in RRMM patients, including carfilzomib-refractory patients. Registered at ClinicalTrials.gov (NCT02199665).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Análise Citogenética , Dexametasona/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hidrazinas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Oligopeptídeos/administração & dosagem , Prognóstico , Recidiva , Retratamento , Resultado do Tratamento , Triazóis/administração & dosagem
2.
Br J Haematol ; 170(1): 66-79, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25824111

RESUMO

Toward our goal of personalized medicine, we comprehensively profiled pre-treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib-based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially-regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of 'universal response' pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA-damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib-based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti-myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly-diagnosed myeloma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Adulto , Idoso , Ácidos Borônicos/administração & dosagem , Bortezomib , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Humanos , Lenalidomida , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Polietilenoglicóis/administração & dosagem , Medicina de Precisão/métodos , Proteômica/métodos , Pirazinas/administração & dosagem , Talidomida/administração & dosagem , Talidomida/análogos & derivados
3.
Future Oncol ; 7(5): 613-7, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21568677

RESUMO

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a prototypical cancer that occurs in the setting of chronic inflammation and an important model for understanding how deregulated NF-κB transcriptional activity contributes to malignancy. Most gastric MALT lymphomas require ongoing antigenic stimulation for continued tumor growth, and Stage I disease is usually cured by eradicating the causative microorganism, Helicobacter pylori, with antibiotics. However, in a subset of MALT lymphomas, chromosomal translocations are acquired that render the lymphoma antigen-independent. The recurrent translocation t(11;18)(q21;q21) is associated with failure to respond to antibiotic therapy and increased rate of dissemination. This translocation creates the API2-MALT1 fusion oncoprotein, which comprises the amino terminus of inhibitor of apoptosis 2 (API2 or cIAP2) fused to the carboxy terminus of MALT1. A common characteristic of chromosomal translocations in MALT lymphoma, including t(11;18), is that genes involved in the regulation of the NF-κB transcription factor are targeted by the translocations, and these genetic perturbations thereby result in deregulated, constitutive NF-κB stimulation. In the last decade, great insights into the roles of API2 and MALT1 in NF-κB signaling have been made. For example, recent pivotal studies have uncovered the long sought-after proteolytic activity of MALT1 and have demonstrated its critical involvement in the survival of certain lymphomas. Here, we review the current understanding of the role of MALT1 in normal lymphocyte function and lymphomagenesis. We then highlight our recent work that has revealed an intriguing link between the proteolytic activity of the API2-MALT1 fusion and its ability to influence lymphomagenesis by cleaving a key NF-κB regulatory protein, NF-κB-inducing kinase.


Assuntos
Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Peptídeo Hidrolases/metabolismo , Humanos , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas de Fusão Oncogênica/genética , Peptídeo Hidrolases/genética , Transdução de Sinais/genética , Translocação Genética
4.
Cancer Med ; 9(1): 324-334, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31714026

RESUMO

Multiple myeloma (MM) continues to be considered incurable, necessitating new drug discovery. The mitotic kinase T-LAK cell-originated protein kinase/PDZ-binding kinase (TOPK/PBK) is associated with proliferation of tumor cells, maintenance of cancer stem cells, and poor patient prognosis in many cancers. In this report, we demonstrate potent anti-myeloma effects of the TOPK inhibitor OTS514 for the first time. OTS514 induces cell cycle arrest and apoptosis at nanomolar concentrations in a series of human myeloma cell lines (HMCL) and prevents outgrowth of a putative CD138+ stem cell population from MM patient-derived peripheral blood mononuclear cells. In bone marrow cells from MM patients, OTS514 treatment exhibited preferential killing of the malignant CD138+ plasma cells compared with the CD138- compartment. In an aggressive mouse xenograft model, OTS964 given orally at 100 mg/kg 5 days per week was well tolerated and reduced tumor size by 48%-81% compared to control depending on the initial graft size. FOXO3 and its transcriptional targets CDKN1A (p21) and CDKN1B (p27) were elevated and apoptosis was induced with OTS514 treatment of HMCLs. TOPK inhibition also induced loss of FOXM1 and disrupted AKT, p38 MAPK, and NF-κB signaling. The effects of OTS514 were independent of p53 mutation or deletion status. Combination treatment of HMCLs with OTS514 and lenalidomide produced synergistic effects, providing a rationale for the evaluation of TOPK inhibition in existing myeloma treatment regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Tiofenos/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Leucócitos Mononucleares , Camundongos , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Cultura Primária de Células , Inibidores de Proteínas Quinases/uso terapêutico , Quinolonas/uso terapêutico , Tiofenos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Apoptosis ; 13(4): 562-72, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18330707

RESUMO

ISG12a is one of the most highly induced genes following treatment of cells with type I interferons (IFNs). The encoded protein belongs to a family of poorly characterized, low molecular weight IFN-inducible proteins that includes 6-16 (G1P3), 1-8U (IFITM3), and 1-8D (IFITM2). Our studies demonstrate that the ISG12a protein associates with or inserts into the mitochondrial membrane. Transient expression of ISG12a led to decreased viable cell numbers and enhanced sensitivity to DNA-damage induced apoptosis, effects that were blocked by Bcl-2 co-expression or treatment with a pan-caspase inhibitor. ISG12a enhanced etoposide induced cytochrome c release, Bax activation and loss of mitochondrial membrane potential. siRNA-mediated inhibition of ectopic ISG12a protein expression prevented the sensitization to etoposide-induced apoptosis and also decreased the ability of IFN-beta pretreatment to sensitize cells to etoposide, thereby demonstrating a role for ISG12a in this process. These data suggest that ISG12a contributes to IFN-dependent perturbation of normal mitochondrial function, thus adding ISG12a to a growing list of IFN-induced proteins that impact cellular apoptosis.


Assuntos
Apoptose/fisiologia , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Fibrossarcoma/ultraestrutura , Humanos
6.
World J Biol Chem ; 7(1): 128-37, 2016 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-26981201

RESUMO

Lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the most common extranodal B cell tumor and accounts for 8% of non-Hodgkin's lymphomas. Gastric MALT lymphoma is the best-studied example and is a prototypical neoplasm that occurs in the setting of chronic inflammation brought on by persistent infection or autoimmune disease. Cytogenetic abnormalities are commonly acquired during the course of disease and the most common is chromosomal translocation t(11;18)(q21;q21), which creates the API2-MALT1 fusion oncoprotein. t(11;18)-positive lymphomas can be clinically aggressive and have a higher rate of dissemination than t(11;18)-negative tumors. Many cancers, including MALT lymphomas, characteristically exhibit deregulated over-activation of cellular survival pathways, such as the nuclear factor-κB (NF-κB) pathway. Molecular characterization of API2-MALT1 has revealed it to be a potent activator of NF-κB, which is required for API2-MALT1-induced cellular transformation, however the mechanisms by which API2-MALT1 exerts these effects are only recently becoming apparent. The API2 moiety of the fusion binds tumor necrosis factor (TNF) receptor associated factor (TRAF) 2 and receptor interacting protein 1 (RIP1), two proteins essential for TNF receptor-induced NF-κB activation. By effectively mimicking ligand-bound TNF receptor, API2-MALT1 promotes TRAF2-dependent ubiquitination of RIP1, which then acts as a scaffold for nucleating and activating the canonical NF-κB machinery. Activation occurs, in part, through MALT1 moiety-dependent recruitment of TRAF6, which can directly modify NF-κB essential modulator, the principal downstream regulator of NF-κB. While the intrinsic MALT1 protease catalytic activity is dispensable for this canonical NF-κB signaling, it is critical for non-canonical NF-κB activation. In this regard, API2-MALT1 recognizes NF-κB inducing kinase (NIK), the essential upstream regulator of non-canonical NF-κB, and cleaves it to generate a stable, constitutively active fragment. Thus, API2-MALT1 harnesses multiple unique pathways to achieve deregulated NF-κB activation. Emerging data from our group and others have also detailed additional gain-of-function activities of API2-MALT1 that extend beyond NF-κB activation. Specifically, API2-MALT1 recruits and subverts multiple other signaling factors, including LIM domain and actin-binding protein 1 (LIMA1) and Smac/DIABLO. Like NIK, LIMA1 represents a unique substrate for API2-MALT1 protease activity, but unlike NIK, its cleavage sets in motion a major NF-κB-independent pathway for promoting oncogenesis. In this review, we highlight the most recent results characterizing these unique and diverse gain-of-function activities of API2-MALT1 and how they contribute to lymphomagenesis.

7.
Mol Cancer Ther ; 15(1): 60-71, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26637366

RESUMO

Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line-derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 10/metabolismo , Hidrazinas/farmacologia , Mieloma Múltiplo/metabolismo , Oligopeptídeos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Caspase 8/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Humanos , Espaço Intracelular , Camundongos , Inibidores de Proteassoma/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Virology ; 417(2): 293-303, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21742363

RESUMO

Noxa is a Bcl-2 homology domain-containing pro-apoptotic mitochondrial protein. Noxa mRNA and protein expression are upregulated by dsRNA or virus, and ectopic Noxa expression enhances cellular sensitivity to virus or dsRNA-induced apoptosis. Here we demonstrate that Noxa null baby mouse kidney (BMK) cells are deficient in normal cytopathic response to lytic viruses, and that reconstitution of the knockout cells with wild-type Noxa restored normal cytopathic responses. Noxa regulation by virus mirrored its regulation by proteasome inhibitors or ER stress inducers and the ER stress response inhibitor salubrinal protected cells against viral cytopathic effects. Noxa mRNA and protein were synergistically upregulated by IFN or dsRNA when combined with ER stress inducers, leading to Noxa/Mcl-1 interaction, activation of Bax and pro-apoptotic caspases, degradation of Mcl-1, loss of mitochondrial membrane potential and initiation of apoptosis. These data highlight the importance of ER stress in augmenting the expression of Noxa following viral infection.


Assuntos
Apoptose , Regulação da Expressão Gênica , Interferons/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , RNA de Cadeia Dupla/imunologia , Animais , Efeito Citopatogênico Viral , Vírus da Encefalomiocardite/patogenicidade , Retículo Endoplasmático/metabolismo , Teste de Complementação Genética , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-2/deficiência , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Vesiculovirus/patogenicidade
9.
Cell Cycle ; 10(15): 2485-96, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21750409

RESUMO

The advent of molecular cytogenetics has led to the elucidation of genetic abnormalities that cause various congenital and oncological disorders. In B cell lymphoma, for example, a number of chromosomal translocations have been identified in and associated with the etiology of specific subtypes of lymphoma. Several recurrent chromosomal translocations have been identified in extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Cloning and characterization of the products of three mutually exclusive translocation breakpoints found in MALT lymphoma led to the discovery of a novel NF-κB-activating complex comprising the CARMA, Bcl10, and MALT1 proteins. This "CBM signalosome" acts downstream of the antigen receptors in lymphocytes as well as a number of non-lymphoid cell-surface receptors involved in a variety of biological processes. CBM signalosome activity is important for normal cellular functions and is perturbed in neoplastic and inflammatory disorders, making it a viable target for novel therapeutic design.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspases/metabolismo , Linfoma de Zona Marginal Tipo Células B/metabolismo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteína 10 de Linfoma CCL de Células B , Proteínas Adaptadoras de Sinalização CARD/fisiologia , Caspases/fisiologia , Cromossomos/metabolismo , Humanos , Linfoma de Zona Marginal Tipo Células B/patologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , NF-kappa B/metabolismo , Proteínas de Neoplasias/fisiologia
10.
Science ; 331(6016): 468-72, 2011 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-21273489

RESUMO

Proper regulation of nuclear factor κB (NF-κB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-κB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB-inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-κB pathway in B lymphoproliferative disease.


Assuntos
Linfócitos B/metabolismo , Linfoma de Zona Marginal Tipo Células B/metabolismo , NF-kappa B/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Apoptose , Adesão Celular , Linhagem Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Quinase I-kappa B/metabolismo , Linfoma de Zona Marginal Tipo Células B/genética , Subunidade p52 de NF-kappa B/metabolismo , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Especificidade por Substrato , Quinase Induzida por NF-kappaB
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