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1.
Blood ; 144(10): 1061-1068, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38754046

RESUMO

ABSTRACT: Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from patients with relapsed/refractory CLL in ELEVATE-RR (NCT02477696; median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up, 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 acalabrutinib-treated (66%) and 11 ibrutinib-treated patients (37%; median variant allele fraction [VAF], 16.1% vs 15.6%, respectively). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, whereas neither mutation occurred with ibrutinib. L528W and A428D comutations presented in 1 ibrutinib-treated patient. Preexisting TP53 mutations were present in 25 acalabrutinib-treated (53.2%) and 16 ibrutinib-treated patients (53.3%) at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF, 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and 1 ibrutinib-treated patient had emergent TP53/BTK comutations. Emergent PLCG2 mutations occurred in 3 acalabrutinib-treated (6%) and 6 ibrutinib-treated patients (20%). One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 comutations. Although common BTK C481 mutations were observed with both treatments, patterns of mutation and comutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W and A428D) in this patient population. The trial was registered at www.clinicaltrials.gov as #NCT02477696.


Assuntos
Adenina , Tirosina Quinase da Agamaglobulinemia , Benzamidas , Leucemia Linfocítica Crônica de Células B , Mutação , Piperidinas , Pirazinas , Pirazóis , Pirimidinas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/genética , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/uso terapêutico , Progressão da Doença , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Pirazinas/uso terapêutico , Pirazinas/administração & dosagem , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem
2.
Haematologica ; 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39113656

RESUMO

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eµ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.

3.
Blood ; 128(26): 3101-3112, 2016 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-27756747

RESUMO

Bruton's tyrosine kinase (BTK) is a critical mediator of survival in B-cell neoplasms. Although BTK inhibitors have transformed therapy in chronic lymphocytic leukemia (CLL), patients with high-risk genetics are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of microRNAs (miRs) that target BTK in primary CLL cells and show that the histone deacetylase (HDAC) repressor complex is recruited to these miR promoters to silence their expression. Targeting the HDACs by using either RNA interference against HDAC1 in CLL or a small molecule inhibitor (HDACi) in CLL and mantle cell lymphoma restored the expression of the BTK-targeting miRs with loss of BTK protein and downstream signaling and consequent cell death. We have also made the novel and clinically relevant discovery that inhibition of HDAC induces the BTK-targeting miRs in ibrutinib-sensitive and resistant CLL to effectively reduce both wild-type and C481S-mutant BTK. This finding identifies a novel strategy that may be promising as a therapeutic modality to eliminate the C481S-mutant BTK clone that drives resistance to ibrutinib and provides the rationale for a combination strategy that includes ibrutinib to dually target BTK to suppress its prosurvival signaling.


Assuntos
Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/genética , MicroRNAs/metabolismo , Terapia de Alvo Molecular , Proteínas Tirosina Quinases/metabolismo , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Animais , Benzofuranos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Epigênese Genética/efeitos dos fármacos , Perfilação da Expressão Gênica , Inativação Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Camundongos Endogâmicos C57BL , Proteínas Mutantes/metabolismo , Proteínas de Neoplasias/metabolismo , Piperidinas , Regiões Promotoras Genéticas/genética , Pirazóis/farmacologia , Pirimidinas/farmacologia , Interferência de RNA/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
4.
Blood Adv ; 7(12): 2897-2911, 2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-36287107

RESUMO

Chronic lymphocytic leukemia (CLL) is a quiescent B-cell malignancy that depends on transcriptional dysregulation for survival. The histone deacetylases are transcriptional regulators whose role within the regulatory chromatin and consequence on the CLL transcriptome is poorly characterized. Here, we profiled and integrated the genome-wide occupancy of HDAC1, BRD4, H3K27Ac, and H3K9Ac signals with chromatin accessibility, Pol2 occupancy, and target expression signatures in CLL cells. We identified that when HDAC1 was recruited within super-enhancers (SEs) marked by acetylated H3K27 and BRD4, it functioned as a transcriptional activator that drove the de novo expression of select genes to facilitate survival and progression in CLL. Targeting HDACs reduced BRD4 and Pol2 engagement to downregulate the transcript and proteins levels of specific oncogenic driver genes in CLL such as BLK, a key mediator of the B-cell receptor pathway, core transcription factors such as PAX5 and IKZF3, and the antiapoptotic gene, BCL2. Concurrently, HDAC1, when recruited in the absence of SEs, repressed target gene expression. HDAC inhibition reversed silencing of a defined set of protein-coding and noncoding RNA genes. We focused on a specific set of microRNA genes and showed that their upregulation was inversely correlated with the expression of CLL-specific survival, transcription factor, and signaling genes. Our findings identify that the transcriptional activator and repressor functions of HDACs cooperate within the same tumor to establish the transcriptional dependencies essential for survival in CLL.


Assuntos
Cromatina , Leucemia Linfocítica Crônica de Células B , Humanos , Cromatina/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Regulação da Expressão Gênica , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Proteínas de Ciclo Celular/genética
5.
Clin Cancer Res ; 28(9): 1979-1990, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35140124

RESUMO

PURPOSE: Proficient DNA repair by homologous recombination (HR) facilitates resistance to chemoradiation in glioma stem cells (GSC). We evaluated whether compromising HR by targeting HSP90, a molecular chaperone required for the function of key HR proteins, using onalespib, a long-acting, brain-penetrant HSP90 inhibitor, would sensitize high-grade gliomas to chemoradiation in vitro and in vivo. EXPERIMENTAL DESIGN: The ability of onalespib to deplete HR client proteins, impair HR repair capacity, and sensitize glioblastoma (GBM) to chemoradiation was evaluated in vitro in GSCs, and in vivo using zebrafish and mouse intracranial glioma xenograft models. The effects of HSP90 inhibition on the transcriptome and cytoplasmic proteins was assessed in GSCs and in ex vivo organotypic human glioma slice cultures. RESULTS: Treatment with onalespib depleted CHK1 and RAD51, two key proteins of the HR pathway, and attenuated HR repair, sensitizing GSCs to the combination of radiation and temozolomide (TMZ). HSP90 inhibition reprogrammed the transcriptome of GSCs and broadly altered expression of cytoplasmic proteins including known and novel client proteins relevant to GSCs. The combination of onalespib with radiation and TMZ extended survival in a zebrafish and a mouse xenograft model of GBM compared with the standard of care (radiation and TMZ) or onalespib with radiation. CONCLUSIONS: The results of this study demonstrate that targeting HR by HSP90 inhibition sensitizes GSCs to radiation and chemotherapy and extends survival in zebrafish and mouse intracranial models of GBM. These results provide a preclinical rationale for assessment of HSP90 inhibitors in combination with chemoradiation in patients with GBM.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Glioma , Animais , Antineoplásicos/farmacologia , Benzamidas , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Reparo do DNA , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/radioterapia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/radioterapia , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Isoindóis , Camundongos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
6.
J Bacteriol ; 193(12): 2924-30, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21498646

RESUMO

Anaplasma platys infects peripheral blood platelets and causes infectious cyclic thrombocytopenia in canines. The genes, proteins, and antigens of A. platys are largely unknown, and an antigen for serodiagnosis of A. platys has not yet been identified. In this study, we cloned the A. platys major outer membrane protein cluster, including the P44/Msp2 expression locus (p44ES/msp2ES) and outer membrane protein (OMP), using DNA isolated from the blood of four naturally infected dogs from Venezuela and Taiwan, Republic of China. A. platys p44ES is located within a 4-kb genomic region downstream from a putative transcriptional regulator, tr1, and a homolog of the Anaplasma phagocytophilum, identified here as A. platys omp-1X. The predicted molecular masses of the four mature A. platys P44ES proteins ranged from 43.3 to 43.5 kDa. Comparative analyses of the deduced amino acid sequences of Tr1, OMP-1X, and P44/Msp2 proteins from A. platys with those from A. phagocytophilum showed sequence identities of 86.4% for Tr1, 45.9% to 46.3% for OMP-1X, and 55.0% to 56.9% for P44/Msp2. Comparison between A. platys and Anaplasma marginale proteins showed sequence identities of 73.1% for Tr1/Tr, 39.8% for OMP-1X/OMP1, and 41.5% to 42.1% for P44/Msp2. A synthetic OMP-1X peptide was shown to react with A. platys-positive sera but not with A. platys-negative sera or A. phagocytophilum-positive sera. Together, determination of the genomic locus of A. platys outer membrane proteins not only contributes to the fundamental understanding of this enigmatic pathogen but also helps in developing A. platys-specific PCR and serodiagnosis.


Assuntos
Anaplasma/metabolismo , Anaplasmose/microbiologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/química , Proteínas da Membrana Bacteriana Externa/genética , Clonagem Molecular , Doenças do Cão/microbiologia , Cães , Regulação Bacteriana da Expressão Gênica/fisiologia , Dados de Sequência Molecular , Filogenia , Especificidade da Espécie
7.
J Bacteriol ; 191(3): 693-700, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18978058

RESUMO

Anaplasma phagocytophilum, the etiologic agent of human granulocytic anaplasmosis (HGA), has genes predicted to encode three sensor kinases, one of which is annotated PleC, and three response regulators, one of which is PleD. Prior to this study, the roles of PleC and PleD in the obligatory intracellular parasitism of A. phagocytophilum and their biochemical activities were unknown. The present study illustrates the relevance of these factors by demonstrating that both pleC and pleD were expressed in an HGA patient. During A. phagocytophilum development in human promyelocytic HL-60 cells, PleC and PleD were synchronously upregulated at the exponential growth stage and downregulated prior to extracellular release. A recombinant PleC kinase domain (rPleCHKD) has histidine kinase activity; no activity was observed when the conserved site of phosphorylation was replaced with alanine. A recombinant PleD (rPleD) has autokinase activity using phosphorylated rPleCHKD as the phosphoryl donor but not with two other recombinant histidine kinases. rPleCHKD could not serve as the phosphoryl donor for a mutant rPleD (with a conserved aspartic acid, the site of phosphorylation, replaced by alanine) or two other A. phagocytophilum recombinant response regulators. rPleD had diguanylate cyclase activity to generate cyclic (c) di-GMP from GTP in vitro. UV cross-linking of A. phagocytophilum lysate with c-di-[(32)P]GMP detected an approximately 47-kDa endogenous protein, presumably c-di-GMP downstream receptor. A new hydrophobic c-di-GMP derivative, 2'-O-di(tert-butyldimethylsilyl)-c-di-GMP, inhibited A. phagocytophilum infection in HL-60 cells. Our results suggest that the two-component PleC-PleD system is a diguanylate cyclase and that a c-di-GMP-receptor complex regulates A. phagocytophilum intracellular infection.


Assuntos
Anaplasma phagocytophilum/enzimologia , Anaplasmose/metabolismo , Anaplasmose/patologia , GMP Cíclico/análogos & derivados , Fósforo-Oxigênio Liases/metabolismo , Proteínas Quinases/metabolismo , Anaplasmose/enzimologia , Western Blotting , GMP Cíclico/metabolismo , Ehrlichiose/enzimologia , Proteínas de Escherichia coli , Células HL-60 , Histidina Quinase , Humanos , Modelos Genéticos , Fósforo-Oxigênio Liases/genética , Fosforilação , Proteínas Quinases/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Methods Mol Biol ; 1881: 153-163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30350204

RESUMO

Assays that measure DNA damage and repair are critical in evaluating the extent to which therapeutic agents damage DNA and in identifying whether DNA repair can limit the toxicity of chemotherapy. The COMET assays described in this guide should help readers evaluate single and double-strand breaks cause by chemotherapeutic agents and also monitor the ability of the cells to repair such damage. The EJDR assay described is a valuable tool to assess the ability of drugs and DNA repair proteins to modulate DNA repair capacity. Finally, the immunofluorescence assay described should allow accurate assessments of DNA damage and the kinetics of repair as measured by Ɣ-H2AX foci. This procedure can also be used to mechanistically investigate the recruitment of specific DNA damage and repair proteins in CLL cells.


Assuntos
Antineoplásicos/farmacologia , Separação Celular/métodos , Ensaio Cometa/métodos , Citometria de Fluxo/métodos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Antineoplásicos/uso terapêutico , Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Separação Celular/instrumentação , Ensaio Cometa/instrumentação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Citometria de Fluxo/instrumentação , Imunofluorescência/instrumentação , Imunofluorescência/métodos , Corantes Fluorescentes/química , Humanos , Leucemia Linfocítica Crônica de Células B/genética
9.
Blood Adv ; 3(3): 242-255, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30692102

RESUMO

Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.


Assuntos
Acrilamidas/farmacologia , Aminopiridinas/farmacologia , Citocinas/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cancer Discov ; 8(4): 458-477, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29386193

RESUMO

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.


Assuntos
Regulação Leucêmica da Expressão Gênica , Isoxazóis/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas Nucleares/genética , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Transdução de Sinais , Fatores de Transcrição/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Isoxazóis/farmacologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Camundongos , Camundongos SCID , Proteínas Nucleares/metabolismo , Piridinas/farmacologia , Pirróis/farmacologia , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Vector Borne Zoonotic Dis ; 16(9): 581-7, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27327629

RESUMO

Anaplasma platys is an uncultivable tick-borne obligatory intracellular bacterium, which is known to infect platelets of dogs. A. platys causes infectious canine cyclic thrombocytopenia in subtropical and tropical regions throughout the world. Several cases of human infection with A. platys infection have also been reported. However, seroprevalence of A. platys exposure and infection has not been determined in most of the regions, in part, due to lack of a simple and reliable assay method. Furthermore, A. platys antigens recognized by dogs are unknown. We previously sequenced gene encoding A. platys major outer membrane proteins P44 and Omp-1X. In the present study, we obtained purified recombinant A. platys P44 and Omp-1X proteins, and using them as antigens in immunoblotting examined seroreactivity in dogs. Of 34 specimens from Venezuela where A. platys infection was previously reported, 25 specimens (73.5%) reacted to rAplP44 and/or rAplOMP-1X. Neither Anaplasma phagocytophilum-seropositive (N = 10) nor A. phagocytophilum-seronegative canine specimens (N = 10) from the geographic regions where A. platys infection has never been reported, reacted rAplP44 or rAplOMP-1X. The result indicates a high A. platys seroprevalence rate in tested dogs from Venezuela and suggests that the immunoblot analysis based on recombinant A. platys major outer membrane proteins can provide a simple and defined tool to enlighten the prevalence of A. platys infection.


Assuntos
Anaplasma/isolamento & purificação , Proteínas da Membrana Bacteriana Externa/metabolismo , Regulação Bacteriana da Expressão Gênica/fisiologia , Immunoblotting/métodos , Animais , Proteínas da Membrana Bacteriana Externa/genética , Clonagem Molecular , Doenças do Cão/epidemiologia , Doenças do Cão/microbiologia , Doenças do Cão/parasitologia , Cães , Humanos , Infestações por Carrapato/epidemiologia , Infestações por Carrapato/parasitologia , Infestações por Carrapato/veterinária , Venezuela/epidemiologia , Zoonoses
12.
Clin Cancer Res ; 22(24): 6142-6152, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27358488

RESUMO

PURPOSE: Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore, we asked whether adding already established effective drugs such as topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML. EXPERIMENTAL DESIGN: The efficacy of combinatorial drug treatment using Topo II inhibitors (idarubicin, daunorubicin, mitoxantrone, etoposide) and selinexor was evaluated in established cellular and animal models of AML. RESULTS: Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared with each single therapy. CONCLUSIONS: Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of patients with AML that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC-dependent reduction of DNA damage repair genes (Rad51 and Chk1) mRNA and protein expression and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML. Clin Cancer Res; 22(24); 6142-52. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Reparo do DNA/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Hidrazinas/farmacologia , Carioferinas/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos SCID , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/metabolismo , Inibidores da Topoisomerase II/farmacologia , Proteína Exportina 1
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