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Recent studies in Diffuse Midline Gliomas (DMG) demonstrated a strong connection between epigenome dysregulation and metabolic rewiring. Here, we evaluated the value of targeting a glycolytic protein named Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase 3 (PFKFB3) in H3.3K27M DMG. We observed that the viability of H3.3K27M cells is dramatically reduced by PFK15, a potent inhibitor of PFKFB3. Furthermore, PFKFB3 inhibition induced apoptosis and G2/M arrest. Interestingly, CRISPR-Knockout of the K27M mutant allele has a synergistic effect on the observed phenotype. Altogether, we identified PFKFB3 as a new target for H3.3K27M DMG, making PFK15 a potential candidate for future animal studies and clinical trials.
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Glioma , Histonas , Fosfofrutoquinase-2 , Humanos , Glioma/metabolismo , Glioma/patologia , Glioma/genética , Fosfofrutoquinase-2/metabolismo , Fosfofrutoquinase-2/genética , Histonas/metabolismo , Histonas/genética , Linhagem Celular Tumoral , Criança , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Apoptose , Mutação , Glicólise/efeitos dos fármacosRESUMO
The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children's Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and higher 3-year relapse risk after AML standard treatment compared to low expressions (52% vs. 29%, p = 0.005). The high-HME profile correlated with more transposase-accessible chromatin, as demonstrated via ATAC-sequencing, and the bortezomib addition improved the 3-year overall survival compared with standard therapy (62% vs. 75%, p = 0.033). These data suggest that there are pediatric AML populations that respond well to bortezomib-containing chemotherapy.
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Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p <0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06-0.55], p = 0.002). The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001). Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.). Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.
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Pediatric acute myeloid leukemia (AML) remains a fatal disease for at least 30% of patients, stressing the need for improved therapies and better risk stratification. As proteins are the unifying feature of (epi)genetic and environmental alterations, and are often targeted by novel chemotherapeutic agents, we studied the proteomic landscape of pediatric AML. Protein expression and activation levels were measured in 500 bulk leukemic patients' samples and 30 control CD34+ cell samples, using reverse phase protein arrays with 296 strictly validated antibodies. The multistep MetaGalaxy analysis methodology was applied and identified nine protein expression signatures (PrSIG), based on strong recurrent protein expression patterns. PrSIG were associated with cytogenetics and mutational state, and with favorable or unfavorable prognosis. Analysis based on treatment (i.e., ADE vs. ADE plus bortezomib) identified three PrSIG that did better with ADE plus bortezomib than with ADE alone. When PrSIG were studied in the context of cytogenetic risk groups, PrSIG were independently prognostic after multivariate analysis, suggesting a potential value for proteomics in combination with current classification systems. Proteins with universally increased (n=7) or decreased (n=17) expression were observed across PrSIG. Certain proteins significantly differentially expressed from normal could be identified, forming a hypothetical platform for personalized medicine.
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Leucemia Mieloide Aguda , Proteômica , Bortezomib , Criança , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Prognóstico , Análise Serial de Proteínas , ProteínasRESUMO
Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.
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The chronic lymphocytic leukemia (CLL) armamentarium has evolved significantly, with novel therapies that inhibit Bruton Tyrosine Kinase, PI3K delta and/or the BCL2 protein improving outcomes. Still, the clinical course of CLL patients is highly variable and most previously recognized prognostic features lack the capacity to predict response to modern treatments indicating the need for new prognostic markers. In this study, we identified four epigenetically distinct proteomic signatures of a large cohort of CLL and related diseases derived samples (n = 871) using reverse phase protein array technology. These signatures are associated with clinical features including age, cytogenetic abnormalities [trisomy 12, del(13q) and del(17p)], immunoglobulin heavy-chain locus (IGHV) mutational load, ZAP-70 status, Binet and Rai staging as well as with the outcome measures of time to treatment and overall survival. Protein signature membership was identified as predictive marker for overall survival regardless of other clinical features. Among the analyzed epigenetic proteins, EZH2, HDAC6, and loss of H3K27me3 levels were the most independently associated with poor survival. These findings demonstrate that proteomic based epigenetic biomarkers can be used to better classify CLL patients and provide therapeutic guidance.
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Epigênese Genética , Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Idoso , Aberrações Cromossômicas , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Pessoa de Meia-Idade , Mutação , ProteômicaRESUMO
PURPOSE: The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin, and etoposide) did not improve overall outcome of pediatric AML patients in the Children's Oncology Group AAML1031 phase 3 randomized clinical trial (AAML1031) . Bortezomib prevents protein degradation, including RelA via the intracellular NF-kB pathway. In this study, we hypothesized that subgroups of pediatric AML patients benefitting from standard therapy plus bortezomib (ADEB) could be identified based on pre-treatment RelA expression and phosphorylation status. EXPERIMENTAL DESIGN: RelA-total and phosphorylation at serine 536 (RelA-pSer536 ) were measured in 483 patient samples using reverse phase protein array technology. RESULTS: In ADEB-treated patients, low-RelA-pSer536 was favorably prognostic when compared to high-RelA-pSer536 (3-yr overall survival (OS): 81% vs. 68%, p = 0.032; relapse risk (RR): 30% vs. 49%, p = 0.004). Among low-RelA-pSer536 patients, RR significantly decreased with ADEB compared to ADE (RR: 30% vs. 44%, p = 0.035). Correlation between RelA-pSer536 and 295 other assayed proteins identified a strong correlation with HSF1-pSer326 , another protein previously identified as modifying ADEB response. The combination of low-RelA-pSer536 and low-HSF1-pSer326 was a significant predictor of ADEB response (3-yr OS: 86% vs. 67%, p = 0.013). CONCLUSION AND CLINICAL RELEVANCE: Bortezomib may improve clinical outcome in a subgroup of AML patients identified by low-RelA-pSer536 and low-HSF1-pSer326 .
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Leucemia Mieloide Aguda , NF-kappa B , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Criança , Citarabina/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Fosforilação , Fator de Transcrição RelA/uso terapêuticoRESUMO
While there has been significant progress in the molecular characterization of the childhood brain cancer medulloblastoma, the tumor proteome remains less explored. However, it is important to obtain a complete understanding of medulloblastoma protein biology, since interactions between proteins represent potential new drug targets. Using previously generated phosphoprotein signaling-profiles of a large cohort of primary medulloblastoma, we discovered that phosphorylation of transcription factor CREB strongly correlates with medulloblastoma survival and associates with a differentiation phenotype. We further found that during normal cerebellar development, phosphorylated CREB was selectively expressed in differentiating cerebellar granule neuron progenitor (CGNP) cells. In line, we observed increased differentiation in CGNPs treated with Forskolin, Bmp6 and Bmp12 (Gdf7), which induce CREB phosphorylation. Lastly, we demonstrated that inducing CREB activation via PKA-mediated CREB signaling, but not Bmp/MEK/ERK mediated signalling, enhances medulloblastoma cell sensitivity to chemotherapy.
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Diferenciação Celular/fisiologia , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Transdução de Sinais/fisiologia , Animais , Células Cultivadas , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurogênese/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Fosforilação/fisiologia , Fatores de Transcrição/metabolismoRESUMO
Bortezomib (BTZ) was recently evaluated in a randomized phase 3 clinical trial by the Children's Oncology Group (COG) that compared standard chemotherapy (cytarabine, daunorubicin, and etoposide [ADE]) vs standard therapy with BTZ (ADEB) for de novo pediatric acute myeloid leukemia (AML). Although the study concluded that BTZ did not improve outcome overall, we examined patient subgroups benefiting from BTZ-containing chemotherapy using proteomic analyses. The proteasome inhibitor BTZ disrupts protein homeostasis and activates cytoprotective heat shock responses. Total heat shock factor 1 (HSF1) and phosphorylated HSF1 (HSF1-pSer326) were measured in leukemic cells from 483 pediatric patients using reverse phase protein arrays. HSF1-pSer326 phosphorylation was significantly lower in pediatric AML compared with CD34+ nonmalignant cells. We identified a strong correlation between HSF1-pSer326 expression and BTZ sensitivity. BTZ significantly improved outcome of patients with low-HSF1-pSer326 with a 5-year event-free survival of 44% (ADE) vs 67% for low-HSF1-pSer326 treated with ADEB (P = .019). To determine the effect of HSF1 expression on BTZ potency in vitro, cell viability with HSF1 gene variants that mimicked phosphorylated (S326A) and nonphosphorylated (S326E) HSF1-pSer326 were examined. Those with increased HSF1 phosphorylation showed clear resistance to BTZ vs those with wild-type or reduced HSF1-phosphorylation. We hypothesize that HSF1-pSer326 expression could identify patients who benefit from BTZ-containing chemotherapy.
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Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Fatores de Transcrição de Choque Térmico/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Criança , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Masculino , Mutação Puntual , Prognóstico , TranscriptomaRESUMO
Introduction: The biological heterogeneity of acute myeloid leukemia (AML) complicates personalized medicine. Individual prognosis is typically based on the presence of chromosomal and genetic lesions. Nevertheless, these classifications often lack a priori information about response to therapy. Since the protein expression landscape reflects the functional activity state of cells, we hypothesize that analyzing this can be used for the identification of protein activity markers to provide better risk stratification as well as may provide targeted therapeutic guidance in AML.Areas covered: Herein, we review recently new adopted drugs in the treatment for AML and discuss how quantitative proteomic techniques may contribute to better therapeutic selection in AML.Expert commentary: The net functional state of the cell is defined by the activity of protein within all the pathways that are active in the cell. Recognition of the proteomic profile of the leukemic blast could, therefore, complement current classification systems by providing a better a priori description of what pathways are important within a cell as a guide to the selection of therapy for the patient.
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Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Proteômica/métodos , Animais , Antineoplásicos/uso terapêutico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Espectrometria de Massas/métodos , Proteoma/genética , Proteoma/metabolismo , Pesquisa Translacional Biomédica/métodosRESUMO
Brain tumors (BTs) are a common pediatric malignancy. Improved treatment has resulted in higher survival rates. There is, however, increasing concern about adverse effects of the disease and its treatment, including effects on social competence (i.e. effective social functioning in everyday life). The aim of this study is to examine multiple levels of social competence (i.e. social skills and social adjustment) in newly diagnosed pediatric BT patients. Thirty newly diagnosed BT patients aged 5-12 years were assessed shortly after diagnosis with a neuropsychological test battery focusing on social competence, including tests for IQ, social skills (i.e. social-affective and executive functioning) and social adjustment (rated by parents and teachers). Their performance was compared to 95 healthy controls who completed the same assessment. Patients and healthy controls were largely comparable with regard to demographic and environmental factors and did not differ on measures of IQ, social skills and social adjustment. Furthermore, age was found to have a positive significant effect on social skills independent of group. Shortly after diagnosis, pediatric BT patients did not perform different from healthy controls on IQ and measures of social skills and social adjustment. This is an encouraging finding. However, because of potentially neurotoxic adjuvant therapy and the ongoing development of social skills, longitudinal follow-up studies are needed to investigate long-term outcome regarding social competence in BT survivors.
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Neoplasias Encefálicas/psicologia , Ajustamento Social , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
The majority of acute myeloid leukemia (AML) patients suffer from relapse and the exact etiology of AML remains unclear. The aim of this study was to gain comprehensive insights into the activity of signaling pathways in AML. In this study, using a high-throughput PepChip™ Kinomics microarray system, pediatric AML samples were analyzed to gain insights of active signal transduction pathway. Unsupervised hierarchical cluster analysis separated the AML blast profiles into two clusters. These two clusters were independent of patient characteristics, whereas the cumulative incidence of relapse (CIR) was significantly higher in the patients belonging to cluster-2. In addition, cluster-2 samples showed to be significantly less sensitive to various chemotherapeutic drugs. The activated peptides in cluster-1 and cluster-2 reflected the activity of cell cycle regulation, cell proliferation, cell differentiation, apoptosis, PI3K/AKT, MAPK, metabolism regulation, transcription factors and GPCRs signaling pathways. The difference between two clusters might be explained by the higher cell cycle arrest response in cluster-1 patients and higher DNA repair mechanism in cluster-2 patients. In conclusion, our study identifies different signaling profiles in pediatric AML in relation with CIR involving DNA damage response and repair.
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This international study aimed to assess the effect of imatinib discontinuation in paediatric patients with chronic myeloid leukaemia (CML) after deep molecular remission (DMR) had been achieved and maintained for at least 2 years. The primary endpoint of this analysis was the molecular relapse-free survival, estimated by the non-parametric Kaplan-Meier method. Major endpoint was the estimated rate of patients without molecular relapse at 6 months. Fourteen patients were enrolled; 4 patients maintained DMR with a follow-up of 24 (two patients), 34 and 66 months, respectively, whereas 10 patients relapsed. All molecular relapses occurred within 6 months (median 3 months, range 1-6) after imatinib discontinuation. The overall probability of maintaining DMR at 6 months was 28·6%. No parameters associated with molecular relapse could be identified. Keeping in mind the rarity of paediatric CML, which contributed to the small size of the cohort, our findings illustrate that imatinib cessation after sustained DMR is successful in only limited numbers of patients, whereas much higher rates are reported in adult patients. Further research is needed to extend the cohort of paediatric CML patients who might achieve treatment-free remission with an ideal prerequisite of predicting the occurrence of molecular relapse l after imatinib cessation.
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Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adolescente , Criança , Substituição de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Acute promyelocytic leukemia (APL) is the most prognostically favorable subtype of Acute myeloid leukemia (AML). Defining the features that allow identification of APL patients likely to relapse after therapy remains challenging. EXPERIMENTAL DESIGN: Proteomic profiling is performed on 20 newly diagnosed APL, 205 non-APL AML, and 10 normal CD34+ samples using Reverse Phase Protein Arrays probed with 230 antibodies. RESULTS: Comparison between APL and non-APL AML samples identifies 8.3% of the proteins to be differentially expressed. Proteins higher expressed in APL are involved in the pro-apoptotic pathways or are linked to higher proliferation. The "MetaGalaxy" approach that considers proteins in relation to other assayed proteins stratifies the APL patients into two protein signatures. All of the relapse patients (n = 4/4) are in protein signature 2 (S2). Comparison of proteins between the signatures shows significant differences in relative expression for 38 proteins. Protein expression summary plots suggest less translational activity in combination with a less proliferative character for S2 compared to signature 1. CONCLUSIONS AND CLINICAL RELEVANCE: This study provides a potential proteomic-based classification of APL patients that may be useful for risk stratification and therapeutic guidance. Validation in a larger independent cohort is required.
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Perfilação da Expressão Gênica , Leucemia Promielocítica Aguda/sangue , Proteínas de Neoplasias/sangue , Análise Serial de Proteínas , Proteômica , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Self-renewal and differentiation of pluripotent murine embryonic stem cells (ESCs) is regulated by extrinsic signaling pathways. It is less clear whether cellular metabolism instructs developmental progression. In an unbiased genome-wide CRISPR/Cas9 screen, we identified components of a conserved amino-acid-sensing pathway as critical drivers of ESC differentiation. Functional analysis revealed that lysosome activity, the Ragulator protein complex, and the tumor-suppressor protein Folliculin enable the Rag GTPases C and D to bind and seclude the bHLH transcription factor Tfe3 in the cytoplasm. In contrast, ectopic nuclear Tfe3 represses specific developmental and metabolic transcriptional programs that are associated with peri-implantation development. We show differentiation-specific and non-canonical regulation of Rag GTPase in ESCs and, importantly, identify point mutations in a Tfe3 domain required for cytoplasmic inactivation as potentially causal for a human developmental disorder. Our work reveals an instructive and biomedically relevant role of metabolic signaling in licensing embryonic cell fate transitions.
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Diferenciação Celular , Lisossomos/metabolismo , Transdução de Sinais , Alelos , Animais , Autorrenovação Celular , Feminino , GTP Fosfo-Hidrolases/metabolismo , Genoma , Humanos , Masculino , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Fosforilação , Mutação Puntual/genética , Ligação Proteica , Transcrição GênicaRESUMO
Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.
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Cariótipo Anormal , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adolescente , Aloenxertos , Criança , Pré-Escolar , Citogenética , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Taxa de SobrevidaRESUMO
High expression of VEGFC predicts adverse prognosis in acute myeloid leukemia (AML). We therefore explored VEGFC-targeting efficacy as an AML therapy using a VEGFC mAb. VEGFC antibody therapy enforced myelocytic differentiation of clonal CD34+ AML blasts. Treatment of CD34+ AML blasts with the antibody reduced expansion potential by 30% to 50% and enhanced differentiation via FOXO3A suppression and inhibition of MAPK/ERK proliferative signals. VEGFC antibody therapy also accelerated leukemia cell differentiation in a systemic humanized AML mouse model. Collectively, these results define a regulatory function of VEGFC in CD34+ AML cell fate decisions via FOXO3A and serve as a new potential differentiation therapy for patients with AML.Significance: These findings reveal VEGFC targeting as a promising new differentiation therapy in AML. Cancer Res; 78(20); 5940-8. ©2018 AACR.
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Anticorpos Monoclonais/farmacologia , Leucemia Mieloide Aguda/terapia , Fator C de Crescimento do Endotélio Vascular/imunologia , Animais , Antígenos CD34/metabolismo , Diferenciação Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HEK293 , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Fosforilação , PrognósticoRESUMO
A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m2, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.
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Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores , Medula Óssea/patologia , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Falha de Tratamento , Resultado do TratamentoRESUMO
INTRODUCTION: Although cure rates for acute leukemia have steadily improved over the past decades, leukemia remains a deadly disease. Enhanced risk stratification and new therapies are needed to improve outcome. Extensive genetic analyses have identified many mutations that contribute to the development of leukemia. However, most mutations occur infrequently and most gene alterations have been difficult to target. Most patients have more than one driver mutation in combination with secondary mutations, that result in a leukemic transformation via the alteration of proteins. The proteomics of acute leukemia could more directly identify proteins to facilitate risk stratification, predict chemoresistance and aid selection of therapy. Areas covered: This review discusses aberrantly expressed proteins identified by mass spectrometry and reverse phase protein arrays and their relationship to survival. In addition, we will discuss proteins in the context of functionally related protein groups. Expert commentary: Proteomics is a powerful tool to analyze protein abundance and functional alterations simultaneously for large numbers of patients. In the forthcoming years, validation of tools to quickly assess protein levels to enable routine rapid profiling of proteins with differential abundance and functional activation may be used as adjuncts to aid in therapy selection and to provide additional prognostic insights.
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Leucemia/metabolismo , Proteômica/métodos , Pesquisa Translacional Biomédica , Animais , Biomarcadores Tumorais/metabolismo , Humanos , Leucemia/diagnóstico , Transdução de SinaisRESUMO
Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m2/day × 5 days) and liposomal daunorubicin (40-80 mg/m2/day) were administered with cytarabine (2 g/m2/day × 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), ≥2nd relapse (n=8). Dose level 3 (30 mg/m2clofarabine; 60 mg/m2liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m2 clofarabine with 60 mg/m2 liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine exposure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub) clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.