RESUMO
Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy resulting in the production of abnormal lymphoid precursor cells. Occurring in B-cell and T-cell subtypes, ALL is more common in children, comprising nearly 30% of pediatric malignancies, but also constitutes 1% of adult cancer diagnoses. Outcomes are age-dependent, with five-year overall survival of greater than 90% in children and less than 20% in older adults. L-asparaginase, an enzyme not found in humans, depletes serum levels of L-asparagine. As leukemic cells are unable to synthesize this amino acid, its deprivation results in cell death. The success of asparaginase-containing regimens in the treatment of pediatric ALL, and poor outcomes with conventional cytotoxic regimens in adults, have led to trials of pediatric or pediatric-inspired regimens incorporating asparaginase in the adolescent and young adult (AYA) and adult populations. Initially purified from Escherichia coli, newer formulations of asparaginase have been developed to address short half-life, high immunogenic potential, and manufacturing difficulties. Unfamiliarity with asparaginase use and management of its unique toxicities may result in treatment-decisions that negatively impact outcomes. In this review, we address the current use of asparaginase in the treatment of ALL, with an emphasis on its role in the treatment of adults, key clinical trials, recognition and management of toxicities, and ongoing directions of study.
RESUMO
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies; however, it is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high-grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this deficit, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov; NCT01865617), with primary end points of absolute neutrophil count and platelet count at day-28 after CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75%, respectively, at 28 days after infusion. Hematologic toxicity was noted in a significant subset of patients, with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Using debiased least absolute shrinkage selector and operator regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower prelymphodepletion platelet count as an independent predictor of both decreased neutrophil and platelet counts after CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of interleukin-6 and lower day-28 cell counts; in contrast, higher serum concentrations of transforming growth factor-ß1 were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery after CD19 CAR T-cell therapy.
Assuntos
Imunoterapia Adotiva , Trombocitopenia , Antígenos CD19 , Contagem de Células , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Recidiva , Estudos Retrospectivos , Trombocitopenia/etiologiaRESUMO
INTRODUCTION: Primary pancreatic neuroendocrine tumors are a well-established disease entity, however, neuroendocrine metastases to the pancreas from other sites have been scarcely documented. Specifically, pancreatic metastases from a pulmonary carcinoid tumor have only previously been described in a single case report. PRESENTATION OF CASE: We sought to outline our institutional experience of two patients with pulmonary neuroendocrine tumors that developed metastases to the pancreas, confirmed by gross pathology and immunohistochemistry. In both cases, the pancreatic metastases were surgically resected and their pulmonary origin were discovered post-operatively. DISCUSSION: Our findings should raise awareness to the possibility of metastatic disease when evaluating a pancreatic mass in a patient with a clinical history of pulmonary carcinoid tumor. Expert opinion on immunohistochemically differentiating a primary pancreatic neuroendocrine malignancy from a metastasis should be employed in these cases. CONCLUSION: Establishing this diagnosis pre-operatively could affect the decision to proceed with surgical resection, given the morbidity of pancreatectomy and the unknown long-term clinical outcome of patients with pulmonary carcinoid tumors metastatic to the pancreas.
RESUMO
mTOR complex 1 (mTORC1; mammalian target of rapamycin [mTOR] in complex with raptor) is a key regulator of protein synthesis and cell growth in response to nutrient amino acids. Here we report that inositol polyphosphate multikinase (IPMK), which possesses both inositol phosphate kinase and lipid kinase activities, regulates amino acid signaling to mTORC1. This regulation is independent of IPMK's catalytic function, instead reflecting its binding with mTOR and raptor, which maintains the mTOR-raptor association. Thus, IPMK appears to be a physiologic mTOR cofactor, serving as a determinant of mTORC1 stability and amino acid-induced mTOR signaling. Substances that block IPMK-mTORC1 binding may afford therapeutic benefit in nutrient amino acid-regulated conditions such as obesity and diabetes.
Assuntos
Aminoácidos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Substituição de Aminoácidos , Animais , Biocatálise , Linhagem Celular , Fibroblastos/metabolismo , Humanos , Camundongos , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Ligação Proteica , Transdução de SinaisRESUMO
The inositol pyrophosphate, diphosphoinositol pentakisphosphate, regulates p53 and protein kinase Akt signaling, and its aberrant increase in cells has been implicated in apoptosis and insulin resistance. Inositol hexakisphosphate kinase-2 (IP6K2), one of the major inositol pyrophosphate synthesizing enzymes, mediates p53-linked apoptotic cell death. Casein kinase-2 (CK2) promotes cell survival and is upregulated in tumors. We show that CK2 mediated cell survival involves IP6K2 destabilization. CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. IP6K2 mutants at the CK2 sites that are resistant to CK2 phosphorylation are metabolically stable.
Assuntos
Apoptose , Caseína Quinase II/metabolismo , Regulação Enzimológica da Expressão Gênica , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Transdução de Sinais , Regulação para Cima , Motivos de Aminoácidos , Sobrevivência Celular , Estabilidade Enzimática , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Resistência à Insulina , Neoplasias/enzimologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/metabolismo , UbiquitinaçãoRESUMO
The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3ß and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3ß signaling reduced in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 affects this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby affecting insulin signaling. IP6K1 knockout mice manifest insulin sensitivity and are resistant to obesity elicited by high-fat diet or aging. Inhibition of IP6K1 may afford a therapeutic approach to obesity and diabetes.
Assuntos
Fosfatos de Inositol/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Aumento de Peso , Adipogenia , Envelhecimento/metabolismo , Animais , Técnicas de Cultura de Células , Dieta , Difosfatos/metabolismo , Inositol/metabolismo , Insulina/metabolismo , Resistência à Insulina , Camundongos , Obesidade/metabolismo , Fosforilação , Fosfotransferases (Aceptor do Grupo Fosfato)/genéticaRESUMO
Inositol pyrophosphates have been implicated in numerous biological processes. Inositol hexakisphosphate kinase-2 (IP6K2), which generates the inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP7), influences apoptotic cell death. The tumor suppressor p53 responds to genotoxic stress by engaging a transcriptional program leading to cell-cycle arrest or apoptosis. We demonstrate that IP6K2 is required for p53-mediated apoptosis and modulates the outcome of the p53 response. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets such as the cyclin-dependent kinase inhibitor p21.
Assuntos
Apoptose/genética , Neoplasias do Colo/patologia , Fosfotransferases (Aceptor do Grupo Fosfato)/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p21/genética , Dano ao DNA , Humanos , Fosfotransferases (Aceptor do Grupo Fosfato)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Ligação Proteica , Proteína Supressora de Tumor p53/metabolismoRESUMO
S-nitrosylation of proteins by nitric oxide is a major mode of signalling in cells. S-nitrosylation can mediate the regulation of a range of proteins, including prominent nuclear proteins, such as HDAC2 (ref. 2) and PARP1 (ref. 3). The high reactivity of the nitric oxide group with protein thiols, but the selective nature of nitrosylation within the cell, implies the existence of targeting mechanisms. Specificity of nitric oxide signalling is often achieved by the binding of nitric oxide synthase (NOS) to target proteins, either directly or through scaffolding proteins such as PSD-95 (ref. 5) and CAPON. As the three principal isoforms of NOS--neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)--are primarily non-nuclear, the mechanisms by which nuclear proteins are selectively nitrosylated have been elusive. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is physiologically nitrosylated at its Cys 150 residue. Nitrosylated GAPDH (SNO-GAPDH) binds to Siah1, which possesses a nuclear localization signal, and is transported to the nucleus. Here, we show that SNO-GAPDH physiologically transnitrosylates nuclear proteins, including the deacetylating enzyme sirtuin-1 (SIRT1), histone deacetylase-2 (HDAC2) and DNA-activated protein kinase (DNA-PK). Our findings reveal a novel mechanism for targeted nitrosylation of nuclear proteins and suggest that protein-protein transfer of nitric oxide groups may be a general mechanism in cellular signal transduction.
Assuntos
Proteína Quinase Ativada por DNA/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Histona Desacetilase 2/metabolismo , Proteínas Nucleares/metabolismo , Sirtuína 1/metabolismo , Células Cultivadas , Humanos , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Transdução de Sinais , Sirtuína 1/antagonistas & inibidoresRESUMO
Glutathione (GSH) and bilirubin are prominent endogenous antioxidant cytoprotectants. Despite tissue levels that are thousands of times lower than GSH, bilirubin is effective because of the biosynthetic cycle wherein it is generated from biliverdin by biliverdin reductase (BVR). When bilirubin acts as an antioxidant, it is oxidized to biliverdin, which is immediately reduced by BVR to bilirubin. Why does the body employ both of these 2 distinct antioxidant systems? We show that the water-soluble GSH primarily protects water soluble proteins, whereas the lipophilic bilirubin protects lipids from oxidation. Mice with deletion of heme oxygenase-2, which generates biliverdin, display greater lipid than protein oxidation, while the reverse holds for GSH depletion. RNA interference depletion of BVR increases oxidation of lipids more than protein. Depletion of BVR or GSH augments cell death in an oxidant-specific fashion.
Assuntos
Bilirrubina/fisiologia , Glutationa/fisiologia , Antioxidantes , Bilirrubina/deficiência , Bilirrubina/metabolismo , Biliverdina/metabolismo , Citoproteção , Glutationa/deficiência , Glutationa/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Humanos , Peroxidação de Lipídeos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/deficiência , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Proteínas/metabolismoRESUMO
Inositol pyrophosphates, also designated inositol diphosphates, possess high-energy beta-phosphates that can pyrophosphorylate proteins and regulate various cellular processes. They are formed by a family of inositol hexakisphosphate kinases (IP6Ks). We have created mice with a targeted deletion of IP6K1 in which production of inositol pyrophosphates is markedly diminished. Defects in the mutants indicate important roles for IP6K1 and inositol pyrophosphates in several physiological functions. Male mutant mice are sterile with defects in spermiogenesis. Mutant mice are smaller than wild-type despite normal food intake. The mutants display markedly lower circulating insulin.
Assuntos
Deleção de Genes , Fosfatos de Inositol/metabolismo , Insulina/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Espermatogênese , Animais , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Secreção de Insulina , Masculino , Camundongos , Camundongos Knockout , Fosfotransferases (Aceptor do Grupo Fosfato)/deficiência , Fosfotransferases (Aceptor do Grupo Fosfato)/genéticaRESUMO
Heat-shock proteins (HSPs) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90-IP6K2 binding elicit activation of IP6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy.
Assuntos
Proteínas de Choque Térmico HSP90/fisiologia , Fosfotransferases (Aceptor do Grupo Fosfato)/fisiologia , Motivos de Aminoácidos/genética , Sequência de Aminoácidos , Antineoplásicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Cisplatino/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Células HeLa , Humanos , Dados de Sequência Molecular , Novobiocina/farmacologia , Fosfotransferases (Aceptor do Grupo Fosfato)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Fosfato)/deficiência , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Ligação Proteica/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/fisiologiaRESUMO
In a previous study, we showed that the inositol pyrophosphate diphosphoinositol pentakisphosphate (IP(7)) physiologically phosphorylates mammalian and yeast proteins. We now report that this phosphate transfer reflects pyrophosphorylation. Thus, proteins must be prephosphorylated by ATP to prime them for IP(7) phosphorylation. IP(7) phosphorylates synthetic phosphopeptides but not if their phosphates have been masked by methylation or pyrophosphorylation. Moreover, IP(7) phosphorylated peptides are more acid-labile and more resistant to phosphatases than ATP phosphorylated peptides, indicating a different type of phosphate bond. Pyrophosphorylation may represent a novel mode of signaling to proteins.