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1.
Blood ; 135(7): 463-471, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31841594

RESUMO

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.


Assuntos
Glicina/análogos & derivados , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação/genética , Piridinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue , Feminino , Glicina/efeitos adversos , Glicina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Indução de Remissão , Análise de Sobrevida , Pesquisa Translacional Biomédica , Resultado do Tratamento
2.
Genes Dev ; 28(5): 479-90, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24589777

RESUMO

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2(R140Q) and IDH2(R172K) alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2(R140Q)-expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2(R140Q) in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.


Assuntos
Cardiomiopatias/genética , Glutaratos/metabolismo , Isocitrato Desidrogenase/genética , Mutação , Doenças Neurodegenerativas/genética , Animais , Cardiomiopatias/enzimologia , Cardiomiopatias/patologia , Linhagem Celular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Coração/fisiopatologia , Humanos , Isocitrato Desidrogenase/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/patologia
3.
N Engl J Med ; 378(25): 2386-2398, 2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29860938

RESUMO

BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).


Assuntos
Inibidores Enzimáticos/administração & dosagem , Glicina/análogos & derivados , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Piridinas/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Seguimentos , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Hemoglobinas/análise , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Piridinas/efeitos adversos , Piridinas/farmacocinética , Recidiva , Indução de Remissão , Taxa de Sobrevida , Adulto Jovem
4.
Blood ; 133(7): 676-687, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30510081

RESUMO

Approximately 8% to 19% of patients with acute myeloid leukemia (AML) have isocitrate dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), which leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase 1/2 study evaluated enasidenib doses of 50 to 650 mg/d, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies. Overall, 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8% (95% confidence interval [CI], 32.2-45.7). Median overall survival was 8.8 months (95% CI, 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%) or were refractory to intensive (37.5%) or nonintensive (43.2%) therapies. Sixty-six (43.1%) red blood cell transfusion-dependent and 53 (40.2%) platelet transfusion-dependent patients achieved transfusion independence. The magnitude of 2-HG reduction on study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered at www.clinicaltrials.gov as #NCT01915498.


Assuntos
Aminopiridinas/uso terapêutico , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Mutantes/antagonistas & inibidores , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Triazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Feminino , Seguimentos , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Adulto Jovem
5.
Nature ; 513(7516): 110-4, 2014 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-25043045

RESUMO

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Diferenciação Celular/genética , Colangiocarcinoma/patologia , Fator 4 Nuclear de Hepatócito/antagonistas & inibidores , Hepatócitos/patologia , Isocitrato Desidrogenase/genética , Proteínas Mutantes/metabolismo , Animais , Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos/enzimologia , Ductos Biliares Intra-Hepáticos/patologia , Divisão Celular/genética , Linhagem da Célula/genética , Colangiocarcinoma/enzimologia , Colangiocarcinoma/genética , Modelos Animais de Doenças , Feminino , Glutaratos/metabolismo , Fator 4 Nuclear de Hepatócito/biossíntese , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Mutantes/genética , Mutação/genética , Metástase Neoplásica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Células-Tronco/patologia , Proteínas ras/genética , Proteínas ras/metabolismo
6.
Genes Dev ; 26(18): 2038-49, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22925884

RESUMO

Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knock-in (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP(+)/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1α (Hif1α) and up-regulated Hif1α target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects.


Assuntos
Membrana Basal/patologia , Colágeno/metabolismo , Glutaratos/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Animais , Membrana Basal/metabolismo , Encéfalo/citologia , Encéfalo/patologia , Técnicas de Introdução de Genes , Genótipo , Glioma/patologia , Camundongos , Mutação , Estabilidade Proteica , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico
7.
Cancer ; 125(4): 541-549, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30422308

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. METHODS: Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 × 106 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. RESULTS: Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. CONCLUSIONS: Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Glutaratos/sangue , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/mortalidade , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
8.
Blood ; 130(6): 732-741, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28588019

RESUMO

Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 (IDH2) occur in many cancers, including ∼12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Glutaratos/metabolismo , Hematopoese/efeitos dos fármacos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Triazinas/uso terapêutico , Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Feminino , Frequência do Gene , Glutaratos/antagonistas & inibidores , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Triazinas/farmacologia
9.
Blood ; 130(6): 722-731, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28588020

RESUMO

Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Triazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/patologia , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Triazinas/efeitos adversos , Triazinas/farmacocinética , Adulto Jovem
10.
Blood ; 125(2): 296-303, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25398940

RESUMO

Mutations of IDH1 and IDH2, which produce the oncometabolite 2-hydroxyglutarate (2HG), have been identified in several tumors, including acute myeloid leukemia. Recent studies have shown that expression of the IDH mutant enzymes results in high levels of 2HG and a block in cellular differentiation that can be reversed with IDH mutant-specific small-molecule inhibitors. To further understand the role of IDH mutations in cancer, we conducted mechanistic studies in the TF-1 IDH2 R140Q erythroleukemia model system and found that IDH2 mutant expression caused both histone and genomic DNA methylation changes that can be reversed when IDH2 mutant activity is inhibited. Specifically, histone hypermethylation is rapidly reversed within days, whereas reversal of DNA hypermethylation proceeds in a progressive manner over the course of weeks. We identified several gene signatures implicated in tumorigenesis of leukemia and lymphoma, indicating a selective modulation of relevant cancer genes by IDH mutations. As methylation of DNA and histones is closely linked to mRNA expression and differentiation, these results indicate that IDH2 mutant inhibition may function as a cancer therapy via histone and DNA demethylation at genes involved in differentiation and tumorigenesis.


Assuntos
Metilação de DNA/genética , Inibidores Enzimáticos/farmacologia , Histonas/genética , Isocitrato Desidrogenase/genética , Mutação , Transcriptoma/efeitos dos fármacos , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Cromatografia Líquida , Histonas/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/genética , Compostos de Fenilureia/farmacologia , Análise de Componente Principal , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfonamidas/farmacologia , Espectrometria de Massas em Tandem
11.
J Inherit Metab Dis ; 39(6): 807-820, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27469509

RESUMO

D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus. Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice; treatment withdrawal resulted in deterioration of cardiac function. We observed differential expression of multiple genes and metabolites that are associated with cardiomyopathy, which were largely reversed by AGI-026. These findings demonstrate the potential therapeutic benefit of an IDH2R140Q inhibitor in patients with D2HGA type II.


Assuntos
Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Isocitrato Desidrogenase/antagonistas & inibidores , Mutação/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Encefalopatias Metabólicas Congênitas/genética , Modelos Animais de Doenças , Isocitrato Desidrogenase/genética , Camundongos , Mutação/genética
13.
Blood ; 121(24): 4917-24, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23641016

RESUMO

Cancer-associated isocitrate dehydrogenase (IDH) mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of 2HG has not been established. We studied whether 2HG measurements in acute myeloid leukemia (AML) patients correlate with IDH mutations, and whether diagnostic or remission 2HG measurements predict survival. Sera from 223 de novo AML patients were analyzed for 2HG concentration by reverse-phase liquid chromatography-mass spectrometry. Pretreatment 2HG levels ranged from 10 to 30 000 ng/mL and were elevated in IDH-mutants (median, 3004 ng/mL), compared to wild-type IDH (median, 61 ng/mL) (P < .0005). 2HG levels did not differ among IDH1 or IDH2 allelic variants. In receiver operating characteristic analysis, a discriminatory level of 700 ng/mL optimally segregated patients with and without IDH mutations, and on subsequent mutational analysis of the 13 IDH wild-type samples with 2HG levels >700 ng/mL, 9 were identified to have IDH mutations. IDH-mutant patients with 2HG levels >200 at complete remission had shorter overall survival compared to 2HG ≤200 ng/mL (hazard ratio, 3.9; P = .02). We establish a firm association between IDH mutations and serum 2HG concentration in AML, and confirm that serum oncometabolite measurements provide useful diagnostic and prognostic information that can improve patient selection for IDH-targeted therapies.


Assuntos
Glutaratos/sangue , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade
14.
Nature ; 462(7274): 739-44, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-19935646

RESUMO

Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glutaratos/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Arginina/genética , Neoplasias Encefálicas/patologia , Domínio Catalítico , Linhagem Celular , Cristalografia por Raios X , Progressão da Doença , Ensaios Enzimáticos , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Histidina/genética , Histidina/metabolismo , Humanos , Ácidos Cetoglutáricos/metabolismo , Modelos Moleculares , Mutação/genética , Conformação Proteica
15.
Oncologist ; 19(6): 602-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24760710

RESUMO

Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR+) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR+ breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme.


Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Isocitrato Desidrogenase/genética , Neoplasias Hormônio-Dependentes/genética , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adenocarcinoma/urina , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Neoplasias da Mama/urina , Feminino , Glutaratos/sangue , Glutaratos/urina , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Hormônio-Dependentes/sangue , Neoplasias Hormônio-Dependentes/patologia , Neoplasias Hormônio-Dependentes/urina
16.
Blood ; 120(23): 4649-52, 2012 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-23074281

RESUMO

Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glutaratos/metabolismo , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/metabolismo , Doença Aguda , Idoso , Azacitidina/administração & dosagem , Azacitidina/análogos & derivados , Citarabina/administração & dosagem , Análise Mutacional de DNA , Decitabina , Feminino , Glutaratos/sangue , Glutaratos/urina , Células Precursoras de Granulócitos/metabolismo , Humanos , Idarubicina/administração & dosagem , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Fatores de Tempo
17.
Nat Chem Biol ; 8(10): 839-47, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22922757

RESUMO

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.


Assuntos
Biopolímeros/metabolismo , Transformação Celular Neoplásica , Ativadores de Enzimas/farmacologia , Piruvato Quinase/metabolismo , Animais , Biopolímeros/química , Western Blotting , Proliferação de Células , Humanos , Camundongos , Neoplasias/enzimologia , Neoplasias/metabolismo , Neoplasias/patologia , Piruvato Quinase/química
18.
Nat Med ; 29(6): 1358-1363, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37248298

RESUMO

D-2-hydroxyglutaric aciduria type II (D2HGA2) is a severe inborn disorder of metabolism caused by heterozygous R140 mutations in the IDH2 (isocitrate dehydrogenase 2) gene. Here we report the results of treatment of two children with D2HGA2, one of whom exhibited severe dilated cardiomyopathy, with the selective mutant IDH2 enzyme inhibitor enasidenib. In both children, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. At doses of 50 mg and 60 mg per day, no side effects were observed, except for asymptomatic hyperbilirubinemia. For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. Treatment of the child with cardiomyopathy led to therapy-coordinated changes in serum phospholipid levels, which were partly recapitulated in cultured fibroblasts, associated with complex effects on lipid and redox-related gene pathways. These findings indicate that targeted inhibition of a mutant enzyme can partly reverse the pathology of a chronic neurometabolic genetic disorder.


Assuntos
Cardiomiopatias , Isocitrato Desidrogenase , Criança , Humanos , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/genética , Inibidores Enzimáticos/efeitos adversos , Células Germinativas/metabolismo , Isocitrato Desidrogenase/metabolismo , Mutação/genética
19.
J Neurooncol ; 107(1): 197-205, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22015945

RESUMO

Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(-)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography-mass spectrometry (LC-MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC-MS (r (2) = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r ( 2 ) = 0.59; P = 0.026). In conclusion, water-suppressed proton ((1)H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.


Assuntos
Biomarcadores Tumorais/metabolismo , Glioma/genética , Glioma/metabolismo , Glutaratos/metabolismo , Isocitrato Desidrogenase/genética , Espectroscopia de Ressonância Magnética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Cromatografia Líquida , DNA de Neoplasias/genética , Feminino , Seguimentos , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Estudos Prospectivos , Adulto Jovem
20.
Cancer Cell ; 4(3): 223-38, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14522256

RESUMO

Increased Myc gene copy number is observed in human prostate cancer. To define Myc's functional role, we generated transgenic mice expressing human c-Myc in the mouse prostate. All mice developed murine prostatic intraepithelial neoplasia followed by invasive adenocarcinoma. Microarray-based expression profiling identified a Myc prostate cancer expression signature, which included the putative human tumor suppressor NXK3.1. Human prostate tumor databases revealed modules of human genes that varied in concert with the Myc prostate cancer signature. This module includes the Pim-1 kinase, a gene known to cooperate with Myc in tumorigenesis, and defines a subset of human, "Myc-like" human cancers. This approach illustrates how genomic technologies can be applied to mouse cancer models to guide evaluation of human tumor databases.


Assuntos
Adenocarcinoma/fisiopatologia , Genes myc/fisiologia , Próstata/fisiopatologia , Neoplasias da Próstata/fisiopatologia , Androgênios/metabolismo , Animais , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes myc/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neovascularização Patológica , Orquiectomia , Neoplasia Prostática Intraepitelial/fisiopatologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-pim-1 , Fatores de Transcrição/metabolismo
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