Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Más filtros

Bases de datos
Tipo del documento
Intervalo de año de publicación
1.
Nature ; 513(7516): 110-4, 2014 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-25043045

RESUMEN

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.


Asunto(s)
Neoplasias de los Conductos Biliares/patología , Diferenciación Celular/genética , Colangiocarcinoma/patología , Factor Nuclear 4 del Hepatocito/antagonistas & inhibidores , Hepatocitos/patología , Isocitrato Deshidrogenasa/genética , Proteínas Mutantes/metabolismo , Animales , Neoplasias de los Conductos Biliares/enzimología , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/enzimología , Conductos Biliares Intrahepáticos/patología , División Celular/genética , Linaje de la Célula/genética , Colangiocarcinoma/enzimología , Colangiocarcinoma/genética , Modelos Animales de Enfermedad , Femenino , Glutaratos/metabolismo , Factor Nuclear 4 del Hepatocito/biosíntesis , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Isocitrato Deshidrogenasa/metabolismo , Masculino , Ratones , Ratones Transgénicos , Proteínas Mutantes/genética , Mutación/genética , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Células Madre/patología , Proteínas ras/genética , Proteínas ras/metabolismo
2.
Cancer ; 125(4): 541-549, 2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30422308

RESUMEN

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.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Glutaratos/sangre , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/mortalidad , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Adulto Joven
3.
Proc Natl Acad Sci U S A ; 113(5): 1387-92, 2016 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-26787889

RESUMEN

Gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) are key drivers of hematopoietic malignancies. Although these mutations are most commonly associated with myeloid diseases, they also occur in malignancies of the T-cell lineage. To investigate their role in these diseases and provide tractable disease models for further investigation, we analyzed the T-cell compartment in a conditional knock-in (KI) mouse model of mutant Idh1. We observed the development of a spontaneous T-cell acute lymphoblastic leukemia (T-ALL) in these animals. The disease was transplantable and maintained expression of mutant IDH1. Whole-exome sequencing revealed the presence of a spontaneous activating mutation in Notch1, one of the most common mutations in human T-ALL, suggesting Idh1 mutations may have the capacity to cooperate with Notch1 to drive T-ALL. To further investigate the Idh1 mutation as an oncogenic driver in the T-cell lineage, we crossed Idh1-KI mice with conditional Trp53 null mice, a well-characterized model of T-cell malignancy, and found that T-cell lymphomagenesis was accelerated in mice bearing both mutations. Because both IDH1 and p53 are known to affect cellular metabolism, we compared the requirements for glucose and glutamine in cells derived from these tumors and found that cells bearing the Idh1 mutation have an increased dependence on both glucose and glutamine. These data suggest that mutant IDH1 contributes to malignancy in the T-cell lineage and may alter the metabolic profile of malignant T cells.


Asunto(s)
Isocitrato Deshidrogenasa/genética , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animales , Exoma , Genes p53 , Ratones
4.
Proc Natl Acad Sci U S A ; 112(9): 2829-34, 2015 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-25730874

RESUMEN

Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d-2-hydroxyglutarate (d-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.


Asunto(s)
Condrocitos , Encondromatosis , Regulación Enzimológica de la Expresión Génica , Isocitrato Deshidrogenasa , Mutación Missense , Sustitución de Aminoácidos , Animales , Condrocitos/enzimología , Condrocitos/patología , Colágeno Tipo II/biosíntesis , Colágeno Tipo II/genética , Encondromatosis/enzimología , Encondromatosis/genética , Encondromatosis/patología , Glutaratos/efectos adversos , Glutaratos/farmacología , Humanos , Isocitrato Deshidrogenasa/biosíntesis , Isocitrato Deshidrogenasa/genética , Ratones , Ratones Mutantes
5.
Blood ; 125(2): 296-303, 2015 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-25398940

RESUMEN

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.


Asunto(s)
Metilación de ADN/genética , Inhibidores Enzimáticos/farmacología , Histonas/genética , Isocitrato Deshidrogenasa/genética , Mutación , Transcriptoma/efectos de los fármacos , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Cromatografía Liquida , Histonas/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/genética , Compuestos de Fenilurea/farmacología , Análisis de Componente Principal , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sulfonamidas/farmacología , Espectrometría de Masas en Tándem
6.
J Inherit Metab Dis ; 39(6): 807-820, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27469509

RESUMEN

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.


Asunto(s)
Encefalopatías Metabólicas Innatas/tratamiento farmacológico , Cardiomiopatías/tratamiento farmacológico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Mutación/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Encefalopatías Metabólicas Innatas/genética , Modelos Animales de Enfermedad , Isocitrato Deshidrogenasa/genética , Ratones , Mutación/genética
8.
J Biol Chem ; 289(20): 13717-25, 2014 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-24668804

RESUMEN

Two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases. In this study, we investigated the mechanism of action of a newly discovered inhibitor, ML309, using biochemical, cellular, and biophysical approaches. Substrate binding and product inhibition studies helped to further elucidate the IDH1 R132H catalytic cycle. This rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active (IC50 = 68 nm), whereas the (-) isomer is over 400-fold less active (IC50 = 29 µm) for IDH1 R132H inhibition. IDH1 R132C was similarly inhibited by (+)-ML309. WT IDH1 was largely unaffected by (+)-ML309 (IC50 >36 µm). Kinetic analyses combined with microscale thermophoresis and surface plasmon resonance indicate that this reversible inhibitor binds to IDH1 R132H competitively with respect to α-ketoglutarate and uncompetitively with respect to NADPH. A reaction scheme for IDH1 R132H inhibition by ML309 is proposed in which ML309 binds to IDH1 R132H after formation of the IDH1 R132H NADPH complex. ML309 was also able to inhibit 2-HG production in a glioblastoma cell line (IC50 = 250 nm) and had minimal cytotoxicity. In the presence of racemic ML309, 2-HG levels drop rapidly. This drop was sustained until 48 h, at which point the compound was washed out and 2-HG levels recovered.


Asunto(s)
Acetamidas/farmacología , Bencimidazoles/farmacología , Fenómenos Biofísicos , Inhibidores Enzimáticos/farmacología , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/genética , Mutación , Acetamidas/metabolismo , Acetamidas/farmacocinética , Animales , Bencimidazoles/metabolismo , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Humanos , Isocitrato Deshidrogenasa/metabolismo , Ratones , Proteínas Mutantes/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología
9.
Blood ; 121(24): 4917-24, 2013 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-23641016

RESUMEN

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.


Asunto(s)
Glutaratos/sangre , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/genética , Mutación Missense , Adolescente , Adulto , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Humanos , Isocitrato Deshidrogenasa/metabolismo , Masculino , Persona de Mediana Edad
10.
Oncologist ; 19(6): 602-7, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24760710

RESUMEN

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.


Asunto(s)
Adenocarcinoma/genética , Neoplasias de la Mama/genética , Isocitrato Deshidrogenasa/genética , Neoplasias Hormono-Dependientes/genética , Adenocarcinoma/sangre , Adenocarcinoma/patología , Adenocarcinoma/orina , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Neoplasias de la Mama/orina , Femenino , Glutaratos/sangre , Glutaratos/orina , Humanos , Persona de Mediana Edad , Mutación , Neoplasias Hormono-Dependientes/sangre , Neoplasias Hormono-Dependientes/patología , Neoplasias Hormono-Dependientes/orina
11.
Blood ; 120(23): 4649-52, 2012 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-23074281

RESUMEN

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.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glutaratos/metabolismo , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , Enfermedad Aguda , Anciano , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Citarabina/administración & dosificación , Análisis Mutacional de ADN , Decitabina , Femenino , Glutaratos/sangre , Glutaratos/orina , Células Precursoras de Granulocitos/metabolismo , Humanos , Idarrubicina/administración & dosificación , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mieloide/genética , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Factores de Tiempo
12.
Proc Natl Acad Sci U S A ; 108(46): 18843-8, 2011 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-21976485

RESUMEN

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC(50), 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.


Asunto(s)
Aminopiridinas/uso terapéutico , Benzodioxoles/uso terapéutico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Mutación , Bronquios/citología , Línea Celular , Células Cultivadas , Química Farmacéutica/métodos , Cloruros/química , Fibrosis Quística/genética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Células Epiteliales/citología , Homocigoto , Humanos , Técnicas In Vitro , Pulmón/patología , Modelos Genéticos
13.
Oncologist ; 17(1): 72-9, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22180306

RESUMEN

Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad-based mutational profiling for patients diagnosed with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site-specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.


Asunto(s)
Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/genética , Neoplasias de la Vesícula Biliar/genética , Isocitrato Deshidrogenasa/genética , Mutación , Adolescente , Adulto , Neoplasias de los Conductos Biliares/enzimología , Niño , Colangiocarcinoma/enzimología , Femenino , Neoplasias de la Vesícula Biliar/enzimología , Genotipo , Humanos , Isocitrato Deshidrogenasa/metabolismo , Masculino , Persona de Mediana Edad , Adulto Joven
14.
ACS Med Chem Lett ; 11(2): 101-107, 2020 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-32071674

RESUMEN

Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.

15.
ACS Med Chem Lett ; 9(4): 300-305, 2018 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-29670690

RESUMEN

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.

16.
Cancer Discov ; 7(5): 478-493, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28193778

RESUMEN

Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies.Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478-93. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Shih et al., p. 494This article is highlighted in the In This Issue feature, p. 443.


Asunto(s)
Aminopiridinas/farmacología , Antineoplásicos/farmacología , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/genética , Triazinas/farmacología , Animales , Línea Celular Tumoral , Humanos , Isocitrato Deshidrogenasa/genética , Ratones , Mutación , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Neuro Oncol ; 18(2): 283-90, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26691210

RESUMEN

BACKGROUND: The majority of WHO grades II and III gliomas harbor a missense mutation in the metabolic gene isocitrate dehydrogenase (IDH) and accumulate the metabolite R-2-hydroxyglutarate (R-2HG). Prior studies showed that this metabolite can be detected in vivo using proton magnetic-resonance spectroscopy (MRS), but the sensitivity of this methodology and its clinical implications are unknown. METHODS: We developed an MR imaging protocol to integrate 2HG-MRS into routine clinical glioma imaging and examined its performance in 89 consecutive glioma patients. RESULTS: Detection of 2-hydroxyglutarate (2HG) in IDH-mutant gliomas was closely linked to tumor volume, with sensitivity ranging from 8% for small tumors (<3.4 mL) to 91% for larger tumors (>8 mL). In patients undergoing 2HG-MRS prior to surgery, tumor levels of 2HG corresponded with tumor cellularity but not with tumor grade or mitotic index. Cytoreductive therapy resulted in a gradual decrease in 2HG levels with kinetics that closely mirrored changes in tumor volume. CONCLUSIONS: Our study demonstrates that 2HG-MRS can be linked with routine MR imaging to provide quantitative measurements of 2HG in glioma and may be useful as an imaging biomarker to monitor the abundance of IDH-mutant tumor cells noninvasively during glioma therapy and disease monitoring.


Asunto(s)
Neoplasias Encefálicas/patología , Glioma/patología , Glutaratos/metabolismo , Isocitrato Deshidrogenasa/metabolismo , Guías de Práctica Clínica como Asunto , Espectroscopía de Protones por Resonancia Magnética/métodos , Adulto , Anciano , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Femenino , Estudios de Seguimiento , Glioma/metabolismo , Glioma/terapia , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Adulto Joven
18.
Cancer Cell ; 30(2): 337-348, 2016 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-27424808

RESUMEN

Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Daño del ADN , Reparación del ADN , Proteínas de Unión al ADN/genética , Células Madre Hematopoyéticas/enzimología , Isocitrato Deshidrogenasa/genética , Proteínas Proto-Oncogénicas/genética , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de Unión al ADN/metabolismo , Dioxigenasas , Regulación hacia Abajo , Células Madre Hematopoyéticas/citología , Humanos , Isocitrato Deshidrogenasa/metabolismo , Ratones , Mutación , Proteínas Proto-Oncogénicas/metabolismo
19.
Cell Stem Cell ; 14(3): 329-41, 2014 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-24440599

RESUMEN

Mutations in the metabolic enzymes isocitrate dehydrogenase-1 (IDH1) and IDH2 that produce the oncometabolite D-2-hydroxyglutarate (2-HG) occur frequently in human acute myeloid leukemia (AML). 2-HG modulates numerous biological pathways implicated in malignant transformation, but the contribution of mutant IDH proteins to maintenance and progression of AML in vivo is currently unknown. To answer this crucial question we have generated transgenic mice that express IDH2(R140Q) in an on/off- and tissue-specific manner using a tetracycline-inducible system. We found that IDH2(R140Q) can cooperate with overexpression of HoxA9 and Meis1a and with mutations in FMS-like tyrosine kinase 3 (FLT3) to drive acute leukemia in vivo. Critically, we show that genetic deinduction of mutant IDH2 in leukemic cells in vivo has profound effects on their growth and/or maintenance. Our data demonstrate the proto-oncogenic role of mutant IDH2 and support its relevance as a therapeutic target for the treatment of human AML.


Asunto(s)
Carcinogénesis/patología , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/patología , Mutación/genética , Oncogenes , Animales , Médula Ósea/patología , Carcinogénesis/genética , Diferenciación Celular , Proliferación Celular , Transformación Celular Neoplásica/patología , Modelos Animales de Enfermedad , Células Eritroides/metabolismo , Células Eritroides/patología , Hematopoyesis , Células Madre Hematopoyéticas/patología , Proteínas de Homeodominio/metabolismo , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mieloide Aguda/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Proteínas de Neoplasias/metabolismo , Bazo/patología , Transcripción Genética , Tirosina Quinasa 3 Similar a fms/metabolismo
20.
Clin Cancer Res ; 20(7): 1884-90, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24478380

RESUMEN

PURPOSE: Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in intrahepatic cholangiocarcinoma. EXPERIMENTAL DESIGN: We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort. Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status, tumor burden, and a number of clinical variables. RESULTS: Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1/2-mutant (median, 478 ng/mL) versus IDH1/2-wild-type (median, 118 ng/mL) tumors (P < 0.001). This significance was maintained in the validation cohort (343 ng/mL vs. 55 ng/mL, P < 0.0001) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases (P < 0.05). Serum 2HG levels ≥170 ng/mL could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG. CONCLUSIONS: This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden. Clin Cancer Res; 20(7); 1884-90. ©2014 AACR.


Asunto(s)
Neoplasias de los Conductos Biliares/genética , Biomarcadores de Tumor/sangre , Colangiocarcinoma/genética , Glutaratos/sangre , Isocitrato Deshidrogenasa/genética , Adulto , Anciano , Neoplasias de los Conductos Biliares/sangre , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/sangre , Colangiocarcinoma/patología , Femenino , Humanos , Isocitrato Deshidrogenasa/sangre , Masculino , Persona de Mediana Edad , Mutación
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA