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1.
Haematologica ; 106(2): 565-573, 2021 02 01.
Article in English | MEDLINE | ID: mdl-32241846

ABSTRACT

Mutant IDH1 (mIDH1) inhibitors have shown single-agent activity in relapsed/refractory AML, though most patients eventually relapse. We evaluated the efficacy and molecular mechanism of the combination treatment with azacitidine, which is currently the standard of care in older AML patients, and mIDH1 inhibitor BAY1436032. Both compounds were evaluated in vivo as single agents and in combination with sequential (azacitidine, followed by BAY1436032) or simultaneous application in two human IDH1 mutated AML xenograft models. Combination treatment significantly prolonged survival compared to single agent or control treatment (P<.005). The sequential combination treatment depleted leukemia stem cells (LSC) by 470-fold. Interestingly, the simultaneous combination treatment depleted LSCs by 33,150-fold compared to control mice. This strong synergy is mediated through inhibition of MAPK/ERK and RB/E2F signaling. Our data strongly argues for the concurrent application of mIDH1 inhibitors and azacitidine and predicts improved outcome of this regimen in IDH1 mutated AML patients.


Subject(s)
Azacitidine , Leukemia, Myeloid, Acute , Aged , Aniline Compounds , Animals , Benzimidazoles , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mice
2.
Leukemia ; 34(2): 416-426, 2020 02.
Article in English | MEDLINE | ID: mdl-31586149

ABSTRACT

Mutations in isocitrate dehydrogenase 1 (IDH1) are found in 6% of AML patients. Mutant IDH produces R-2-hydroxyglutarate (R-2HG), which induces histone- and DNA-hypermethylation through the inhibition of epigenetic regulators, thus linking metabolism to tumorigenesis. Here we report the biochemical characterization, in vivo antileukemic effects, structural binding, and molecular mechanism of the inhibitor HMS-101, which inhibits the enzymatic activity of mutant IDH1 (IDH1mut). Treatment of IDH1mut primary AML cells reduced 2-hydroxyglutarate levels (2HG) and induced myeloid differentiation in vitro. Co-crystallization of HMS-101 and mutant IDH1 revealed that HMS-101 binds to the active site of IDH1mut in close proximity to the regulatory segment of the enzyme in contrast to other IDH1 inhibitors. HMS-101 also suppressed 2HG production, induced cellular differentiation and prolonged survival in a syngeneic mutant IDH1 mouse model and a patient-derived human AML xenograft model in vivo. Cells treated with HMS-101 showed a marked upregulation of the differentiation-associated transcription factors CEBPA and PU.1, and a decrease in cell cycle regulator cyclin A2. In addition, the compound attenuated histone hypermethylation. Together, HMS-101 is a unique inhibitor that binds to the active site of IDH1mut directly and is active in IDH1mut preclinical models.


Subject(s)
Binding Sites/drug effects , Enzyme Inhibitors/pharmacology , Isocitrate Dehydrogenase/antagonists & inhibitors , Mutation/drug effects , Animals , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Differentiation/drug effects , DNA Methylation/drug effects , Histones/metabolism , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins/metabolism , Trans-Activators/metabolism , Up-Regulation/drug effects
3.
Exp Hematol ; 43(8): 685-97, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26032956

ABSTRACT

The discovery of oncogenic mutations in isocitrate dehydrogenase (IDH) enzymes has highlighted the delicate interplay of metabolism, cellular signaling, and transcriptional regulation that was off-focus for some time in the genomic era. Although IDH inhibitors are being evaluated for clinical efficacy, an in-depth understanding of disease pathogenesis linked to IDH mutations is required to develop rational combination treatments and to be evaluated in the clinic. To gain such an understanding, several questions need to be addressed: Why do IDH mutations occur selectively in subsets of a disease entity although they are found to be present in a very heterogeneous set of unrelated tumors? Why are 2-hydroxyglutarate-producing tumors specifically selected for the R-enantiomer and not for the S-enantiomer? Are the changes in 2-hydroxyglutarate-induced DNA methylation primary or secondary alterations in tumorigenesis? What are the roles of hypoxia-inducible factor (HIF) and its prolyl 4-hydroxylases in IDH-mutant tumors? Here, we address these questions and discuss the consequences for basic and clinical research related to IDH-mutant tumors.


Subject(s)
Enzyme Inhibitors/therapeutic use , Hematologic Neoplasms , Isocitrate Dehydrogenase , Mutation , Animals , DNA Methylation/drug effects , DNA Methylation/genetics , Glutarates/metabolism , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/enzymology , Hematologic Neoplasms/genetics , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Stereoisomerism
4.
J Clin Virol ; 61(1): 125-31, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24954472

ABSTRACT

BACKGROUND: We recently reported significant association of non-polio enteroviruses (NPEVs) with acute diarrhea in children. Persistent diarrhea (PD) remains a major cause of morbidity and mortality in infants below two years of age in developing countries. Understanding age-dependent frequency and duration of NPEV infections is important to determine their association with persistent diarrhea and disease burden. OBJECTIVES: A cohort of 140 infants was followed for 6 months to 2 years of age to determine the frequency, duration, and association with PD of NPEV infections in comparison with rotavirus and other agents. STUDY DESIGN: Stool samples were collected every 14 days, and diarrheal episodes and their duration were recorded. Enteroviruses were characterized by RT-PCR and VP1 gene sequence analysis, rotavirus by electropherotyping, and other agents by PCR. RESULTS: Of 4545 samples, negative for oral polio vaccine strains, 3907 (85.96%) and 638 (14.04%) were NPEV-negative and NPEV-positive, respectively, representing 403 (8.87%) infection episodes. About 68% of NPEV infections occurred during the first year with every child having at least one episode lasting between four days and four months. Approximately 38% and 22% of total diarrheal episodes were positive for NPEV and RV, respectively. While about 18% of NPEV infection episodes were associated with diarrhea, 6% being persistent, 13% of total diarrheal episodes were persistent involving infections by monotype NPEV strains or sequential infections by multiple strains and other agents. CONCLUSIONS: This is the first report revealing NPEVs as the single most frequently and persistently detected viral pathogen in every PD episode.


Subject(s)
Diarrhea/virology , Enterovirus Infections/virology , Child, Preschool , Cohort Studies , Enterovirus , Feces/virology , Female , Follow-Up Studies , Humans , India , Infant , Infant, Newborn , Male , Molecular Sequence Data , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA , Viral Structural Proteins/genetics
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