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Project description:Acute myeloid leukemia (AML) tumors are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 or -2 that result in over-production of the onco-metabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission even in heavily pre-treated AML patients. However, almost all patients eventually relapse with analysis of clinical samples suggesting that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 (Ivosidenib) at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that inhibition of mutant IDH1 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although single agent AG-120 treatment was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells (LSCs) and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to the cytosine analogue hypomethylating agent azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials.
2022-08-17 | GSE201663 | GEO
Project description:Acute myeloid leukemia (AML) tumors are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 or -2 that result in over-production of the onco-metabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission even in heavily pre-treated AML patients. However, almost all patients eventually relapse with analysis of clinical samples suggesting that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 (Ivosidenib) at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that inhibition of mutant IDH1 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although single agent AG-120 treatment was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells (LSCs) and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to the cytosine analogue hypomethylating agent azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials.
2022-08-17 | GSE201662 | GEO
Project description:Acute myeloid leukemia (AML) tumors are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 or -2 that result in over-production of the onco-metabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission even in heavily pre-treated AML patients. However, almost all patients eventually relapse with analysis of clinical samples suggesting that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 (Ivosidenib) at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that inhibition of mutant IDH1 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although single agent AG-120 treatment was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells (LSCs) and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to the cytosine analogue hypomethylating agent azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials.
2022-08-17 | GSE201661 | GEO
Project description:Acute myeloid leukemia (AML) tumors are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 or -2 that result in over-production of the onco-metabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission even in heavily pre-treated AML patients. However, almost all patients eventually relapse with analysis of clinical samples suggesting that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 (Ivosidenib) at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that inhibition of mutant IDH1 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although single agent AG-120 treatment was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells (LSCs) and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to the cytosine analogue hypomethylating agent azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials.
2022-08-17 | GSE201664 | GEO
Project description:Recently, the discovery of biological and clinical properties of mutated isoforms 1 and 2 mutations of isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with acute myeloid leukemia (AML), lead to the development of an individualized treatment strategy. Promoting differentiation and maturation of the malignant clone targeting IDH is an emerging strategy to promote clinical responses in AML. Phase I/II trials have shown evidence of safety, tolerability, and encouraging evidence of efficacy of two small molecule inhibitors targeting IDH2 and IDH1 gene mutations, respectively enasidenib and ivosidenib. In this review, the contribution of IDH1/IDH2 mutations in leukemogenesis and progress of targeted therapeutics in AML will be highlighted.
| S-EPMC8063727 | biostudies-literature
Project description:Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia.
| S-EPMC5155016 | biostudies-literature
Project description:Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known.Experimental Design: Well-characterized primary IDH1MUT, IDH2MUT, and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors.Results:IDH1/2MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2MUT cells was caused by D2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2MUT cells.Conclusions:IDH1/2MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent, such as daunorubicin, whereas concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2MUT AML. Clin Cancer Res; 24(7); 1705-15. ©2018 AACR.
| S-EPMC5884732 | biostudies-literature
Project description: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.
| S-EPMC7849562 | biostudies-literature
Project description:Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.
| S-EPMC5629366 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2015-09-21 | GSE72253 | GEO