Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation

Wang, Fang; Travins, Jeremy; DeLaBarre, Byron; Penard-Lacronique, Virginie; Schalm, Stefanie; Hansen, Erica; Straley, Kimberly; Kernytsky, Andrew; Liu, Wei; Gliser, Camelia; Yang, Hua; Größ, Stefan; Artin, Erin; Saada, Véronique; Mylonás, Elena; Quivoron, Cyril; Popovici‐Muller, Janeta; Saunders, Jeffrey O.; Salituro, Francesco G.; Yan, Shunqi; Murray, Stuart; Wei, Wentao; Gao, Yi; Dang, Lenny; Dorsch, Marion; Agresta, Sam; Schenkein, David P.; Biller, Scott A.; Su, Shinsan M.; Botton, Stéphane de; Yen, Katharine

doi:10.1126/science.1234769

Cited by 737 publications

(667 citation statements)

References 31 publications

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“…The altered methylation patterns thereby promote dedifferentiation of the tumors. Consequently, the specific inhibition of the mutant isocitrate dehydrogenase enzyme normalizes the methylation pattern in the tumor and leads to differentiation of tumor cells and inhibition of tumor proliferation [207][208][209]. Mutant isocitrate dehydrogenase inhibitors thereby constitute an ideal case of a drug target, since the mutation is only present in the tumor but not in any healthy tissue throughout the body.…”

Section: Therapeutic Opportunities Of Cancer Metabolismmentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

101

104

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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Section: Therapeutic Opportunities Of Cancer Metabolismmentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

101

104

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“…This epigenetic dysregulation is associated with impairment of cellular differentiation in multiple cell types, including hematopoietic cells (15)(16)(17)(18)(19)(20)(21). AGI-6780, a selective sulfonamide inhibitor of the mutant IDH2 enzyme, lowered 2HG levels and induced differentiation of TF-1 erythroleukemia cells and primary human AML cells harboring the IDH2 R140Q mutation (17), providing in vitro evidence that inhibition of the mutant IDH2 enzyme can reverse some of the phenotypic changes it induces. Others have reported similar findings with mutant IDH1 inhibitor tool compounds in AML models (22).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, its poor in vitro liver microsomal stability translated to high clearance in vivo. X-ray crystallography revealed binding of a compound 1 molecule to an allosteric site located within the homodimer interface of the IDH2 R140Q -mutant enzyme, to which the selective sulfonamide inhibitor AGI-6780 also binds (17). These insights guided optimization of the substituents around the triazine core.…”

Section: Introductionmentioning

confidence: 99%

“…2HG accumulation competitively inhibits αKG-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family that regulate cellular epigenetic status (12)(13)(14)(15). This epigenetic dysregulation is associated with impairment of cellular differentiation in multiple cell types, including hematopoietic cells (15)(16)(17)(18)(19)(20)(21). AGI-6780, a selective sulfonamide inhibitor of the mutant IDH2 enzyme, lowered 2HG levels and induced differentiation of TF-1 erythroleukemia cells and primary human AML cells harboring the IDH2 R140Q mutation (17), providing in vitro evidence that inhibition of the mutant IDH2 enzyme can reverse some of the phenotypic changes it induces.…”

Section: Introductionmentioning

confidence: 99%

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AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

et al. 2017

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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 IDH2 R140Q -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.

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“…68 In addition, work is underway to identify specific inhibitors of mutated components of the epigenome, and such inhibitors are now in early-phase clinical trials. 69,70 The recent observation of the induction of cellular differentiation by an IDH1-mutant inhibitor in a refractory AML xenograft model and the candidacy of TET2 mutations as a predictive biomarker for response to hypomethylating agents in myelodysplastic syndromes (MDS) patients are also of some interest. 71,72 IMPACT OF PATIENT-RELATED FACTORS At present the very considerable advances in the understanding of the genomic landscape in MF appear not to have been validated sufficiently for adaptation in treatment algorithms to assess candidacy for allo-SCT compared to conventional therapy.…”

Section: Impact Of Targeting the Jak/signal Transducers And Activatormentioning

confidence: 99%

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

Tamari

Mughal

Rondelli

et al. 2015

Bone Marrow Transplant

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At present, allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment for patients with myelofibrosis (MF). Unfortunately a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at time of diagnosis. The approval of the first JAK inhibitor, Ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support to assess the drug’s candidacy in the peri-transplant period. The drug’s precise impact on clinical outcome following allo-SCT is currently not known; nor is the drug’s long term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who are undergoing allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology’s meeting in New Orleans, USA, on 6th December 2013 and the European Hematology Association meeting in Milan, Italy on 13th June 2014. This document summarizes the results of these efforts.

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Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation

Cited by 737 publications

References 31 publications

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Organ-Specific Cancer Metabolism and Its Potential for Therapy

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

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