Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in <i>IDH2</i>- and <i>TET2</i>-Mutant Acute Myeloid Leukemia

Shih, Alan H.; Meydan, Cem; Shank, Kaitlyn; Garrett-Bakelman, Francine E.; Ward, Patrick S.; Intlekofer, Andrew M.; Nazir, Abbas; Stein, Eytan M.; Knapp, Kristina M.; Glass, Jacob L.; Travins, Jeremy; Straley, Kim; Gliser, Camelia; Mason, Christopher E.; Yen, Katharine; Thompson, Craig B.; Melnick, Ari; Levine, Ross L.

doi:10.1158/2159-8290.cd-16-1049

Cited by 101 publications

(107 citation statements)

References 47 publications

(50 reference statements)

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“…Moreover, new single-base resolution methods are also emerging, which can leverage regional, phased, and long-range information from differentially methylated regions, single molecule sequencing, and new nanopore-based methods [28–30]. Notabl, y these techniques are already leading to new combined therapies and measure in leukemia patients with specifical mutations, like DNMT3A and TET mutations [31–32]. But beyond improving the reliability and accuracy of these low-input methods (which often involve extensive PCR or signal amplification), there is an ongoing debate about the applicability of these methods for improving clinical care.…”

Section: Resultsmentioning

confidence: 99%

Genetic and epigenetic heterogeneity and the impact on cancer relapse

Hassan

Afshinnekoo

et al. 2017

Experimental Hematology

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Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with an exceedingly poor prognosis, showing a 5-year overall survival rate of 40–45% in the young and a 5-year survival rate of below 10% in the elderly (>60y). Though a high percentage of patients enter complete remission following chemotherapeutic intervention, the majority of patients relapse within three years. Such stark prognostic outcomes highlight the need for additional clinical research, basic discovery, and molecular delineation of the etiologies and mechanisms behind responses to therapy that lead to relapse. Here we summarize recent discoveries in tumor heterogeneity at the genetic and epigenetic levels, and their independent molecular trajectories and dynamics in response to therapy. These new discoveries may have significant implications for understanding, monitoring, and treating leukemia and other cancers.

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Section: Resultsmentioning

confidence: 99%

Genetic and epigenetic heterogeneity and the impact on cancer relapse

Hassan

Afshinnekoo

et al. 2017

Experimental Hematology

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“…[11][12][13] In preclinical studies, enasidenib (AG-221/CC-90007), a small-molecule inhibitor of mIDH2, reduced serum 2-HG, DNA hypermethylation, and repressive histone marks and promoted hematopoietic differentiation in R140 and R172 mIDH2 models. [14][15][16][17] In a phase 1/2 clinical trial, enasidenib demonstrated clinical activity in patients with both R140 and R172 mIDH2 relapsed/refractory AML (rrAML) with an overall response rate (ORR) of 40.3%. 18 Here, we analyzed samples from this study to elucidate the mechanisms of action of enasidenib in R140 and R172 mIDH2 rrAML patients and to identify response biomarkers to targeted mIDH2 therapy.…”

Section: Introductionmentioning

confidence: 99%

Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response

Amatangelo¹,

Quek

Shih

et al. 2017

Blood

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• Enasidenib inhibits mIDH2, leading to leukemic cell differentiation with emergence of functional mIDH2 neutrophils in rrAML patients.• RAS pathway mutations and increased mutational burden overall are associated with a decreased response rate to mIDH2 inhibition.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. (Blood. 2017;130(6):732-741)

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“…Although intensive efforts have been made to investigate the cellular functions of IDH-mutant derived D-2HG, and a selective, potent inhibitor of mutant IDH2, AG-221, was shown to be effective in IDH2 mutation-positive acute myeloid leukemia (55,56), its mirrorimage enantiomer L-2HG is less understood. Interestingly, recent studies found that hypoxia dramatically induces production of L-2HG in both normal and malignant cells (57,58).…”

Section: L-2-hydroxyglutarate (L-2hg) Production and Functionmentioning

confidence: 99%

Oxygen availability and metabolic reprogramming in cancer

Xie

Simon

2017

Journal of Biological Chemistry

155

130

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Edited by Ruma BanerjeeHypoxia and dysregulated metabolism are defining features of solid tumors. How cancer cells adapt to low O 2 has been illuminated by numerous studies, with "reprogrammed" metabolism being one of the most important mechanisms. This metabolic reprogramming not only promotes cancer cell plasticity, but also provides novel insights for treatment strategies. As the most studied O 2 "sensor," hypoxia-inducible factor (HIF) is regarded as an important regulator of hypoxia-induced transcriptional responses. This minireview will summarize our current understanding of hypoxia-induced changes in cancer cell metabolism, with an initial focus on HIF-mediated effects, and will highlight how these metabolic alterations affect malignant phenotypes.Molecular oxygen (O 2 ) is a key nutrient required for aerobic metabolism to maintain intracellular bioenergetics and as a substrate in numerous organic and inorganic reactions. Hypoxia, defined by a deficiency in the amount of tissue O 2 levels, occurs in a variety of physiological as well as pathological conditions. Significant research interest in variable O 2 availability in cancers can be traced to the early 20th century, when Otto Warburg found that unlike most normal tissues, cancer cells preferentially "ferment" glucose to pyruvate and then lactate even in the presence of sufficient O 2 to support mitochondrial metabolism (the "Warburg effect"). Although the underlying mechanisms of this observation were not clear and numerous subsequent studies demonstrated certain limitations in this theory (especially the hypothesis that cancer cells develop a defect in mitochondria that leads to impaired aerobic respiration), it opened a new territory of investigating how cancer cells rewire metabolism to adapt to changes in O 2 levels. When facing hypoxia, cells modulate a number of conserved molecular responses, including those regulated by hypoxiainducible factors (HIFs), 3 endoplasmic reticulum (ER) stress responses, mechanistic target of rapamycin signaling, autophagy, and others. These processes promote altered metabolism to match O 2 supply. In this minireview, we will discuss hypoxia responses according to HIF-dependent and -independent pathways and how they impact progression of solid tumors. HIF-dependent metabolic reprogrammingThe HIF hydroxylase systemThe HIF system itself has been reviewed extensively elsewhere (1, 2). Initially identified as a transcriptional regulator bound to a hypoxia-response element (HRE) of the erythropoietin (EPO) gene to promote EPO production, it readily became apparent that this pathway operated much more widely, and it is currently recognized as a key modulator of the transcriptional response to hypoxic stress. Briefly, HIFs are heterodimeric transcription factors consisting of ␣ and ␤ subunits. Three HIF␣ isoforms exist in the mammalian genome (1␣, 2␣, and 3␣), of which HIF1␣ and HIF2␣ are the best characterized. HIF␣ subunits heterodimerize with stable HIF1␤ (or ARNT), recognize, and then bind to HREs ((G/A)CGTG) throughout...

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Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia

Cited by 101 publications

References 47 publications

Genetic and epigenetic heterogeneity and the impact on cancer relapse

Genetic and epigenetic heterogeneity and the impact on cancer relapse

Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response

Oxygen availability and metabolic reprogramming in cancer

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