scholarly journals PF225 AZACITIDINE (AZA) ENHANCES ANTILEUKEMIC ACTIVITY OF THE MDM2 INHIBITOR MILADEMETAN IN TP53 WILD-TYPE ACUTE MYELOID LEUKEMIA (AML)

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 65 ◽  
Author(s):  
S. Noguchi ◽  
T. Seki ◽  
N. Adachi ◽  
H. Sumi ◽  
R. Nakano ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Wild Type ◽  
Antileukemic Activity ◽  
Mdm2 Inhibitor ◽  
Acute Myeloid

scholarly journals Low-Dose Triptolide Promotes MDM2 Inhibitor Nutlin3a to Induce Acute Myeloid Leukemia Cell Death Via p53-Dependent and -Independent Mechanisms

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-24
Author(s):  
Qinwei Chen ◽  
Suqi Deng ◽  
Zhijuan Lin ◽  
Manman Deng ◽  
Lihong Ding ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Herbal Medicine ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Negative Regulator ◽  
Immune Disorders ◽  
Wild Type ◽  
Mdm2 Inhibitor ◽  
Acute Myeloid

The tumor suppressor p53 is central to hematopoietic stem cell function. Loss of p53 function is associated with poor prognosis of acute myeloid leukemia (AML). P53 negative regulator MDM2 is frequently overexpressed in AML, thus it becomes an attractive therapeutic target for the treatment of AML with wild-type p53 (Wt-p53). Targeting MDM2 to restore p53 activity has been assessed in AML, but clinical outcomes are less promising. Notably, p53-mutated AML still lacks effective treatment approaches. Therefore, our study strived to explore potent therapeutics to target AML with p53 wild-type and mutations. Triptolide (TPL), an ancient herbal medicine, has been used to treat immune disorders for centuries. Accumulating evidence including ours have proven that low dose of TPL potentiates the efficacy of chemotherapies in a broad range of tumor types. In this study, we evaluated the anti-leukemic efficacy of combining low dose TPL with Nutlin3a, a MDM2 inhibitor, against AML with p53 wild-type and mutations. We found that low-dose TPL synergized with Nutlin3a to induce mitochondrial apoptosis in AML cells with Wt-p53 bothin vitroandin vivo. Underlying mechanism for the synergy showed that Nutlin3a upregulated pro-apoptosis factors (e.g. PUMA, p21), while low-dose TPL suppressed MDM2 transcription and reduced anti-apoptosis proteins (e.g. XIAP, Mcl-1) in Wt-p53 AML cells. Interestingly, we also observed that TPL but not Nutlin3a induced cell death in p53 shRNA knockdown, p53 deficiency cell lines (e.g. THP-1, HL-60) and primary samples. Thus, the p53-independent role of TPL was consequently focused. Our RNA-Seq analysis identified 621 differential expression genes (DEGs) after TPL treatment. These genes, including MYC, ATF4 and 4EBP1, were enriched in intrinsic apoptosis pathway responding to ER stress and thus we concluded that Triptolide played its p53 independent role via MYC-ATF4 axis. Collectively, these findings suggest that coadministration of Nutlin3a with low dose TPL would benefit for AML patients. Disclosures Carter: AstraZeneca:Research Funding;Syndax:Research Funding;Ascentage:Research Funding;Amgen:Research Funding. OffLabel Disclosure: Triptolide (TPL), an ancient herbal medicine, is applying to treat immune disorders.

scholarly journals MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Douglas D. Fang ◽  
Qiuqiong Tang ◽  
Yanhui Kong ◽  
Tao Rong ◽  
Qixin Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Standard Of Care ◽  
Tumor Burden ◽  
Antileukemic Activity ◽  
Medical Needs ◽  
Mdm2 Inhibitor ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a clinically and genetically heterogeneous clonal disease associated with unmet medical needs. Paralleling the pathology of other cancers, AML tumorigenesis and propagation can be ascribed to dysregulated cellular processes, including apoptosis. This function and others are regulated by tumor suppressor P53, which plays a pivotal role in leukemogenesis. Opposing P53-mediated activities is the mouse double minute 2 homolog (MDM2), which promotes P53 degradation. Because the TP53 mutation rate is low, and MDM2 frequently overexpressed, in patients with leukemia, targeting the MDM2-P53 axis to restore P53 function has emerged as an attractive AML treatment strategy. APG-115 is a potent MDM2 inhibitor under clinical development for patients with solid tumors. In cellular cultures and animal models of AML, we demonstrate that APG-115 exerted substantial antileukemic activity, as either a single agent or when combined with standard-of-care (SOC) hypomethylating agents azacitidine (AZA) and decitabine (DAC), or the DNA-damaging agent cytarabine (Ara-C). By activating the P53/P21 pathway, APG-115 exhibited potent antiproliferative and apoptogenic activities, and induced cell cycle arrest, in TP53 wild-type AML lines. In vivo, APG-115 significantly reduced tumor burden and prolonged survival. Combinations of APG-115 with SOC treatments elicited synergistic antileukemic activity. To explain these effects, we propose that APG-115 and SOC agents augment AML cell killing by complementarily activating the P53/P21 pathway and upregulating DNA damage. These findings and the emerging mechanism of action afford a sound scientific rationale to evaluate APG-115 (with or without SOC therapies) in patients with AML.

scholarly journals Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia

2020 ◽  
Vol 38 (5) ◽  
pp. 1430-1441
Author(s):  
Geoffrey L. Uy ◽  
Sarit Assouline ◽  
Anne-Marie Young ◽  
Steven Blotner ◽  
Brian Higgins ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Active Principle ◽  
Wild Type ◽  
Antileukemic Activity ◽  
Platelet Recovery ◽  
Mdm2 Antagonist ◽  
Acute Myeloid

Abstract In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120–300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment–related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%–47% (22%–54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.

scholarly journals Phase I/II Study of Combination Therapy With Sorafenib, Idarubicin, and Cytarabine in Younger Patients With Acute Myeloid Leukemia

2010 ◽  
Vol 28 (11) ◽  
pp. 1856-1862 ◽  
Author(s):  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Daniel Jones ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Wild Type ◽  
Platelet Recovery ◽  
Probability Of Survival ◽  
Target Effect ◽  
Acute Myeloid

Purpose To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. Patients and Methods In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. Results Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. Conclusion Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

scholarly journals High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1517-1524 ◽  
Author(s):  
Marjan J. T. Veuger ◽  
M. Willy Honders ◽  
Jim E. Landegent ◽  
Roel Willemze ◽  
Renée M. Y. Barge
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Deoxycytidine Kinase ◽  
Wild Type ◽  
Healthy Donors ◽  
Alternatively Spliced ◽  
Acute Myeloid

Deficiency of functional deoxycytidine kinase (dCK) is a common characteristic for in vitro resistance to cytarabine (AraC). To investigate whether dCK is also a target for induction of AraC resistance in patients with acute myeloid leukemia (AML), we determined dCK messenger RNA (mRNA) expression in (purified) leukemic blasts and phytohemagglutinin-stimulated T cells (PHA T cells) from patients with chemotherapy-sensitive and chemotherapy-resistant AML. In control samples from healthy donors (PHA T cells and bone marrow), only wild-type dCK complementary DNA (cDNA) was amplified. Also, in (purified) leukemic blasts from patients with sensitive AML, only wild-type dCK cDNAs were observed. These cDNAs coded for active dCK proteins in vitro. However, in 7 of 12 (purified) leukemic blast samples from patients with resistant AML, additional polymerase chain reaction fragments with a deletion of exon 5, exons 3 to 4, exons 3 to 6, or exons 2 to 6 were detected in coexpression with wild-type dCK. Deletion of exons 3 to 6 was also identified in 6 of 12 PHA T cells generated from the patients with resistant AML. The deleted dCK mRNAs were formed by alternative splicing and did code for inactive dCK proteins in vitro. These findings suggest that the presence of inactive, alternatively spliced dCK mRNA transcripts in resistant AML blasts may contribute to the process of AraC resistance in patients with AML.

Detection of the JAK2V617F Mutation in Myeloproliferative Disorders by Melting Curve Analysis Using the LightCycler System

2006 ◽  
Vol 130 (7) ◽  
pp. 997-1003
Author(s):  
Randall J. Olsen ◽  
Zhouwen Tang ◽  
Daniel H. Farkas ◽  
David W. Bernard ◽  
Youli Zu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clinical Laboratory ◽  
Melting Curve ◽  
Myeloproliferative Disorder ◽  
Curve Analysis ◽  
Melting Curve Analysis ◽  
Wild Type ◽  
Acute Myeloid

Abstract Context.—A specific mutation, JAK2V617F, was recently recognized as having diagnostic value for myeloproliferative disorders. No practical assay is currently available for routine use in a clinical laboratory. Objective.—We report the development of a real-time polymerase chain reaction melting curve analysis assay that is appropriate for molecular diagnostics testing. Design.—Specific primers and fluorescence resonance energy transfer probes were designed, and patients with a previously diagnosed myeloproliferative disorder, de novo acute myeloid leukemia, or reactive condition were selected. The DNA was extracted from fresh and archived peripheral blood and bone marrow specimens, and real-time polymerase chain reaction melting curve analysis was performed on the LightCycler platform (Roche Applied Science, Indianapolis, Ind). Results.—The JAK2 region was successfully amplified, and wild-type amplicons were reproducibly discriminated from JAK2V617F amplicons. Titration studies using homozygous wild-type and mutant cell lines showed the relative areas under a melting curve were proportional to allele proportion, and the assay reliably detected one mutant in 20 total cells. JAK2V617F was identified in patients previously diagnosed with a myeloproliferative disorder or acute myeloid leukemia transformed from myeloproliferative disorder, whereas a wild-type genotype was identified in patients with reactive conditions or de novo acute myeloid leukemia. Conclusions.—These findings demonstrate the suitability of this assay for identifying JAK2V617F in a clinical laboratory setting. Furthermore, the semiquantitative detection of JAK2V617F in archived specimens provides a new tool for studying the prognostic significance of this mutation.

scholarly journals Preferential transcription of the mutated allele in NPM1 mutated acute myeloid leukaemia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
G. D. Bailey ◽  
L. Doolan ◽  
A. Baskar ◽  
L. C. Smith ◽  
C. H. Seedhouse
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Myeloid Leukemia ◽  
Splice Variants ◽  
Wild Type ◽  
Significant Bias ◽  
Acute Myeloid

Abstract Nucleophosmin is commonly both over-expressed and mutated in acute myeloid leukemia (AML). NPM1 mutations are always heterozygous. In addition, NPM1 has a number of different splice variants with the major variant encoded by exons 1–9 and 11–12 (NPM1.1). Further variants include NPM1.2 which lacks exons 8 and 10 and NPM1.3 which comprises exons 1–10 (and so lacks the region of sequence mutated in AML). In this study we quantified the expression of these three variants in 108 AML patient samples with and without NPM1 mutations and also assessed the level of expression from the wild-type and mutant alleles in variants NPM1.1 and NPM1.2. The results show that NPM1.1 is the most commonly expressed variant, however transcripts from wild-type and mutated alleles do not occur at equal levels, with a significant bias toward the mutated allele. Considering the involvement of mutant nucleophosmin in the progression and maintenance of AML, a bias towards mutated transcripts could have a significant impact on disease maintenance.

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