19 results on '"Park, Sophie"'
Search Results
2. CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 study.
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Peterlin P, Le Bris Y, Turlure P, Chevallier P, Ménard A, Gourin MP, Dumas PY, Thepot S, Berceanu A, Park S, Hospital MA, Cluzeau T, Bouzy S, Torregrosa-Diaz JM, Drevon L, Sapena R, Chermat F, Ades L, Dimicoli-Salazar S, Chevret S, Béné MC, and Fenaux P
- Subjects
- Humans, Male, Female, Adolescent, Young Adult, Adult, Middle Aged, Aged, Cytarabine, Daunorubicin therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myelomonocytic, Chronic drug therapy, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes etiology
- Abstract
Background: CPX-351, an encapsulated form of cytarabine and daunorubicin, has shown greater efficacy than the classic 3 + 7 treatment administration in secondary acute myeloid leukaemia. Given that higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia share similarities with secondary acute myeloid leukaemia, we aimed to investigate the safety and efficacy of CPX-351 in this context., Methods: This investigator-initiated two-cohort phase 2 trial was conducted by the Groupe Francophone des Myélodysplasies, with 12 participating centres in France. It comprised cohort A (reported here and completed), which included patients in first-line treatment, and cohort B, which was stopped for lack of inclusion (ie, not enough patients met the inclusion criteria), for patients with hypomethylating agent failure that is not reported here. Cohort A enrolled patients with newly diagnosed higher-risk myelodysplastic syndrome or chronic myelomonocytic leukaemia (aged 18-70 years old) with an Eastern Cooperative Oncology Group performance status of 0-1. Intravenous CPX-351 (100 mg/m
2 cytarabine and 44 mg/m2 daunorubicin) was given on days 1, 3, and 5, with a second induction cycle given (same daily dose on days 1 and 3) if at least a partial response was not reached. Patients who responded could receive up to four monthly consolidation cycles (same daily dose on day 1) or allogeneic haematopoietic stem-cell transplantation (HSCT). Overall response rate after one or two induction courses according to European LeukemiaNet 2017 acute myeloid leukaemia was the primary endpoint after CPX-351 induction, whether patients received one or two induction cycles. Safety was assessed in all patients enrolled (in cohort A). This trial is registered with ClinicalTrials.gov, NCT04273802., Findings: Between April 29, 2020, and Feb 10, 2021, 21 (68%) male and ten (32%) female patients were enrolled. 27 (87%) of 31 patients responded (95% CI 70-96). 16 (52%) of the 31 patients received at least one consolidation cycle. 30 (97%) of the 31 patients included were initially considered eligible for allogeneic HSCT and 29 (94%) of the 31 patients had the procedure. Median follow-up was 16·1 months (IQR 8·3-18·1). The most common grade 3-4 adverse events were pulmonary (eight [26%] of 31 patients) and cardiovascular (six [19%] of 31 patients). There were 14 serious adverse events (mainly hospitalisation for infection [n=5] and only one was treatment-related) and no treatment-related death., Interpretation: CPX-351 appears to be active and safe in patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia, allowing bridging to allogenic HSCT in most patients., Funding: Jazz Pharmaceuticals., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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3. A randomised phase II study of azacitidine (AZA) alone or with Lenalidomide (LEN), Valproic acid (VPA) or Idarubicin (IDA) in higher-Risk MDS or low blast AML: GFM's "pick a winner" trial, with the impact of somatic mutations.
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Adès L, Duployez N, Guerci-Bresler A, Laribi K, Peterlin P, Vey N, Thepot S, Wickenhauser S, Zerazhi H, Stamatoullas A, Wattel E, Recher C, Toma A, Dimicoli-Salazar S, Braun T, Beyne-Rauzy O, Marolleau JP, Cheze S, Park S, Cluzeau T, Nimubona S, Bordessoule D, Benramdane R, Quesnel B, Amé S, de Botton S, Chermat F, Preudhomme C, Chevret S, and Fenaux P
- Subjects
- Humans, Idarubicin therapeutic use, Lenalidomide therapeutic use, Mutation, Treatment Outcome, Valproic Acid therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Azacitidine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
In order to improve the outcome observed with azacitidine (AZA) in higher-risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA-PLUS was a phase II trial that, in a "pick a winner" approach, randomly assigned patients with higher-risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six cycles, 69 (21.4%) CR + PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7 months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six cycles were higher in the AZA-LEN And AZA-IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy-related MDS and, in the case of TP53, PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our "pick a winner" randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2022
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4. Increased S100A8 expression in bone marrow plasma by monocytic cells from acute myeloid leukemia patients.
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Mondet J, Laurin D, Lo Presti C, Jacob MC, Meunier M, Giraudon E, Lefebvre C, Berthier S, Leer AM, Park S, and Mossuz P
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- Bone Marrow pathology, Humans, Monocytes pathology, Prognosis, Biomarkers, Tumor blood, Bone Marrow metabolism, Calgranulin A blood, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute pathology, Monocytes metabolism
- Published
- 2020
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5. Adult patients with de novo acute myeloid leukemia show a functional deregulation of redox balance at diagnosis which is correlated with molecular subtypes and overall survival.
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Mondet J, Presti CL, Garrel C, Skaare K, Mariette C, Carras S, Park S, Carré M, Bulabois CE, Molina L, Gressin R, Thiebaut A, Courby S, Socoro-Yuste N, Faure P, Leer-Florin AM, Cahn JY, and Mossuz P
- Subjects
- Adult, Aged, Antimycin A pharmacology, Antioxidants metabolism, Female, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute mortality, Lipid Peroxidation, Male, Middle Aged, Mitochondria metabolism, NADPH Oxidases metabolism, Onium Compounds pharmacology, Prognosis, Proportional Hazards Models, Prospective Studies, Reactive Oxygen Species metabolism, Rotenone pharmacology, Tetradecanoylphorbol Acetate pharmacology, Translocation, Genetic, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute genetics, Oxidation-Reduction
- Published
- 2019
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6. A phase II study of guadecitabine in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure.
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Sébert M, Renneville A, Bally C, Peterlin P, Beyne-Rauzy O, Legros L, Gourin MP, Sanhes L, Wattel E, Gyan E, Park S, Stamatoullas A, Banos A, Laribi K, Jueliger S, Bevan L, Chermat F, Sapena R, Nibourel O, Chaffaut C, Chevret S, Preudhomme C, Adès L, and Fenaux P
- Subjects
- Aged, Female, Humans, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes mortality, Risk, Survival Analysis, Treatment Outcome, Azacitidine analogs & derivatives, Azacitidine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy
- Abstract
High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response ( P =0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high ( P =0.03) primary versus secondary azacitidine failure ( P =0.01) and a high rate of demethylation in blood during the first cycle of treatment ( P =0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered a t clinicaltrials.gov identifier: 02197676 )., (Copyright© 2019 Ferrata Storti Foundation.)
- Published
- 2019
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7. Outcome of Lower-Risk Patients With Myelodysplastic Syndromes Without 5q Deletion After Failure of Erythropoiesis-Stimulating Agents.
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Park S, Hamel JF, Toma A, Kelaidi C, Thépot S, Campelo MD, Santini V, Sekeres MA, Balleari E, Kaivers J, Sapena R, Götze K, Müller-Thomas C, Beyne-Rauzy O, Stamatoullas A, Kotsianidis I, Komrokji R, Steensma DP, Fensterl J, Roboz GJ, Bernal T, Ramos F, Calabuig M, Guerci-Bresler A, Bordessoule D, Cony-Makhoul P, Cheze S, Wattel E, Rose C, Vey N, Gioia D, Ferrero D, Gaidano G, Cametti G, Pane F, Sanna A, Germing U, Sanz GF, Dreyfus F, and Fenaux P
- Subjects
- Aged, Aged, 80 and over, Anemia etiology, Anemia therapy, Antilymphocyte Serum therapeutic use, Antineoplastic Agents therapeutic use, Arsenic therapeutic use, Azacitidine analogs & derivatives, Azacitidine therapeutic use, Cyclosporine therapeutic use, Cytarabine therapeutic use, Decitabine, Disease Progression, Enzyme Inhibitors therapeutic use, Erythrocyte Transfusion, Female, Hematinics therapeutic use, Humans, Hydroxyurea therapeutic use, Immunologic Factors therapeutic use, Lenalidomide, Male, Middle Aged, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes genetics, Recurrence, Retreatment, Retrospective Studies, Risk Factors, Survival Rate, Thalidomide analogs & derivatives, Thalidomide therapeutic use, Treatment Failure, Tretinoin therapeutic use, Valproic Acid therapeutic use, Chromosome Deletion, Chromosomes, Human, Pair 5, Leukemia, Myeloid, Acute etiology, Myelodysplastic Syndromes therapy
- Abstract
Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.
- Published
- 2017
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8. The eukaryotic initiating factor 4E protein is overexpressed, but its level has no prognostic impact in acute myeloid leukaemia.
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Green AS, Grabar S, Tulliez M, Park S, Al-Nawakil C, Chapuis N, Jacque N, Willems L, Azar N, Ifrah N, Dreyfus F, Lacombe C, Mayeux P, Bouscary D, and Tamburini J
- Subjects
- Adult, Aged, Female, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Prognosis, Young Adult, Eukaryotic Initiation Factor-4E metabolism, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute metabolism
- Published
- 2012
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9. Heterogeneous sensitivity of human acute myeloid leukemia to β-catenin down-modulation.
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Gandillet A, Park S, Lassailly F, Griessinger E, Vargaftig J, Filby A, Lister TA, and Bonnet D
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- Adult, Aged, Animals, Apoptosis, Blotting, Western, Cell Cycle, Cell Differentiation, Cell Proliferation, Down-Regulation, Female, Flow Cytometry, Humans, Leukemia, Myeloid, Acute genetics, Male, Mice, Mice, Inbred NOD, Mice, SCID, Middle Aged, RNA, Messenger genetics, RNA, Small Interfering genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transplantation, Heterologous, Tumor Cells, Cultured, beta Catenin antagonists & inhibitors, beta Catenin genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, beta Catenin metabolism
- Abstract
Dysregulation of the Wnt/β-catenin pathway has been observed in various malignancies, including acute myeloid leukemia (AML), where the overexpression of β-catenin is an independent adverse prognostic factor. β-catenin was found upregulated in the vast majority of AML samples and more frequently localized in the nucleus of leukemic stem cells compared with normal bone marrow CD34(+) cells. The knockdown of β-catenin, using a short hairpin RNA (shRNA) lentiviral approach, accelerates all-trans retinoic acid-induced differentiation and impairs the proliferation of HL60 leukemic cell line. Using in vivo quantitative tracking of these cells, we observed a reduced engraftment potential after xenotransplantation when β-catenin was silenced. However, when studying primary AML cells, despite effective downregulation of β-catenin we did not observe any impairment of their in vitro long-term maintenance on MS-5 stroma nor of their engraftment potential in vivo. Altogether, these results show that despite a frequent β-catenin upregulation in AML, leukemia-initiating cells might not be 'addicted' to this pathway and thus targeted therapy against β-catenin might not be successful in all patients.
- Published
- 2011
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10. The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation.
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Green AS, Chapuis N, Maciel TT, Willems L, Lambert M, Arnoult C, Boyer O, Bardet V, Park S, Foretz M, Viollet B, Ifrah N, Dreyfus F, Hermine O, Moura IC, Lacombe C, Mayeux P, Bouscary D, and Tamburini J
- Subjects
- AMP-Activated Protein Kinase Kinases, Adaptor Proteins, Signal Transducing metabolism, Animals, Biocatalysis drug effects, Cell Cycle Proteins, Cell Death drug effects, Cell Proliferation drug effects, Enzyme Activation drug effects, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Metformin pharmacology, Mice, Phosphoproteins metabolism, Phosphorylation drug effects, Polyribosomes drug effects, Polyribosomes metabolism, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins metabolism, Leukemia, Myeloid, Acute enzymology, Neoplasm Proteins biosynthesis, Protein Biosynthesis drug effects, Protein Kinases metabolism, Protein Serine-Threonine Kinases metabolism, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism
- Abstract
Finding an effective treatment for acute myeloid leukemia (AML) remains a challenge, and all cellular processes that are deregulated in AML cells should be considered in the design of targeted therapies. We show in our current study that the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin (mTOR) catalytic activity. This induces a multisite dephosphorylation of the key translation regulator, 4E-BP1, which markedly inhibits the initiation step of mRNA translation. Consequently, metformin reduces the recruitment of mRNA molecules encoding oncogenic proteins to the polysomes, resulting in a strong antileukemic activity against primary AML cells while sparing normal hematopoiesis ex vivo and significantly reducing the growth of AML cells in nude mice. The induction of the LKB1/AMPK tumor-suppressor pathway thus represents a promising new strategy for AML therapy.
- Published
- 2010
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11. IκB kinase overcomes PI3K/Akt and ERK/MAPK to control FOXO3a activity in acute myeloid leukemia.
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Chapuis N, Park S, Leotoing L, Tamburini J, Verdier F, Bardet V, Green AS, Willems L, Agou F, Ifrah N, Dreyfus F, Bismuth G, Baud V, Lacombe C, Mayeux P, and Bouscary D
- Subjects
- Apoptosis drug effects, Cell Nucleus drug effects, Cell Nucleus metabolism, Cell Proliferation drug effects, Forkhead Box Protein O3, Green Fluorescent Proteins metabolism, Humans, I-kappa B Kinase antagonists & inhibitors, MAP Kinase Signaling System drug effects, Mutant Proteins metabolism, Protein Kinase Inhibitors pharmacology, Protein Transport drug effects, Recombinant Fusion Proteins metabolism, Serine metabolism, Structure-Activity Relationship, Extracellular Signal-Regulated MAP Kinases metabolism, Forkhead Transcription Factors metabolism, I-kappa B Kinase metabolism, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute pathology, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism
- Abstract
The FOXO transcription factors are involved in multiple signaling pathways and have tumor-suppressor functions. In acute myeloid leukemia (AML), deregulation of oncogenic kinases, including Akt, extra-signal-regulated kinase, or IκB kinase, is frequently observed, which may potentially inactivate FOXO activity. We therefore investigated the mechanism underlying the regulation of FOXO3a, the only FOXO protein constantly expressed in AML blast cells. We show that in both primary AML samples and in a MV4-11/FOXO3a-GFP cell line, FOXO3a is in a constant inactive state due to its cytoplasmic localization, and that neither PI3K/Akt nor extra-signal-regulated kinase-specific inhibition resulted in its nuclear translocation. In contrast, the anti-Nemo peptide that specifically inhibits IKK activity was found to induce FOXO3a nuclear localization in leukemic cells. Furthermore, an IKK-insensitive FOXO3a protein mutated at S⁶⁴⁴ translocated into the nucleus and activated the transcription of the Fas-L and p21(Cip1) genes. This, in turn, inhibited leukemic cell proliferation and induced apoptosis. These results thus indicate that IKK activity maintains FOXO3a in the cytoplasm and establishes an important role of FOXO3a inactivation in the proliferation and survival of AML cells. The restoration of FOXO3a activity by interacting with its subcellular distribution may thus represent a new attractive therapeutic strategy for AML.
- Published
- 2010
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12. Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia.
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Chapuis N, Tamburini J, Green AS, Vignon C, Bardet V, Neyret A, Pannetier M, Willems L, Park S, Macone A, Maira SM, Ifrah N, Dreyfus F, Herault O, Lacombe C, Mayeux P, and Bouscary D
- Subjects
- Antineoplastic Agents therapeutic use, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Imidazoles therapeutic use, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute metabolism, Mechanistic Target of Rapamycin Complex 1, Multiprotein Complexes, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors therapeutic use, Proteins metabolism, Quinolines therapeutic use, RNA Caps antagonists & inhibitors, RNA Caps genetics, Signal Transduction drug effects, Structure-Activity Relationship, TOR Serine-Threonine Kinases, Transcription Factors metabolism, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Imidazoles pharmacology, Leukemia, Myeloid, Acute drug therapy, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology, Proteins antagonists & inhibitors, Quinolines pharmacology, Transcription Factors antagonists & inhibitors
- Abstract
Purpose: The growth and survival of acute myeloid leukemia (AML) cells are enhanced by the deregulation of signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR). Major efforts have thus been made to develop molecules targeting these activated pathways. The mTOR serine/threonine kinase belongs to two separate complexes: mTORC1 and mTORC2. The mTORC1 pathway is rapamycin sensitive and controls protein translation through the phosphorylation of 4E-BP1 in most models. In AML, however, the translation process is deregulated and rapamycin resistant. Furthermore, the activity of PI3K/Akt and mTOR is closely related, as mTORC2 activates the oncogenic kinase Akt. We therefore tested, in this study, the antileukemic activity of the dual PI3K/mTOR ATP-competitive inhibitor NVP-BEZ235 compound (Novartis)., Experimental Design: The activity of NVP-BEZ235 was tested in primary AML samples (n = 21) and human leukemic cell lines. The different signaling pathways were analyzed by Western blotting. The cap-dependent mRNA translation was studied by 7-methyl-GTP pull-down experiments, polysomal analysis, and [(3)H]leucine incorporation assays. The antileukemic activity of NVP-BEZ235 was tested by analyzing its effects on leukemic progenitor clonogenicity, blast cell proliferation, and survival., Results: The NVP-BEZ235 compound was found to inhibit PI3K and mTORC1 signaling and also mTORC2 activity. Furthermore, NVP-BEZ235 fully inhibits the rapamycin-resistant phosphorylation of 4E-BP1, resulting in a marked inhibition of protein translation in AML cells. Hence, NVP-BEZ235 reduces the proliferation rate and induces an important apoptotic response in AML cells without affecting normal CD34(+) survival., Conclusions: Our results clearly show the antileukemic efficiency of the NVP-BEZ235 compound, which therefore represents a promising option for future AML therapies., (©2010 AACR.)
- Published
- 2010
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13. Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia.
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Park S, Chapuis N, Tamburini J, Bardet V, Cornillet-Lefebvre P, Willems L, Green A, Mayeux P, Lacombe C, and Bouscary D
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- Animals, Antineoplastic Agents administration & dosage, Class I Phosphatidylinositol 3-Kinases, Drug Delivery Systems trends, Humans, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Signal Transduction drug effects, TOR Serine-Threonine Kinases antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute enzymology, Phosphatidylinositol 3-Kinases physiology, Proto-Oncogene Proteins c-akt physiology, Signal Transduction physiology, TOR Serine-Threonine Kinases physiology
- Abstract
The PI3K/AKT and mTOR signaling pathways are activated in acute myeloid leukemia, including in the more immature leukemic populations. Constitutive PI3K activation is detectable in 50% of acute myeloid leukemia samples whereas mTORC1 is activated in all cases of this disease. In leukemic cells, the PI3K activity relates to the expression of the p110delta isoform of class IA PI3K. Constitutive PI3K activation is the result of autocrine IGF-1/IGF-1R signaling in 70% of acute myeloid leukemia samples but specific inhibition of this pathway does not induce apoptosis. Specific inhibition of PI3K/AKT or mTORC1 alone in vitro has anti-leukemic effects which are essentially exerted via the suppression of proliferation. However, as mTORC1 activation is independent of PI3K/AKT in acute myeloid leukemia, dual PI3K and mTOR inhibitors may induce apoptosis in blast cells. Moreover, mTORC1 inhibition using sirolimus overactivates PI3K/AKT via the upregulation of IRS2 expression and by favoring IGF-1/IGF-1R autocrine signaling. Recent data also indicate that mTORC1 does not control protein translation in acute myeloid leukemia. These results open the way for the design of direct inhibitors of protein synthesis as novel acute myeloid leukemia therapies and also for the development of second generation mTOR inhibitors (the TORKinhibs).
- Published
- 2010
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14. Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody.
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Chapuis N, Tamburini J, Cornillet-Lefebvre P, Gillot L, Bardet V, Willems L, Park S, Green AS, Ifrah N, Dreyfus F, Mayeux P, Lacombe C, and Bouscary D
- Subjects
- Aged, Aged, 80 and over, Antibodies, Anti-Idiotypic therapeutic use, Apoptosis, Autocrine Communication, Blast Crisis, Blotting, Western, Bone Marrow metabolism, Cell Line, Tumor, Cell Proliferation, Colony-Forming Units Assay, Flow Cytometry, Humans, Insulin-Like Growth Factor I antagonists & inhibitors, Insulin-Like Growth Factor I genetics, Leukemia, Myeloid, Acute therapy, Middle Aged, Phosphorylation, RNA, Messenger genetics, RNA, Messenger metabolism, Receptor, IGF Type 1 antagonists & inhibitors, Receptor, IGF Type 1 immunology, Reverse Transcriptase Polymerase Chain Reaction, Antibodies, Neutralizing therapeutic use, Insulin-Like Growth Factor I metabolism, Leukemia, Myeloid, Acute metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Receptor, IGF Type 1 metabolism, Signal Transduction physiology
- Abstract
Background: Alterations in the PI3K/Akt pathway are found in a wide range of cancers and the development of PI3K inhibitors represents a promising approach to cancer therapy. Constitutive PI3K activation, reflecting an intrinsic oncogenic deregulation of primary blast cells, is detected in 50% of patients with acute myeloid leukemia. However, the mechanisms leading to this activation are currently unknown. As we previously reported IGF-1 autocriny in acute myeloid leukemia cells, we investigated whether IGF-1 signaling was involved in the constitutive activation of PI3K., Design and Methods: We analyzed the IGF-1/IGF-1R signaling pathway and PI3K activity in 40 acute myeloid leukemia bone marrow samples. Specific inhibition of IGF-1/IGF-1R signaling was investigated using neutralizing anti-IGF-1R, anti-IGF-1 antibodies or IGF-1 short interfering RNA. The anti-leukemic activity of the neutralizing anti-IGF-1R was tested by analyzing its effects on leukemic progenitor clonogenicity, blast cell proliferation and survival., Results: In all samples tested, we found that functional IGF-1R was constantly expressed in leukemic cells. In the acute myeloid leukemia samples with PI3K activation, we found that the IGF-1R was constitutively phosphorylated, although no IGF-1R activating mutation was detected. Specific inhibition of IGF-1R signaling with neutralizing anti-IGF-1R strongly inhibited the constitutive phosphorylation of both IGF-1R and Akt in 70% of the PI3K activated samples. Moreover, both incubation with anti-IGF-1 antibody and IGF-1 short interfering RNA inhibited Akt phosphorylation in leukemic cells. Finally, neutralizing anti-IGF-1R treatment decreased the clonogenicity of leukemic progenitors and the proliferation of PI3K activated acute myeloid leukemia cells., Conclusions: Our current data indicate a critical role for IGF-1 autocriny in constitutive PI3K/Akt activation in primary acute myeloid leukemia cells and provide a strong rationale for targeting IGF-1R as a potential new therapy for this disease.
- Published
- 2010
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15. Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia.
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Tamburini J, Green AS, Bardet V, Chapuis N, Park S, Willems L, Uzunov M, Ifrah N, Dreyfus F, Lacombe C, Mayeux P, and Bouscary D
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Antibiotics, Antineoplastic pharmacology, Antibiotics, Antineoplastic therapeutic use, Apoptosis drug effects, Cell Cycle Proteins, Cell Proliferation drug effects, Cells, Cultured, Drug Evaluation, Preclinical, Everolimus, Hematopoiesis drug effects, Humans, Hydrazones, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Mechanistic Target of Rapamycin Complex 1, Multiprotein Complexes, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells pathology, Nitro Compounds pharmacology, Phosphoproteins metabolism, Phosphorylation drug effects, Protein Synthesis Inhibitors pharmacology, Proteins, Sirolimus analogs & derivatives, TOR Serine-Threonine Kinases, Thiazoles pharmacology, Transcription Factors metabolism, Drug Resistance physiology, Leukemia, Myeloid, Acute drug therapy, Protein Biosynthesis drug effects, Sirolimus pharmacology, Sirolimus therapeutic use
- Abstract
The deregulation of translation markedly contributes to the malignant phenotype in cancers, and the assembly of the translation initiating complex eIF4F is the limiting step of this process. The mammalian Target of Rapamycin Complex 1 (mTORC1) is thought to positively regulate eIF4F assembly and subsequent oncogenic protein synthesis through 4E-BP1 phosphorylation. We showed here that the translation inhibitor 4EGI-1 decreased the clonogenic growth of leukemic progenitors and induced apoptosis of blast cells, with limited toxicity against normal hematopoiesis, which emphasize the importance of translation deregulation in acute myeloid leukemia (AML) biology. However, the mTORC1 inhibitor RAD001 (a rapamycin derivate) did not induce AML blast cell apoptosis. We herein demonstrated that mTORC1 disruption using raptor siRNA or RAD001 failed to inhibit 4E-BP1 phosphorylation in AML. Moreover, RAD001 failed to inhibit eIF4F assembly, to decrease the proportion of polysome-bound c-Myc mRNA, and to reduce the translation-dependent accumulation of oncogenic proteins. We identified the Pim-2 serine/threonine kinase as mainly responsible for 4E-BP1 phosphorylation on the S(65) residue and subsequent translation control in AML. Our results strongly implicate an mTORC1-independent deregulation of oncogenic proteins synthesis in human myeloid leukemogenesis. Direct inhibition of the translation initiating complex thus represents an attractive option for the development of new therapies in AML.
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- 2009
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16. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways.
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Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, Ifrah N, Dreyfus F, Mayeux P, Lacombe C, and Bouscary D
- Subjects
- Cell Division drug effects, Everolimus, Humans, In Vitro Techniques, Mechanistic Target of Rapamycin Complex 1, Multiprotein Complexes, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation drug effects, Proteins, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, Sirolimus pharmacology, TOR Serine-Threonine Kinases, Transcription Factors metabolism, Up-Regulation drug effects, Immunosuppressive Agents pharmacology, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Receptor, IGF Type 1 metabolism, Sirolimus analogs & derivatives, Transcription Factors antagonists & inhibitors
- Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt and mTORC1 pathways are frequently activated, representing potential therapeutic targets in acute myeloid leukemia (AML). In 19 AML samples with constitutive PI3K/Akt activation, the rapamycin derivative inhibitor everolimus (RAD001) increased Akt phosphorylation. This mTOR C1-mediated Akt up-regulation was explained by an insulin-like growth factor-1 (IGF-1)/IGF-1 receptor autocrine loop: (1) blast cells expressed functional IGF-1 receptors, and IGF-1-induced Akt activation was increased by RAD001, (2) a neutralizing anti-IGF-1R alpha-IR3 monoclonal antibody reversed the RAD001-induced Akt phosphorylation, and (3) autocrine production of IGF-1 was detected in purified blast cells by quantitative reverse transcription-polymerase chain reaction and immunofluorescence. This RAD001-induced PI3K/Akt up-regulation was due to an up-regulated expression of the IRS2 adaptor. Finally, we observed that concomitant inhibition of mTORC1 and PI3K/Akt by RAD001 and IC87114 induced additive antiproliferative effects. Our results suggest that dual inhibition of the mTORC1 complex and the IGF-1/IGF-1R/PI3K/Akt pathway in AML may enhance the efficacy of mTOR inhibitors in treatment of this disease.
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- 2008
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17. Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients.
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Tamburini J, Elie C, Bardet V, Chapuis N, Park S, Broët P, Cornillet-Lefebvre P, Lioure B, Ugo V, Blanchet O, Ifrah N, Witz F, Dreyfus F, Mayeux P, Lacombe C, and Bouscary D
- Subjects
- Blast Crisis drug therapy, Blast Crisis genetics, Blast Crisis mortality, Bone Marrow enzymology, Bone Marrow pathology, Disease-Free Survival, Enzyme Activation genetics, Female, Humans, L-Lactate Dehydrogenase genetics, L-Lactate Dehydrogenase metabolism, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukocyte Count, Male, Nuclear Proteins genetics, Nuclear Proteins metabolism, Nucleophosmin, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins c-akt genetics, Survival Rate, fms-Like Tyrosine Kinase 3 genetics, fms-Like Tyrosine Kinase 3 metabolism, ras Proteins genetics, ras Proteins metabolism, Blast Crisis enzymology, Leukemia, Myeloid, Acute enzymology, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism
- Abstract
The phosphoinositide 3-kinase (PI3K/Akt) pathway is activated in acute myelogenous leukemia (AML) and is promising for targeted inhibition. Ninety-two patients with primary AML were analyzed for PI3K/Akt constitutive activation. Fifty percent of the patients presented with constitutive PI3K activation (PI3K (+)). No difference was observed between PI3K (+) and PI3K (-) groups concerning age, sex, white blood cell count, lactate dehydrogenase (LDH) level, bone marrow blast cells, French-American-British (FAB) classification, cytogenetics, RAS or nucleophosmin (NPM) mutations. Slightly more FLT3-ITD was detected in the PI3K (-) group (P = .048). The complete remission rate was similar between the 2 groups. With a median follow-up of 26 months, we observed for PI3K (+) and PI3K (-) patients, respectively, 56% and 33% overall survival (P = .001) and 72% and 41% relapse-free survival (P = .001). Constitutive PI3K/Akt activity is a favorable prognosis factor in AML, even after adjustment for FLT3-ITD, and may confer a particular sensitivity to chemotherapy. A better understanding of the downstream effectors of the PI3K/Akt pathway is needed before targeting in AML.
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- 2007
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18. Bortezomib combined with low-dose cytarabine in Intermediate-2 and high risk myelodysplastic syndromes. A phase I/II Study by the GFM
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Natarajan-Amé, Shanti, Park, Sophie, Ades, Lionel, Vey, Norbert, Guerci-Bresler, Agnès, Cahn, Jean-Yves, Etienne, Gabriel, Bordessoule, Dominique, Ravoet, Christophe, Legros, Laurence, Cheze, Stephane, Stamatoullas, Aspasia, Berger, Elisabeth, Schmidt, Aline, Charbonnier, Aude, Chaury, Marie-Pierre, Braun, Thorsten, Fenaux, Pierre, Dreyfus, Francois, Renseigné, Non, Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hematology (IPC-Marseille), Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hematology, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Centre Hospitalier de Jolimont-Lobbes, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP]
- Subjects
Male ,MESH: Anemia, Refractory, with Excess of Blasts ,medicine.medical_treatment ,Low dose cytarabine ,Gastroenterology ,Bortezomib ,0302 clinical medicine ,MESH: Aged, 80 and over ,Antineoplastic Combined Chemotherapy Protocols ,MESH: Cytarabine ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,MESH: Treatment Outcome ,MESH: Aged ,Aged, 80 and over ,0303 health sciences ,MESH: Middle Aged ,Cytarabine ,Hematology ,MESH: Follow-Up Studies ,Middle Aged ,Boronic Acids ,3. Good health ,MESH: Antineoplastic Combined Chemotherapy Protocols ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,MESH: Pyrazines ,MESH: Survival Analysis ,Pyrazines ,Toxicity ,MESH: Boronic Acids ,Drug Therapy, Combination ,Female ,MESH: Leukemia, Myeloid, Acute ,MESH: Myelodysplastic Syndromes ,medicine.drug ,medicine.medical_specialty ,MESH: Drug Administration Schedule ,Drug Administration Schedule ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,In patient ,030304 developmental biology ,Aged ,Chemotherapy ,MESH: Humans ,Anemia, Refractory, with Excess of Blasts ,business.industry ,Myelodysplastic syndromes ,medicine.disease ,Survival Analysis ,MESH: Male ,MESH: Drug Therapy, Combination ,Phase i ii ,Myelodysplastic Syndromes ,Immunology ,Proteasome inhibitor ,business ,MESH: Female ,Follow-Up Studies - Abstract
International audience; Marrow cells from patients with higher-risk myelodysplastic syndrome (MDS) exhibit constitutive nuclear factor (NF)-κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher-risk MDS patients with bortezomib (1*5 mg/m(2) , days 1, 4, 8 and 11) and low dose cytarabine arabinoside (LDAC; 10 mg/m(2) , then 20 mg/m(2) from days 1-14), every 28 d for four cycles. Median follow-up was 29*7 months. Responses were seen in 12 of the 43 patients (28%), including complete response (CR, n = 1), marrow-CR (n = 3), partial response (PR, n = 5) and haematological improvement (HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2*5% HI), compared to none in the 12 previously treated patients (P < 0*01). Responders had better overall survival (median 18*2 vs. 10 months). One CR and 3 marrow-CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1-2 pre-treatment haematotoxicity developed Grade 3-4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher-risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes.
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- 2012
19. Outcome of lower-risk patients with myelodysplastic syndromes without 5q deletion after failure of erythropoiesis-stimulating agents
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Jennifer Kaivers, Ulrich Germing, Rosa Sapena, Giovanni Cametti, Mikkael A. Sekeres, Katharina Götze, Maria Diez Campelo, Agnès Guerci-Bresler, Fabrizio Pane, Stéphane Cheze, François Dreyfus, Teresa Bernal, Enrico Balleari, David P. Steensma, Rami S. Komrokji, Pierre Fenaux, Christian Rose, Guillermo Sanz, Valeria Santini, Catharina Müller-Thomas, Marisa Calabuig, Aspasia Stamatoullas, Norbert Vey, Dario Ferrero, Alessandro Sanna, Jean Francois Hamel, Jaime Fensterl, Dominique Bordessoule, Ioannis Kotsianidis, Sophie Park, Andrea Toma, Charikleia Kelaidi, Gail J. Roboz, Fernando Ramos, Gianluca Gaidano, Sylvain Thepot, Odile Beyne-Rauzy, Pascale Cony-Makhoul, Eric Wattel, Daniela Gioia, Park, Sophie, Hamel, Jean Françoi, Toma, Andrea, Kelaidi, Charikleia, Thépot, Sylvain, Campelo, Maria Diez, Santini, Valeria, Sekeres, Mikkael A, Balleari, Enrico, Kaivers, Jennifer, Sapena, Rosa, Götze, Katharina, Müller Thomas, Catharina, Beyne Rauzy, Odile, Stamatoullas, Aspasia, Kotsianidis, Ioanni, Komrokji, Rami, Steensma, David P, Fensterl, Jaime, Roboz, Gail J, Bernal, Teresa, Ramos, Fernando, Calabuig, Marisa, Guerci Bresler, Agnè, Bordessoule, Dominique, Cony Makhoul, Pascale, Cheze, Stéphane, Wattel, Eric, Rose, Christian, Vey, Norbert, Gioia, Daniela, Ferrero, Dario, Gaidano, Gianluca, Cametti, Giovanni, Pane, Fabrizio, Sanna, Alessandro, Germing, Ulrich, Sanz, Guillermo F, Dreyfus, Françoi, and Fenaux, Pierre
- Subjects
Male ,Cancer Research ,0302 clinical medicine ,Recurrence ,Risk Factors ,hemic and lymphatic diseases ,Hydroxyurea ,Cumulative incidence ,Treatment Failure ,Enzyme Inhibitors ,Lenalidomide ,Aged, 80 and over ,Cytarabine ,Anemia ,Middle Aged ,Thalidomide ,Melodysplastic syndrome ,Survival Rate ,Leukemia, Myeloid, Acute ,Oncology ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Retreatment ,Azacitidine ,Cyclosporine ,Disease Progression ,Chromosomes, Human, Pair 5 ,Female ,Chromosome Deletion ,Erythrocyte Transfusion ,medicine.drug ,medicine.medical_specialty ,Melodysplastic syndrome, erytropoiesis stimulating agents, 5q ,erytropoiesis stimulating agents ,Decitabine ,Antineoplastic Agents ,Tretinoin ,Lower risk ,5q ,Arsenic ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Immunologic Factors ,Survival rate ,Aged ,Antilymphocyte Serum ,Retrospective Studies ,business.industry ,Valproic Acid ,Myelodysplastic syndromes ,Retrospective cohort study ,medicine.disease ,Myelodysplastic Syndromes ,Hematinics ,Physical therapy ,business ,030215 immunology - Abstract
Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.
- Published
- 2017
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