European Journal of Internal Medicine
Volume 20, Issue 8 , Pages 775-778 , December 2009

Evaluation of in vivo antineoplastic effects of rapamycin in patients with chemotherapy-refractory AML

  • Alexandra Boehm

      Affiliations

    • Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria
    • Bone Marrow Transplantation Unit, Medical University of Vienna, Austria
    • ,
  • Matthias Mayerhofer

      Affiliations

    • Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Austria
    • ,
  • Susanne Herndlhofer

      Affiliations

    • Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria
    • ,
  • Paul Knoebl

      Affiliations

    • Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria
    • ,
  • Christian Sillaber

      Affiliations

    • Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria
    • ,
  • Wolfgang R. Sperr

      Affiliations

    • Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria
    • Ludwig Boltzmann Cluster Oncology, Vienna, Austria
    • ,
  • Ulrich Jaeger

      Affiliations

    • Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria
    • Ludwig Boltzmann Cluster Oncology, Vienna, Austria
    • ,
  • Peter Valent

      Affiliations

    • Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria
    • Ludwig Boltzmann Cluster Oncology, Vienna, Austria
    • Corresponding Author InformationCorresponding author. Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, Ludwig Boltzmann Cluster Oncology, Vienna, A-1090 Vienna, Austria. Tel.: +43 1 40400 4415; fax: +43 1 40400 4030.

Received 14 July 2009 ,Revised 6 September 2009 ,Accepted 8 September 2009.

References 

  1. Estey E, Döhner H. Acute myeloid leukaemia. Lancet. 2006;368:1894–1907
  2. Buechner T, Berdel WE, Schoch C, et al. German Acute Myeloid Leukemia Cooperative Group (AMLCG) Treatment of AML in biological subgroups. Hematology. 2005;10(S1):281–285
  3. Haferlach T. Molecular genetic pathways as therapeutic targets in acute myeloid leukemia. Hematol Am Soc Hematol Educ Prog. 2008;400–411
  4. Kornblau SM, Tibes R, Qiu YH, et al. Functional proteomic profiling of AML predicts response and survival. Blood. 2009;113:154–164
  5. Neubauer A, Maharry K, Mrózek K, et al. Patients with acute myeloid leukemia and RAS mutations benefit most from postremission high-dose cytarabine: a Cancer and Leukemia Group B study. J Clin Oncol. 2008;26:4603–4609
  6. Schmid C, Kolb HJ. Allogeneic stem cell transplantation in the management of acute myeloid leukemia. Med Klin. 2007;102:317–323
  7. Meijer E, Cornelissen JJ. Allogeneic stem cell transplantation in acute myeloid leukemia in first or subsequent remission: weighing prognostic markers predicting relapse and risk factors for non-relapse mortality. Semin Oncol. 2008;35:449–457
  8. Ravandi F, Talpaz M, Kantarjian H, Estrov Z. Cellular signalling pathways: new targets in leukaemia therapy. Br J Haematol. 2002;116:57–77
  9. Giles FJ. New drugs in acute myeloid leukemia. Curr Oncol Rep. 2002;4:369–374
  10. O'Brien SG, Guilhot F, Larson RA, et al. IRIS Investigators Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004
  11. Valent P, Lion T, Wolf D, et al. Diagnostic algorithms, monitoring, prognostication, and therapy in chronic myeloid leukemia (CML): a proposal of the Austrian CML platform. Wien Klin Wochenschr. 2008;120:697–709
  12. Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood. 2003;102:972–980
  13. Martelli AM, Nyakern M, Tabellini G, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia. 2006;20:911–928
  14. Grandage VL, Gale RE, Linch DC, Khwaja A. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. Leukemia. 2005;19:586–594
  15. Huang S, Bjornsti MA, Houghton PJ. Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther. 2003;2:222–232
  16. Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol. 2003;3:371–377
  17. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004;4:335–348
  18. Panwalkar A, Verstovsek S, Giles FJ. Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer. 2004;100:657–666
  19. Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood. 2002;100:3767–3775
  20. Mayerhofer M, Aichberger KJ, Florian S, et al. Identification of mTOR as a novel bifunctional target in chronic myeloid leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells. FASEB J. 2005;19:960–962
  21. Récher C, Dos Santos C, Demur C, Payrastre B. mTOR, a new therapeutic target in acute myeloid leukemia. Cell Cycle. 2005;4:1540–1549
  22. Récher C, Beyne-Rauzy O, Demur C, et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood. 2005;105:2527–2534
  23. Sillaber C, Mayerhofer M, Böhm A, et al. Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia. Eur J Clin Invest. 2008;38:43–52
  24. Böhm A, Aichberger KJ, Mayerhofer M, et al. Targeting of mTOR is associated with decreased growth and decreased VEGF expression in AML cells. Eur J Clin Invest. 2009;39:395–405
  25. ISCN. An international system for human cytogenetic nomenclature. Cytogenet Cell Genet. 1981;31:5–23
  26. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–1918
  27. Nishioka C, Ikezoe T, Yang J, Koeffler HP, Yokoyama A. Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia. 2008;22:2159–2168
  28. Calabro A, Tai J, Allen SL, Budman DR. In-vitro synergism of m-TOR inhibitors, statins, and classical chemotherapy: potential implications in acute leukemia. Anticancer Drugs. 2008;19:705–712
  29. Martelli AM, Tazzari PL, Evangelisti C, et al. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside. Curr Med Chem. 2007;14:2009–2023
  30. Park S, Chapuis N, Bardet V, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia. 2008;22:1698–1706
  31. Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7:1851–1863
  32. Yee KW, Zeng Z, Konopleva M, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2006;12:5165–5173
  33. Rizzieri DA, Feldman E, Dipersio JF, et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2008;14:2756–2762

☆ On behalf of all authors Peter Valent states no conflict of interest.

PII: S0953-6205(09)00184-8

doi: 10.1016/j.ejim.2009.09.007

European Journal of Internal Medicine
Volume 20, Issue 8 , Pages 775-778 , December 2009

Article Tools

* Image Usage & Resolution