Pediatric Drugs

, Volume 14, Issue 5, pp 299–316 | Cite as

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

  • David Barrett
  • Valerie I. Brown
  • Stephan A. Grupp
  • David T. Teachey
Review Article

Abstract

The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions.

A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin’s lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.

Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies.

Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.

References

  1. 1.
    Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol 2009 Nov 1; 27(31): 5175–81.PubMedCrossRefGoogle Scholar
  2. 2.
    Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001 Apr 5; 344 (14): 1031–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Yap TA, Garrett MD, Walton MI, et al. Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 2008; 8 (4): 393–412.PubMedCrossRefGoogle Scholar
  4. 4.
    LoPiccolo J, Blumenthal GM, Bernstein WB, et al. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updaat 2008; 11 (1–2): 32–50.CrossRefGoogle Scholar
  5. 5.
    Sugimoto Y, Whitman M, Cantley LC, et al. Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc Natl Acad Sci U S A 1984 Apr; 81 (7): 2117–21.PubMedCrossRefGoogle Scholar
  6. 6.
    Whitman M, Kaplan DR, Schaffhausen B, et al. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 1985 May 16–22; 315 (6016): 239–42.PubMedCrossRefGoogle Scholar
  7. 7.
    Markman B, Atzori F, Perez-Garcia J, et al. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol 2010 Apr; 21 (4): 683–91.PubMedCrossRefGoogle Scholar
  8. 8.
    Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010 Feb 20; 28 (6): 1075–83.PubMedCrossRefGoogle Scholar
  9. 9.
    Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006 Aug; 7 (8): 606–19.PubMedCrossRefGoogle Scholar
  10. 10.
    Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem 1998; 67: 481–507.PubMedCrossRefGoogle Scholar
  11. 11.
    Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005 Dec; 4 (12): 988–1004.PubMedCrossRefGoogle Scholar
  12. 12.
    Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005 Feb 18; 307 (5712): 1098–101.PubMedCrossRefGoogle Scholar
  13. 13.
    Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002 Sep; 4 (9): 648–57.PubMedCrossRefGoogle Scholar
  14. 14.
    Kang S, Denley A, Vanhaesebroeck B, et al. Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase. Proc Natl Acad Sci U S A 2006 Jan 31; 103 (5): 1289–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008 Sep 18; 27 (41): 5486–96.PubMedCrossRefGoogle Scholar
  16. 16.
    Grupp SA, Harmony JA. Increased phosphatidylinositol metabolism is an important but not an obligatory early event in B lymphocyte activation. J Immunol 1985 Jun; 134 (6): 4087–94.PubMedGoogle Scholar
  17. 17.
    Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997 Apr 1; 7 (4): 261–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Yang ZZ, Tschopp O, Baudry A, et al. Physiological functions of protein kinase B/Akt. Biochem Soc Trans 2004 Apr; 32 (Pt 2): 350–4.Google Scholar
  19. 19.
    Garofalo RS, Orena SJ, Rafidi K, et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest 2003 Jul; 112 (2): 197–208.PubMedGoogle Scholar
  20. 20.
    Castaneda CA, Cortes-Funes H, Gomez HL, et al. The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer. Cancer Metastasis Rev 2010 Dec; 29 (4): 751–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Hirsch E, Ciraolo E, Ghigo A, et al. Taming the PI3K team to hold inflammation and cancer at bay. Pharmacol Ther 2008 May; 118 (2): 192–205.PubMedCrossRefGoogle Scholar
  22. 22.
    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 (19): 2009–23.PubMedCrossRefGoogle Scholar
  23. 23.
    Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006 Feb 10; 124 (3): 471–84.PubMedCrossRefGoogle Scholar
  24. 24.
    Gera JF, Mellinghoff IK, Shi Y, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 2004 Jan 23; 279 (4): 2737–46.PubMedCrossRefGoogle Scholar
  25. 25.
    Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Aktdependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004 Jun; 10 (6): 594–601.PubMedCrossRefGoogle Scholar
  26. 26.
    Asnaghi L, Calastretti A, Bevilacqua A, et al. Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene 2004 Jun 21; 23 (34): 5781–91.PubMedCrossRefGoogle Scholar
  27. 27.
    Zeng X, Kinsella TJ. Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Cancer Res 2008 Apr 1; 68 (7): 2384–90.PubMedCrossRefGoogle Scholar
  28. 28.
    Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006 May 25; 441 (7092): 424–30.PubMedCrossRefGoogle Scholar
  29. 29.
    Kharas MG, Janes MR, Scarfone VM, et al. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J Clin Invest 2008 Sep; 118 (9): 3038–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell 2007 Apr; 12 (4): 487–502.PubMedCrossRefGoogle Scholar
  31. 31.
    Harrington LS, Findlay GM, Lamb RF. Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem Sci 2005 Jan; 30 (1): 35–42.PubMedCrossRefGoogle Scholar
  32. 32.
    Huang S, Bjornsti MA, Houghton PJ. Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther 2003 May–Jun; 2 (3): 222–32.PubMedGoogle Scholar
  33. 33.
    Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006 Aug; 5 (8): 671–88.PubMedCrossRefGoogle Scholar
  34. 34.
    Ewen ME, Sluss HK, Sherr CJ, et al. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell 1993 May 7; 73 (3): 487–97.PubMedCrossRefGoogle Scholar
  35. 35.
    Muranyi AL, Dedhar S, Hogge DE. Combined inhibition of integrin linked kinase and FMS-like tyrosine kinase 3 is cytotoxic to acute myeloid leukemia progenitor cells. Exp Hematol 2009 Apr; 37 (4): 450–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Faderl S, Pal A, Bornmann W, et al. Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells. Cancer Res 2009 May 1; 69 (9): 3910–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Birkenkamp KU, Geugien M, Schepers H, et al. Constitutive NF-kappaB DNA-binding activity in AML is frequently mediated by a Ras/PI3-K/PKB-dependent pathway. Leukemia 2004 Jan; 18 (1): 103–12.PubMedCrossRefGoogle Scholar
  38. 38.
    Bader AG, Kang S, Zhao L, et al. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 2005 Dec; 5 (12): 921–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Philp AJ, Campbell IG, Leet C, et al. The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 2001 Oct 15; 61 (20): 7426–9.PubMedGoogle Scholar
  40. 40.
    Feilotter HE, Coulon V, McVeigh JL, et al. Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br J Cancer 1999 Feb; 79 (5–6): 718–23.PubMedCrossRefGoogle Scholar
  41. 41.
    Ligresti G, Militello L, Steelman LS, et al. PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches. Cell Cycle 2009 May 1;8(9): 1352–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007 Jul 26; 448 (7152): 439–44.PubMedCrossRefGoogle Scholar
  43. 43.
    Bilbao C, Rodriguez G, Ramirez R, et al. The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer. Int J Cancer 2006 Aug 1; 119 (3): 563–70.PubMedCrossRefGoogle Scholar
  44. 44.
    Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997 Mar 28; 275 (5308): 1943–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Armengol G, Canellas A, Alvarez Y, et al. Genetic changes including gene copy number alterations and their relation to prognosis in childhood acute myeloid leukemia. Leuk Lymphoma 2010 Jan; 51 (1): 114–24.PubMedCrossRefGoogle Scholar
  46. 46.
    Knobbe CB, Reifenberger G. Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3′-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol 2003 Oct; 13 (4): 507–18.PubMedCrossRefGoogle Scholar
  47. 47.
    Remke M, Pfister S, Kox C, et al. High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-beta and PI3K-AKT pathways and deletions at 6q 15–16.1 as a genomic marker for unfavorable early treatment response. Blood 2009 Jul 30; 114 (5): 1053–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Dancey J. Nat Rev Clin Oncol Apr; 7 (4): 209–19.Google Scholar
  49. 49.
    Sorrells DL, Black DR, Meschonat C, et al. Detection of eIF4E gene amplification in breast cancer by competitive PCR. Ann Surg Oncol 1998 Apr–May; 5 (3): 232–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Perez-Tenorio G, Karlsson E, Waltersson MA, et al. Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer. Breast Cancer Res Treat 2011 Oct 16; 128 (3): 713–23.PubMedCrossRefGoogle Scholar
  51. 51.
    Uchimaru K, Taniguchi T, Yoshikawa M, et al. Detection of cyclin D1 (bcl-1, PRAD1) overexpression by a simple competitive reverse transcription-polymerase chain reaction assay in t(11;14)(q13;q32)-bearing B-cell malignancies and/or mantle cell lymphoma. Blood 1997 Feb 1; 89 (3): 965–74.PubMedGoogle Scholar
  52. 52.
    Sato T, Nakashima A, Guo L, et al. Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene 2010 May 6; 29 (18): 2746–52.PubMedCrossRefGoogle Scholar
  53. 53.
    Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000; 103: 253–62.PubMedCrossRefGoogle Scholar
  54. 54.
    Baur B, Oroszlan M, Hess O, et al. Efficacy and safety of sirolimus and everolimus in heart transplant patients: a retrospective analysis. Transplant Proc 2011 Jun; 43 (5): 1853–61.PubMedCrossRefGoogle Scholar
  55. 55.
    Cutler C, Antin JH. Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation. Bone Marrow Transplant 2004 Sep; 34 (6): 471–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Harper SJ, Gelson W, Harper IG, et al. Switching to sirolimus-based immune suppression after liver transplantation is safe and effective: a single-center experience. Transplantation 2011 Jan 15; 91 (1): 128–32.PubMedCrossRefGoogle Scholar
  57. 57.
    Kahan B. Toxicity spectrum of inhibitors of mammalian target of rapamycin in organ transplantation: etiology, pathogenesis and treatment. Expert Opin Drug Saf 2011 Sep; 10 (5): 727–49.PubMedCrossRefGoogle Scholar
  58. 58.
    McMahon G, Weir MR, Li XC, et al. The evolving role of mTOR inhibition in transplantation tolerance. J Am Soc Nephrol 2011 Mar; 22 (3): 408–15.PubMedCrossRefGoogle Scholar
  59. 59.
    Shitrit D, Yussim A, Kramer MR. Role of siroliumus, a novel immunosuppressive drug in heart and lung transplantation. Respir Med 2004 Sep; 98 (9): 892–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Teachey DT, Grupp SA, Brown VI. Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br J Haematol 2009 Jun; 145 (5): 569–80.PubMedCrossRefGoogle Scholar
  61. 61.
    Loewith R, Jacinto E, Wullschleger S, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002 Sep; 10 (3): 457–68.PubMedCrossRefGoogle Scholar
  62. 62.
    Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006 Apr 21; 22 (2): 159–68.PubMedCrossRefGoogle Scholar
  63. 63.
    Rosner M, Hengstschlager M. Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin 1. Hum Mol Genet 2008 Oct 1; 17 (19): 2934–48.PubMedCrossRefGoogle Scholar
  64. 64.
    Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol 2010 Apr; 7 (4): 209–19.PubMedCrossRefGoogle Scholar
  65. 65.
    Younes A, Samad N. Utility of mTOR inhibition in hematologic malignancies. Oncologist 2011 May 31; 16 (6): 730–41.PubMedCrossRefGoogle Scholar
  66. 66.
    Teachey DT, Greiner R, Seif A, et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol 2009 Apr; 145 (1): 101–6.PubMedCrossRefGoogle Scholar
  67. 67.
    Teachey DT, Jubelirer T, Baluarte HJ, et al. Treatment with sirolimus ameliorates tacrolimus-induced autoimmune cytopenias after solid organ transplant. Pediatr Blood Cancer 2009 Dec; 53 (6): 1114–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008 Aug 9; 372 (9637): 449–56.PubMedCrossRefGoogle Scholar
  69. 69.
    Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007 May 31; 356 (22): 2271–81.PubMedCrossRefGoogle Scholar
  70. 70.
    Kapoor A. Malignancy in kidney transplant recipients. Drugs 2008; 68 Suppl. 1: 11–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Rosenthal J, Pawlowska A, Bolotin E, et al. Transplant-associated thrombotic microangiopathy in pediatric patients treated with sirolimus and tacrolimus. Pediatr Blood Cancer 2011 Jul 15; 57 (1): 142–6.PubMedCrossRefGoogle Scholar
  72. 72.
    Dienstmann R, Rodon J, Markman B, et al. Recent developments in anticancer agents targeting PI3K, Akt and mTORC 1/2. Recent Pat Anticancer Drug Discov 2011 May 1; 6 (2): 210–36.PubMedCrossRefGoogle Scholar
  73. 73.
    Ogita S, Lorusso P. Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs. Target Oncol 2011 May 6; 6 (2): 103–17.PubMedCrossRefGoogle Scholar
  74. 74.
    Sun SY, Rosenberg LM, Wang X, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 2005 Aug 15; 65 (16): 7052–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Roccaro AM, Sacco A, Husu EN, et al. Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia. Blood 2010 Jan 21; 115 (3): 559–69.PubMedCrossRefGoogle Scholar
  76. 76.
    Bhatt AP, Bhende PM, Sin SH, et al. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood 2010 Jun 3; 115 (22): 4455–63.PubMedCrossRefGoogle Scholar
  77. 77.
    Cirstea D, Hideshima T, Rodig S, et al. Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther 2010 Apr; 9 (4): 963–75.PubMedCrossRefGoogle Scholar
  78. 78.
    Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009 Feb 10; 7 (2): e38PubMedCrossRefGoogle Scholar
  79. 79.
    Janes MR, Limon JJ, So L, et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 2010 Feb; 16 (2): 205–13.PubMedCrossRefGoogle Scholar
  80. 80.
    Hoang B, Frost P, Shi Y, et al. Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood 2010 Nov 25; 116 (22): 4560–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Schenone S, Brullo C, Musumeci F, et al. ATP-competitive inhibitors of mTOR: an update. Curr Med Chem 2011; 18 (20): 2995–3014.PubMedCrossRefGoogle Scholar
  82. 82.
    Sanchez CG, Ma CX, Crowder RJ, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res 2011 Mar 1; 13 (2): R21PubMedCrossRefGoogle Scholar
  83. 83.
    Baselga J, De Jonge M, Rodon J, et al. A first-in-human phase 1 study of BKM120, an oral panclass I PI3K inhibitor, in patients with advanced solid tumors. ASCO Meet Abstracts 2010; 28 (15 Suppl.): 3003.Google Scholar
  84. 84.
    Chakrabarty A, Sanchez V, Kuba MG, et al. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A 2012; 109 (8): 2718–23.PubMedCrossRefGoogle Scholar
  85. 85.
    Grana B, Burris H, Rodon J, et al. Oral PI3K kinase inhibitor BKM120 monotherapy in patients with advanced solid tumors: an update on safety and efficacy. ASCO Meet Abstracts 2011; 29 (15 Suppl.): 3043Google Scholar
  86. 86.
    Edelman G, Bedell C, Shapiro G, et al. A phase 1 dose escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients with advanced maligancies. ASCO Meet Abstracts 2010; 28 (15 Suppl.): 3004Google Scholar
  87. 87.
    Moldovan C, Soria J, LoRusso P, et al. A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients with advanced solid tumors. ASCO Meet Abstracts 2010; 28 (15 Suppl.): 3070.Google Scholar
  88. 88.
    Traynor A, Kurzrock R, Bailey H, et al. A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with paclitaxel and carboplatin in patients with advanced solid tumors. ASCO Meet Abstracts 2010; 28 (15 Suppl.): 3078.Google Scholar
  89. 89.
    Vanhaesebroeck B, Welham MJ, Kotani K, et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. roc Natl Acad Sci U S A 1997 Apr 29; 94 (9): 4330–5.CrossRefGoogle Scholar
  90. 90.
    Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010 Sep 23; 116 (12): 2078–88.PubMedCrossRefGoogle Scholar
  91. 91.
    Furman R, Byrd J, Brown JR, et al. An isoform-selective inhibitor of phos-phatidylinositol 3-Kinase P110delta, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia. ASH Ann Meet Abstr 2010; 116 (21): 66.Google Scholar
  92. 92.
    Kahl B, Byrd JC, Flinn I, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of PI3Kdelta, in patients with relapsed or refractory non-hodgkin lymphoma. ASH Ann Meet Abstr 2010; 116(21): 1777Google Scholar
  93. 93.
    Jimeno A, Herbst R, Falchook G, et al. Final results from a phase 1, dose-escalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase. ASCO Meet Abstracts 2010; 28 (15 Suppl.): 3005.Google Scholar
  94. 94.
    Ogita S, Lorusso P. Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs. Target Oncol 2011; 6 (2): 103–17.PubMedCrossRefGoogle Scholar
  95. 95.
    Chiarini F, Grimaldi C, Ricci F, et al. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res 2010 Oct 15; 70 (20): 8097–107.PubMedCrossRefGoogle Scholar
  96. 96.
    Wong J, Welschinger R, Baraz R, et al. Comparison of dual PI3K/mTOR inhibitors with mTOR inhibitors using a pre-clinical model of acute lymphoblastic leukemia. ASH Ann Meet Abstr 2010; 116 (21): 3258.Google Scholar
  97. 97.
    Schultz C, Dahlhaus M, Sekora A, et al. The dual PI3K and mTOR kinase inhibitor NVP-BEZ235 induces cell cycle arrest in acute lymphoblastic leukemia cells and potentiates the cytotoxicity of dexamethasone, cytarabine, and doxorubicin. ASH Ann Meet Abstr 2010; 116 (21): 4115.Google Scholar
  98. 98.
    Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR nhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008 Oct 1; 68 (19): 8022–30.PubMedCrossRefGoogle Scholar
  99. 99.
    Peyton J, Rodon J, Burris H, et al. A dose-escalation study with the novel formulation of the oral pan-class I PI3K inhibitor BEZ235, solid dipersion system (SDS) sachet, in patients with advanced or solid tumors. ASCO Meet Abstracts 2011; 29 (15 Suppl.): 3066.Google Scholar
  100. 100.
    Gajate C, Mollinedo F. Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 2007 Jan 15; 109 (2): 711–9.PubMedCrossRefGoogle Scholar
  101. 101.
    van Blitterswijk WJ, Verheij M. Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects. Curr Pharm Des 2008; 14 (21): 2061–74.PubMedCrossRefGoogle Scholar
  102. 102.
    Sundar S, Jha TK, Thakur CP, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 2002 Nov 28; 347 (22): 1739–46.PubMedCrossRefGoogle Scholar
  103. 103.
    Ghobrial IM, Roccaro A, Hong F, et al. Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom’s macroglobulinemia. Clin Cancer Res 2010 Feb 1; 16 (3): 1033–41.PubMedCrossRefGoogle Scholar
  104. 104.
    Gills JJ, Dennis PA. Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 2009 Mar; 11 (2): 102–10.PubMedCrossRefGoogle Scholar
  105. 105.
    Unger C, Berdel W, Hanauske AR, et al. First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours. Eur J Cancer 2010 Mar; 46 (5): 920–5.PubMedCrossRefGoogle Scholar
  106. 106.
    Mittelman A, Casper ES, Godwin TA, et al. Phase I study of tricyclic nucleoside phosphate. Cancer Treat Rep 1983 Feb; 67 (2): 159–62.PubMedGoogle Scholar
  107. 107.
    Feun LG, Savaraj N, Bodey GP, et al. Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule. Cancer Res 1984 Aug; 44 (8): 3608–12.PubMedGoogle Scholar
  108. 108.
    Garrett CR, Coppola D, Wenham RM, et al. Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT. Invest New Drugs 2011; 29 (6): 1381–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Yap T, Yan L, Patnaik A, et al. Final results of a translational phase 1 study assessing a QOD schedule of the potent AKT inhibitor MK-2206 in-corporatin predictive, pharmacodynamic (PD), and functional imaging biomarkers. ASCO Meet Abstracts 2011; 29 (15 Suppl.): 3001.Google Scholar
  110. 110.
    Burris H, Siu LL, Infante J, et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activityi of the oral AKT inhibitor GSK2141795 (GSK795) in a phase 1 first-in-human study. ASCO Meet Abstracts 2011; 29 (15 Suppl.): 3003.Google Scholar
  111. 111.
    Moerke NJ, Aktas H, Chen H, et al. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 2007 Jan 26; 128 (2): 257–67.PubMedCrossRefGoogle Scholar
  112. 112.
    Zhu J, Huang JW, Tseng PH, et al. From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. Cancer Res 2004 Jun 15; 64 (12): 4309–18.PubMedCrossRefGoogle Scholar
  113. 113.
    Gopalsamy A, Shi M, Boschelli DH, et al. Discovery of dibenzo[c, f][2,7] naphthyridines as potent and selective 3-phosphoinositide-dependent kinase-1 inhibitors. J Med Chem 2007 Nov 15; 50 (23): 5547–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Sato S, Fujita N, Tsuruo T. Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 2002 Mar 7; 21(11): 1727–38.PubMedCrossRefGoogle Scholar
  115. 115.
    Hagner PR, Schneider A, Gartenhaus RB. Targeting the translational machinery as a novel treatment strategy for hematologic malignancies. Blood 2010 Mar 18; 115 (11): 2127–35.PubMedCrossRefGoogle Scholar
  116. 116.
    Kentsis A, Topisirovic I, Culjkovic B, et al. Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci U S A 2004 Dec 28; 101 (52): 18105–10.PubMedCrossRefGoogle Scholar
  117. 117.
    Guo D, Teng Q, Ji C. NOTCH and phosphatidylinositide 3-kinase/phosphatase and tensin homolog deleted on chromosome ten/AKT/mammalian target of rapamycin (mTOR) signaling in T-cell development and T-cell acute lymphoblastic leukemia. Leuk Lymphoma 2011 Apr 4; 52 (7): 1200–10.PubMedCrossRefGoogle Scholar
  118. 118.
    Konicek BW, Stephens JR, McNulty AM, et al. Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases. Cancer Res 2011 Mar 1; 71 (5): 1849–57.PubMedCrossRefGoogle Scholar
  119. 119.
    Leseux L, Hamdi SM, Al Saati T, et al. Syk-dependent mTOR activation in follicular lymphoma cells. Blood 2006 Dec 15; 108 (13): 4156–62.PubMedCrossRefGoogle Scholar
  120. 120.
    Taga M, Hirooka E, Ouchi T. Essential roles of mTOR/Akt pathway in Aurora-A cell transformation. Int J Biol Sci 2009; 5 (5): 444–50.PubMedCrossRefGoogle Scholar
  121. 121.
    Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007 Apr 12; 446 (7137): 758–64.PubMedCrossRefGoogle Scholar
  122. 122.
    Mullighan CG, Phillips LA, Su X, et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008 Nov 28; 322 (5906): 1377–80.PubMedCrossRefGoogle Scholar
  123. 123.
    Mullighan CG, Collins-Underwood JR, Phillips LA, et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 2009 Nov; 41 (11): 1243–6.PubMedCrossRefGoogle Scholar
  124. 124.
    Zhang J, Mullighan CG, Harvey RC, et al. Key pathways are frequently mutated in high risk childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood 2011; 118 (11): 3080–7.PubMedCrossRefGoogle Scholar
  125. 125.
    Guo W, Lasky JL, Chang CJ, et al. Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature 2008 May 22; 453(7194): 529–33.PubMedCrossRefGoogle Scholar
  126. 126.
    Gutierrez A, Sanda T, Grebliunaite R, et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009 Jul 16; 114 (3): 647–50.PubMedCrossRefGoogle Scholar
  127. 127.
    Silva A, Yunes JA, Cardoso BA, et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 2008 Nov; 118 (11): 3762–74.PubMedCrossRefGoogle Scholar
  128. 128.
    Guo D, Ye J, Dai J, et al. Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines. Leuk Res 2009 May; 33 (5): 678–85.PubMedCrossRefGoogle Scholar
  129. 129.
    Kharas MG, Deane JA, Wong S, et al. Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells. Blood 2004 Jun 1; 103 (11): 4268–75.PubMedCrossRefGoogle Scholar
  130. 130.
    Shochat C, Tal N, Bandapalli OR, et al. Gain-of-function mutations in interleukin-7 receptor-alpha (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med 2011 May 9; 208 (5): 901–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Brown VI, Hulitt J, Fish J, et al. Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling. Cancer Res 2007 Oct 15; 67 (20): 9963–70.PubMedCrossRefGoogle Scholar
  132. 132.
    Brown VI, Fang J, Alcorn K, et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A 2003 Dec 9; 100 (25): 15113–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Wasserman R, Zeng XX, Hardy RR. The evolution of B precursor leukemia in the Emu-ret mouse. Blood 1998; 92 (1): 273–82.PubMedGoogle Scholar
  134. 134.
    Avellino R, Romano S, Parasole R, et al. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood 2005 Aug 15; 106 (4): 1400–6.PubMedCrossRefGoogle Scholar
  135. 135.
    Teachey DT, Obzut DA, Cooperman J, et al. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood 2006 Feb 1; 107 (3): 1149–55.PubMedCrossRefGoogle Scholar
  136. 136.
    Teachey DT, Sheen C, Hall J, et al. mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood 2008 Sep 1; 112 (5): 2020–3.PubMedCrossRefGoogle Scholar
  137. 137.
    Hirase C, Maeda Y, Takai S, et al. Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: possible clinical application of mTOR inhibitor. Leuk Res 2009 Mar; 33 (3): 450–9.PubMedCrossRefGoogle Scholar
  138. 138.
    Crazzolara R, Bradstock KF, Bendall LJ. RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia. Autophagy 2009 Jul; 5 (5): 727–8.PubMedCrossRefGoogle Scholar
  139. 139.
    Crazzolara R, Cisterne A, Thien M, et al. Potentiating effects of RAD001 (everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Blood 2009 Apr 2; 113 (14): 3297–306.PubMedCrossRefGoogle Scholar
  140. 140.
    Houghton PJ, Morton CL, Kolb EA, et al. Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer 2008 Apr; 50 (4): 799–805.PubMedCrossRefGoogle Scholar
  141. 141.
    Cullion K, Draheim KM, Hermance N, et al. Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 2009 Jun 11; 113 (24): 6172–81.PubMedCrossRefGoogle Scholar
  142. 142.
    Teachey DT, Vincent T, Willman CL, et al. Targeting mTOR signaling is an effective strategy for IKAROS and JAK kinase mutated acute lymphoblastic leukemia (ALL). ASH Ann Meet Abstr 2010; 116 (21): 3251.Google Scholar
  143. 143.
    Meyer LH, Eckhoff SM, Queudeville M, et al. Early relapse in all is identified by time to leukemia in NOD/SCID mice and is characterized by a gene signature involving survival pathways. Cancer Cell 2011 Feb 15; 19 (2): 206–17.PubMedCrossRefGoogle Scholar
  144. 144.
    Saydam G, Celikkaya H, Cole P, et al. mTOR inhibition leads to increased sensitivity to methotrexate [abstract no. 3303; online]. Available from URL: http://www.aacrmeetingabstracts.org/cgi/content/abstract/2005/1/777-c [Accessed 2012 May 28]
  145. 145.
    Wei G, Twomey D, Lamb J, et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 2006 Oct; 10 (4): 331–42.PubMedCrossRefGoogle Scholar
  146. 146.
    Houghton PJ, Morton CL, Gorlick R, et al. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther 2010 Jan; 9 (1): 101–12.PubMedCrossRefGoogle Scholar
  147. 147.
    Batista A, Barata JT, Raderschall E, et al. Targeting of active mTOR inhibits primary leukemia T cells and synergizes with cytotoxic drugs and signaling inhibitors. Exp Hematol 2011 Apr; 39 (4): 457–72.e3PubMedCrossRefGoogle Scholar
  148. 148.
    Saunders P, Cisterne A, Weiss J, et al. The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia. Haematologica 2011 Jan; 96 (1): 69–77.PubMedCrossRefGoogle Scholar
  149. 149.
    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 Sep 1; 12(17): 5165–73.PubMedCrossRefGoogle Scholar
  150. 150.
    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 May 1; 14 (9): 2756–62.PubMedCrossRefGoogle Scholar
  151. 151.
    Rheingold S, Sacks N, Chang YJ, et al. A phase I trial of sirolimus (rapamycin) in pediatric patients with relapsed/refractory leukemia. Blood (ASH Ann Meet Abstr) 2007 Nov; 110: 2834.Google Scholar
  152. 152.
    Schlis KD, Stubbs M, DeAngelo DJ, et al. A pilot of rapamycin with glucocorticoids in children adults with relapsed ALL. ASH Ann Meet Abstr 2010; 116 (21): 3244.Google Scholar
  153. 153.
    Teachey DT, Sheen C, Brown VI, et al. Targeting eIF4E with ribavirin demonstrates a potentially effective strategy against acute lymphoblastic leukemia (ALL). ASPHO Annual Meeting Abstr 2008 [online]. Available from URL: http://onlinelibrary.wiley.com/store/10.1002/(ISSN)1545-5017/asset/homepages/ASPHO2008_-final_paginated.pdf?v=1&s=fde2ea10743d8e3d9eb18ad379856bb03b224de4 [Accessed 2012 Jul 20]
  154. 154.
    Chiarini F, Fala F, Tazzari PL, et al. Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res 2009 Apr 15; 69 (8): 3520–8.PubMedCrossRefGoogle Scholar
  155. 155.
    Brown VI, Seif AE, Reid GS, et al. Novel molecular and cellular therapeutic targets in acute lymphoblastic leukemia and lymphoproliferative disease. Immunol Res 2008; 42 (1–3): 84–105.PubMedCrossRefGoogle Scholar
  156. 156.
    Evangelisti C, Ricci F, Tazzari P, et al. Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia. Leukemia 2011 May; 25 (5): 781–91.PubMedCrossRefGoogle Scholar
  157. 157.
    Carol H, Morton CL, Gorlick R, et al. Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program. Pediatr Blood Cancer 2010 Dec 15; 55 (7): 1329–37.PubMedCrossRefGoogle Scholar
  158. 158.
    Levy DS, Kahana JA, Kumar R. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood 2009 Feb 19; 113(8): 1723–9.PubMedCrossRefGoogle Scholar
  159. 159.
    Martelli AM, Evangelisti C, Chiarini F, et al. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget 2010 Jun; 1 (2): 89–103.PubMedGoogle Scholar
  160. 160.
    Altman JK, Sassano A, Platanias LC. Targeting mTOR for the treatment of AML: new agents and new directions. Oncotarget 2011 Jun; 2 (6): 510–7.PubMedGoogle Scholar
  161. 161.
    Sujobert P, Bardet V, Cornillet-Lefebvre P, et al. Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 2005 Aug 1; 106 (3): 1063–6.PubMedCrossRefGoogle Scholar
  162. 162.
    Billottet C, Grandage VL, Gale RE, et al. A selective inhibitor of the p110delta isoform of PI3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16. Oncogene 2006 Oct 26; 25 (50): 6648–59.PubMedCrossRefGoogle Scholar
  163. 163.
    Doepfner KT, Spertini O, Arcaro A. Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway. Leukemia 2007 Sep; 21 (9): 1921–30.PubMedCrossRefGoogle Scholar
  164. 164.
    Tazzari PL, Tabellini G, Bortul R, et al. The insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 induces apoptosis in acute myeloid leukemia cells exhibiting autocrine insulin-like growth factor-I secretion. Leukemia 2007 May; 21 (5): 886–96.PubMedGoogle Scholar
  165. 165.
    Wahner Hendrickson AE, Haluska P, Schneider PA, et al. Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro. Cancer Res 2009 Oct 1; 69 (19): 7635–43.PubMedCrossRefGoogle Scholar
  166. 166.
    Imai N, Miwa H, Shikami M, et al. Growth inhibition of AML cells with specific chromosome abnormalities by monoclonal antibodies to receptors for vascular endothelial growth factor. Leuk Res 2009 Dec; 33 (12): 1650–7.PubMedCrossRefGoogle Scholar
  167. 167.
    Bohm A, Aichberger KJ, Mayerhofer M, et al. Targeting of mTOR is associated with decreased growth and decreased VEGF expression in acute myeloid leukaemia cells. Eur J Clin Invest 2009 May; 39 (5): 395–405.PubMedCrossRefGoogle Scholar
  168. 168.
    Pearn L, Fisher J, Burnett AK, et al. The role of PKC and PDK1 in monocyte lineage specification by Ras. Blood 2007 May 15; 109 (10): 4461–9.PubMedCrossRefGoogle Scholar
  169. 169.
    Recher C, Dos Santos C, Demur C, et al. mTOR, a new therapeutic target in acute myeloid leukemia. Cell Cycle 2005 Nov; 4 (11): 1540–9.PubMedCrossRefGoogle Scholar
  170. 170.
    Perl AE, Carroll M. Exploiting signal transduction pathways in acute myelogenous leukemia. Curr Treat Options Oncol 2007 Aug; 8 (4): 265–76.PubMedCrossRefGoogle Scholar
  171. 171.
    Xu Q, Thompson JE, Carroll M. mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood 2005 Dec 15; 106 (13): 4261–8.PubMedCrossRefGoogle Scholar
  172. 172.
    Xu RH, Pelicano H, Zhang H, et al. Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. Leukemia 2005 Dec; 19 (12): 2153–8.PubMedCrossRefGoogle Scholar
  173. 173.
    Nishioka C, Ikezoe T, Yang J, et al. Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia 2008 Dec; 22 (12): 2159–68.PubMedCrossRefGoogle Scholar
  174. 174.
    Janus A, Linke A, Cebula B, et al. Rapamycin, the mTOR kinase inhibitor, sensitizes acute myeloid leukemia cells, HL-60 cells, to the cytotoxic effect of arabinozide cytarabine. Anticancer Drugs 2009 Sep; 20 (8): 693–701.PubMedCrossRefGoogle Scholar
  175. 175.
    Akers LJ, Fang W, Levy AG, et al. Targeting glycolysis in leukemia: a novel inhibitor 3-BrOP in combination with rapamycin. Leuk Res 2011; 35 (6): 814–20.PubMedCrossRefGoogle Scholar
  176. 176.
    Calabro A, Tai J, Allen SL, et al. In-vitro synergism of m-TOR inhibitors, statins, and classical chemotherapy: potential implications in acute leukemia. Anticancer Drugs 2008 Aug; 19 (7): 705–12.PubMedCrossRefGoogle Scholar
  177. 177.
    Perl AE, Kasner MT, Tsai DE, et al. A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clin Cancer Res 2009 Nov 1; 15 (21): 6732–9.PubMedCrossRefGoogle Scholar
  178. 178.
    Wei A, Sadawarte S, Catalano J, et al. A phase 1b study combining the mTOR inhibitor everolimus (RAD001) with low dose cytarabine in untreated elderly AML patients. ASH Ann Meet Abstr 2010; 116 (21): 3299.Google Scholar
  179. 179.
    Wei A, Sadawarte S, Catalano J, et al. Clinical activity of azacitidine in combination with the oral mTOR inhibitor everolimus (RAD001) in relapsed and refractory AML: interim analysis of a phase 1b/II study. ASH Ann Meet Abstr 2010; 116 (21): 3301.Google Scholar
  180. 180.
    Xu Q, Simpson SE, Scialla TJ, et al. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003 Aug 1; 102 (3): 972–80.PubMedCrossRefGoogle Scholar
  181. 181.
    Neri LM, Borgatti P, Tazzari PL, et al. The phosphoinositide 3-kinase/AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells. Mol Cancer Res 2003 Jan; 1 (3): 234–46.PubMedGoogle Scholar
  182. 182.
    Assouline S, Culjkovic B, Cocolakis E, et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood 2009 Jul 9; 114 (2): 257–60.PubMedCrossRefGoogle Scholar
  183. 183.
    Chapuis N, Tamburini J, Green AS, et al. Dual inhibition of PI3K and mTORC1/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia. Clin Cancer Res 2010 Nov 15; 16 (22): 5424–35.PubMedCrossRefGoogle Scholar
  184. 184.
    Altman JK, Sassano A, Kaur S, et al. Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors. Clin Cancer Res 2011 Jul 1; 17 (13): 4378–88.PubMedCrossRefGoogle Scholar
  185. 185.
    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 Sep; 22 (9): 1698–706.PubMedCrossRefGoogle Scholar
  186. 186.
    Zeng Z, SHi Y, Tsao T, et al. Targeting mTORC1/2 by a mTOR kinase inhibitor (PP242) induces apoptosis in AML cells under conditions mimicking the bone marrow environment. ASH Ann Meet Abstr 2010; 116 (21): 778.Google Scholar
  187. 187.
    Papa V, Tazzari PL, Chiarini F, et al. Proapoptotic activity and chemo-sensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia 2008 Jan; 22 (1): 147–60.PubMedCrossRefGoogle Scholar
  188. 188.
    Ly C, Arechiga AF, Melo JV, et al. Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 2003 Sep 15; 63 (18): 5716–22.PubMedGoogle Scholar
  189. 189.
    Mohi MG, Boulton C, Gu TL, et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci U S A 2004 Mar 2; 101 (9): 3130–5.PubMedCrossRefGoogle Scholar
  190. 190.
    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 Jun; 19 (8): 960–2.PubMedGoogle Scholar
  191. 191.
    Sillaber C, Mayerhofer M, Bohm A, et al. Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia. Eur J Clin Invest 2008 Jan; 38 (1): 43–52.PubMedCrossRefGoogle Scholar
  192. 192.
    Mancini M, Corradi V, Petta S, et al. mTOR inhibitor RAD001 (everolimus) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c-ABL protein. Leuk Res 2010 May; 34 (5): 641–8.PubMedCrossRefGoogle Scholar
  193. 193.
    Witzig TE, Gupta M. Signal transduction inhibitor therapy for lymphoma. Hematology Am Soc Hematol Educ Program 2010; 265–70.Google Scholar
  194. 194.
    Zhao XF, Gartenhaus RB. Phospho-p70S6K and cdc2/cdk1 as therapeutic targets for diffuse large B-cell lymphoma. Expert Opin Ther Targets 2009 Sep; 13(9): 1085–93.PubMedCrossRefGoogle Scholar
  195. 195.
    Zhao MY, Auerbach A, D’Costa AM, et al. Phospho-p70S6K/p85S6K and cdc2/cdk1 are novel targets for diffuse large B-cell lymphoma combination therapy. Clin Cancer Res 2009 Mar 1; 15 (5): 1708–20.PubMedCrossRefGoogle Scholar
  196. 196.
    Gupta M, Ansell SM, Novak AJ, et al. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood 2009 Oct 1; 114 (14): 2926–35.PubMedCrossRefGoogle Scholar
  197. 197.
    Witzig TE, Reeder CB, LaPlant BR, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 2011 Feb; 25 (2): 341–7.PubMedCrossRefGoogle Scholar
  198. 198.
    Smith SM, van Besien K, Karrison T, et al. Temsirolimus has activity in nonmantle cell non-Hodgkin’s lymphoma subtypes: the University of Chicago phase II consortium. J Clin Oncol 2010 Nov 1; 28 (31): 4740–6.PubMedCrossRefGoogle Scholar
  199. 199.
    Dutton A, Reynolds GM, Dawson CW, et al. Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin’s lymphoma cells through a mechanism involving Akt kinase and mTOR. J Pathol 2005 Mar; 205 (4): 498–506.PubMedCrossRefGoogle Scholar
  200. 200.
    Jundt F, Raetzel N, Muller C, et al. A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein ta and NF-kappaB activity in Hodgkin and anaplastic large cell lymphomas. Blood 2005 Sep 1; 106 (5): 1801–7.PubMedCrossRefGoogle Scholar
  201. 201.
    Johnston PB, Inwards DJ, Colgan JP, et al. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol 2010 May; 85 (5): 320–4.PubMedGoogle Scholar
  202. 202.
    Vega F, Medeiros LJ, Leventaki V, et al. Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Res 2006 Jul 1; 66 (13): 6589–97.PubMedCrossRefGoogle Scholar
  203. 203.
    Chumsri S, Zhao M, Garofalo M, et al. Inhibition of the mammalian target of rapamycin (mTOR) in a case of refractory primary cutaneous anaplastic large cell lymphoma. Leuk Lymphoma 2008 Feb; 49 (2): 359–61.PubMedCrossRefGoogle Scholar
  204. 204.
    Evens AM, Roy R, Sterrenberg D, et al. Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy. Curr Oncol Rep 2010 Nov; 12 (6): 383–94.PubMedCrossRefGoogle Scholar
  205. 205.
    Wudhikarn K, Holman CJ, Linan M, et al. Post-transplant lymphoprolifeative disorders in lung transplant recipients: 20-yr experience at the University of Minnesota. Clin Transplant 2011; 25 (5): 705–13.PubMedCrossRefGoogle Scholar
  206. 206.
    Filipovich AH, Mathur A, Kamat D, et al. Lymphoproliferative disorders and other tumors complicating immunodeficiencies. Immunodeficiency 1994; 5 (2): 91–112.PubMedGoogle Scholar
  207. 207.
    Tran H, Nourse J, Hall S, et al. Immunodeficiency-associated lymphomas. Blood Rev 2008 Sep; 22 (5): 261–81.PubMedCrossRefGoogle Scholar
  208. 208.
    El-Salem M, Raghunath PN, Marzec M, et al. Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders. Lab Invest 2007 Jan; 87 (1): 29–39.PubMedCrossRefGoogle Scholar
  209. 209.
    Majewski M, Korecka M, Joergensen J, et al. Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation 2003 May 27; 75 (10): 1710–7.PubMedCrossRefGoogle Scholar
  210. 210.
    Andres AM, Lopez Santamaria M, Ramos E, et al. The use of sirolimus as a rescue therapy in pediatric intestinal transplant recipients. Pediatr Transplant 2010 Nov; 14 (7): 931–5.PubMedCrossRefGoogle Scholar
  211. 211.
    Khalpey Z, Miller DV, Schmitto JD, et al. Long-term maintenance therapy for post-cardiac transplant monoclonal lymphoproliferative disorder: caveat Mammalian target of rapamycin. Transplant Proc 2011 Jun; 43 (5): 1893–9.PubMedCrossRefGoogle Scholar
  212. 212.
    Manuelli M, De Luca L, Iaria G, et al. Conversion to rapamycin immunosuppression for malignancy after kidney transplantation. Transplant Proc 2011 May; 42 (4): 1314–6.CrossRefGoogle Scholar
  213. 213.
    Salassa JR, Ozgursoy OB, Weindling SM, et al. Computed tomographic aniography with three-dimensional reconstruction for transoral laser microsurgery. Otolaryngol Head Neck Surg 2010 Mar; 142 (3): 351–4.PubMedCrossRefGoogle Scholar
  214. 214.
    Bleesing JJ, Straus SE, Fleisher TA. Autoimmune lymphoproliferative syndrome: a human disorder of abnormal lymphocyte survival. Pediatr Clin North Am 2000 Dec; 47 (6): 1291–310.PubMedCrossRefGoogle Scholar
  215. 215.
    Lenardo MJ, Oliveira JB, Zheng L, et al. ALPS-ten lessons from an international workshop on a genetic disease of apoptosis. Immunity 2010 Mar 26; 32 (3): 291–5.PubMedCrossRefGoogle Scholar
  216. 216.
    Oliveira JB, Bleesing JJ, Dianzani U, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood 2010; 116 (14): e35–40.PubMedCrossRefGoogle Scholar
  217. 217.
    Rao VK, Dugan F, Dale JK, et al. Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. Br J Haematol 2005 May; 129 (4): 534–8.PubMedCrossRefGoogle Scholar
  218. 218.
    Teachey DT, Obzut DA, Axsom K, et al. Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). Blood 2006 Sep 15; 108 (6): 1965–71.PubMedCrossRefGoogle Scholar
  219. 219.
    Teachey DT. Autoimmune lymphoproliferative syndrome: new approaches to diagnosis and management. Clin Adv Hematol Oncol 2011; 9 (3): 233–5.PubMedGoogle Scholar
  220. 220.
    Janic MD, Brasanac CD, Jankovic JS, et al. Rapid regression of lymphadenopathy upon rapamycin treatment in a child with autoimmune lymphoproliferative syndrome. Pediatr Blood Cancer 2009 Dec; 53 (6): 1117–9.PubMedCrossRefGoogle Scholar
  221. 221.
    Tommasini A, Valencic E, Piscianz E, et al. Immunomodulatory drugs in autoimmune lymphoproliferative syndrome (ALPS). Pediatr Blood Cancer 2012; 58 (2): 310; reply 311PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • David Barrett
    • 1
  • Valerie I. Brown
    • 1
  • Stephan A. Grupp
    • 1
  • David T. Teachey
    • 1
    • 2
  1. 1.Department of Pediatrics, Division of OncologyChildren’s Hospital of Philadelphia, University of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of Pediatrics, Division of HematologyChildren’s Hospital of Philadelphia, University of Pennsylvania School of MedicinePhiladelphiaUSA

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