Targeting the PI3KAKTmTOR signaling axis in children with hematologic malignancies

Pediatric Drugs

Volumn 14, Issue 5, 2012, Pages 299-316

  Barrett, David ^a   Brown, Valerie I ^a   Grupp, Stephan A ^a   Teachey, David T ^a  

^a CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

Author keywords

1 Phosphatidylinositol 3 kinase inhibitors; Acute lymphoblastic leukaemia; Acute myeloid leukaemia; Cancer; Children; Chronic myeloid leukaemia; Corticosteroids; Haematological malignancies; Lymphoma; Lymphoproliferative disorders; Methotrexate; mTOR protein inhibitors; Non Hodgkins lymphoma; Sirolimus.

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 (2 DIFLUOROMETHYLBENZIMIDAZOL 1 YL) 4,6 DIMORPHOLINO 1,3,5 TRIAZINE; 2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; 2 MORPHOLINO 8 PHENYLCHROMONE; 4 (4 AMINO 5 (7 METHOXY 1H INDOL 2 YL)IMIDAZO[5,1 F][1,2,4]TRIAZIN 7 YL)CYCLOHEXANECARBOXYLIC ACID; 4 [2 (4 AMINO 1,2,5 OXADIAZOL 3 YL) 1 ETHYL 7 (3 PIPERIDINYLMETHOXY) 1H IMIDAZO[4,5 C]PYRIDIN 4 YL] 2 METHYL 3 BUTYN 2 OL; 4 DIALLYLAMINOMETHYLENE 1,3,4,7,10,11,12,13,14,15,16,17 DODECAHYDRO 6 HYDROXY 1 METHOXYMETHYL 10,13 DIMETHYL 3,7,17 TRIOXO 2 OXACYCLOPENTA[A]PHENANTHREN 11 YL ACETATE; 5 FLUORO 3 PHENYL 2 [1 (9H PURIN 6 YLAMINO)PROPYL] 3H QUINAZOLIN 4 ONE; 7 HYDROXYSTAUROSPORINE; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; AR 12; AZD 8055; BGT 226; BUPARLISIB; CORTICOSTEROID; EVEROLIMUS; GDC 0068; GDC 0980; GSK 2110183; GSK 2126458; GSK 2141795; INK 128; LY 2780301; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; METHOTREXATE; PERIFOSINE; PF 4691502; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; RAPAMYCIN; RIDAFOROLIMUS; SAR 245409; STATIN; TEMSIROLIMUS; UNCLASSIFIED DRUG; XL 147; XL 499; ANTINEOPLASTIC AGENT; TARGET OF RAPAMYCIN KINASE;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; APOPTOSIS; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; CELL CYCLE PROGRESSION; CELL GROWTH; CELL SURVIVAL; CHRONIC MYELOID LEUKEMIA; DIARRHEA; DOWN REGULATION; DRUG BIOAVAILABILITY; EDEMA; FATIGUE; GENETIC TRANSCRIPTION; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; HYPERLIPIDEMIA; INTERSTITIAL PNEUMONIA; KIDNEY FAILURE; METABOLISM; NONHODGKIN LYMPHOMA; NONHUMAN; PRIORITY JOURNAL; PROTEIN PROCESSING; REMISSION; REVIEW; SIGNAL TRANSDUCTION; SKIN MANIFESTATION; SOLUBILITY; STOMATITIS; THROMBOCYTOPENIA; UPREGULATION; ANIMAL; CHILD; DRUG ANTAGONISM; HEMATOLOGIC DISEASE; LYMPHOPROLIFERATIVE DISEASE; MOLECULARLY TARGETED THERAPY;

ANIMALS; ANTINEOPLASTIC AGENTS; CHILD; HEMATOLOGIC NEOPLASMS; HUMANS; LYMPHOPROLIFERATIVE DISORDERS; MOLECULAR TARGETED THERAPY; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84865348593     PISSN: 11745878     EISSN: 11792019     Source Type: Journal    
DOI: 10.2165/11594740-000000000-00000     Document Type: Review

References (221)

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
2. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitorof the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001 Apr 5; 344 (14): 1031-7
3. Yap TA, GarrettMD,Walton MI, et al. Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 2008; 8 (4): 393-412
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
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
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
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
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
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
10. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem 1998; 67: 481-507
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
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
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
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
15. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008 Sep 18; 27 (41): 5486-96
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
17. Alessi DR, James SR,Downes CP, et al.Characterization of a 3-phosphoinositidedependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997 Apr 1; 7 (4): 261-9
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
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
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
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
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
23. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006 Feb 10; 124 (3): 471-84
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
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
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
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
28. Shaw RJ, Cantley LC. Ras, PI(3)K andmTORsignalling controls tumour cell growth. Nature 2006 May 25; 441 (7092): 424-30
29. Kharas MG, Janes MR, Scarfone VM, et al. Ablation of PI3K blocks BCRABL 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
30. Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell 2007 Apr; 12 (4): 487-502
31. Harrington LS, Findlay GM, Lamb RF. Restraining PI3K: mTOR signaling goes back to the membrane. Trends Biochem Sci 2005 Jan; 30 (1): 35-42
32. Huang S, Bjornsti MA, Houghton PJ. Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther 2003 May-Jun; 2 (3): 222-32
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
34. EwenME, Sluss HK, SherrCJ, et al. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell 1993May 7; 73 (3): 487-97
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
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
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/PKBdependent pathway. Leukemia 2004 Jan; 18 (1): 103-12
38. Bader AG, Kang S, Zhao L, et al. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 2005 Dec; 5 (12): 921-9
39. Philp AJ, Campbell IG, Leet C, et al. The phosphatidylinositol 30-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 2001 Oct 15; 61 (20): 7426-9
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
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
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
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
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
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
46. Knobbe CB, Reifenberger G. Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-30-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol 2003 Oct; 13 (4): 507-18
47. RemkeM, 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 6q15-16.1 as a genomic marker for unfavorable early treatment response. Blood 2009 Jul 30; 114 (5): 1053-62
48. Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol Apr; 7 (4): 209-19
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
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
51. Uchimaru K, Taniguchi T, Yoshikawa M, et al. Detection of cyclin D1 (bcl-1, PRAD1) overexpression by a simple competitive reverse transcriptionpolymerase 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
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
53. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000; 103: 253-62
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
55. Cutler C, Antin JH. Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation. Bone Marrow Transplant 2004 Sep; 34 (6): 471-6
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
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
58. McMahonG, Weir MR, Li XC, et al. The evolving role ofmTORinhibition in transplantation tolerance. J Am Soc Nephrol 2011 Mar; 22 (3): 408-15
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
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
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
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
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 sinq 1 Hum Mol Genet 2008 Oct 1; 17 (19): 2934-48
64. Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol 2010 Apr; 7 (4): 209-19
65. Younes A, Samad N. Utility of mTOR inhibition in hematologic malignancies. Oncologist 2011 May 31; 16 (6): 730-41
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
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
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
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
70. Kapoor A. Malignancy in kidney transplant recipients. Drugs 2008; 68 Suppl. 1: 11-9
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
72. Dienstmann R, Rodon J, Markman B, et al. Recent developments in anticancer agents targeting PI3K, Akt and mTORC1/2. Recent Pat Anticancer Drug Discov 2011 May 1; 6 (2): 210-36
73. Ogita S, Lorusso P. Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs. Target Oncol 2011 May 6; 6 (2): 103-17
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
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
76. Bhatt AP, Bhende PM, Sin SH, et al. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTORaddicted lymphomas. Blood 2010 Jun 3; 115 (22): 4455-63
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
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): E38
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
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
81. Schenone S, Brullo C, Musumeci F, et al. ATP-competitive inhibitors of mTOR: An update. Curr Med Chem 2011; 18 (20): 2995-3014
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): R21
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
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
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.): 3043
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.): 3004
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
88. Traynor A, KurzrockR, BaileyH, et al.Aphase 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
89. Vanhaesebroeck B, Welham MJ, Kotani K, et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A 1997 Apr 29; 94 (9): 4330-5
90. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinasedelta 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
91. Furman R, Byrd J, Brown JR, et al. An isoform-selective inhibitor of phosphatidylinositol 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
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): 1777
93. Jimeno A, Herbst R, Falchook G, et al. Final results from a phase 1, doseescalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase. ASCO Meet Abstracts 2010; 28 (15 Suppl.): 3005
94. Ogita S, Lorusso P. Targeting phosphatidylinositol 3 kinase (PI3K)-Akt beyond rapalogs. Target Oncol 2011; 6 (2): 103-17
95. Chiarini F, Grimaldi C, Ricci F, et al. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVPBEZ235 against T-cell acute lymphoblastic leukemia. Cancer Res 2010 Oct 15; 70 (20): 8097-107
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
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
98. Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008 Oct 1; 68 (19): 8022-30
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
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
101. van Blitterswijk WJ, Verheij M. Anticancer alkylphospholipids: mechanismsof action, cellular sensitivity and resistance, and clinical prospects. Curr Pharm Des 2008; 14 (21): 2061-74
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
103. Ghobrial IM Roccaro A Hong F et al. Clinical 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
104. Gills JJ, Dennis PA. Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 2009 Mar; 11 (2): 102-10
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
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
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
108. Garrett CR, Coppola D, Wenham RM, et al. Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a smallmolecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT. Invest New Drugs 2011; 29 (6): 1381-9
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 incorporatin predictive, pharmacodynamic (PD), and functional imaging biomarkers. ASCO Meet Abstracts 2011; 29 (15 Suppl.): 3001
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
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
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
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
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
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
116. Kentsis A, Topisirovic I, Culjkovic B, et al. Ribavirin suppresses eIF4Emediated 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
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
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
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
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
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
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
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
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
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
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
127. Silva A, Yunes JA, Cardoso BA, et al. PTEN posttranslational inactivationand hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 2008 Nov; 118 (11): 3762-74
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
129. Kharas MG, Deane JA, Wong S, et al. Phosphoinositide 3-kinase signaling isessential for ABL oncogene-mediated transformation of B-lineage cells. Blood 2004 Jun 1; 103 (11): 4268-75
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
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
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
133. Wasserman R, Zeng XX, Hardy RR. The evolution of B precursor leukemia in the Emu-ret mouse. Blood 1998; 92 (1): 273-82
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
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
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
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
138. Crazzolara R, Bradstock KF, Bendall LJ. RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia. Autophagy 2009 Jul; 5 (5): 727-8
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
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
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
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
143. Meyer LH Eckhoff SM Queudeville M et al. Early relapse in all is identified by time to leukemia in NODSCID mice is characterized by A Gene Signature Involving Survival Pathways. Cancer Cell 2011 Feb 15; 19 (2) 206-17
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. 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
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
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.e3
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
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
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
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
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
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/ASPHO-2008-final-paginated.pdf?v=1&s=fde2ea10743d 8e3d9eb18ad379856bb03b224de4 [Accessed 2012 Jul 20]
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
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
156. Evangelisti C, Ricci F, Tazzari P, et al. Targeted inhibition of mTORC1 and mTORC2 by active-sitemTORinhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia. Leukemia 2011 May; 25 (5): 781-91
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
158. Levy DS, Kahana JA, Kumar R.AKTinhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood 2009 Feb 19; 113 (8): 1723-9
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
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
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
162. Billottet C, Grandage VL, Gale RE, et al. A selective inhibitor of the p110delta isoformof PI 3-kinase inhibitsAMLcell proliferation and survival and increases the cytotoxic effects of VP16. Oncogene 2006 Oct 26; 25 (50): 6648-59
163. Doepfner KT, Spertini O, Arcaro A. Autocrine insulin-like growth factor-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
164. Tazzari PL, Tabellini G, Bortul R, et al. The insulin-like growth factor-receptor kinase inhibitor NVP-AEW541 induces apoptosis in acute myeloid
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
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
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
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
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
170. Perl AE, Carroll M. Exploiting signal transduction pathways in acute myelogenous leukemia. Curr Treat Options Oncol 2007 Aug; 8 (4): 265-76
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
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
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
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
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
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
177. Perl AE, KasnerMT, 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
178. Wei A, Sadawarte S, Catalano J, et al.Aphase 1b study combining themTOR inhibitor everolimus (RAD001) with low dose cytarabine in untreated elderly AML patients. ASH Ann Meet Abstr 2010; 116 (21): 3299
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
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
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
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
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
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
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
186. Zeng Z, SHi Y, Tsao T, et al. Targeting mTORC1/2 by a mTORkinase inhibitor (PP242) induces apoptosis in AML cells under conditions mimicking the bone marrow environment. ASH AnnMeet Abstr 2010; 116 (21): 778
187. Papa V, Tazzari PL, Chiarini F, et al. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia 2008 Jan; 22 (1): 147-60
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
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
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
191. Sillaber C, MayerhoferM, 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
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
193. Witzig TE, Gupta M. Signal transduction inhibitor therapy for lymphoma. Hematology Am Soc Hematol Educ Program 2010; 265-70
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
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
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
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
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
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
200. Jundt F, Raetzel N, Muller C, et al. A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein {beta} and NF-{kappa}B activity in Hodgkin and anaplastic large cell lymphomas. Blood 2005 Sep 1; 106 (5): 1801-7
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
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
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
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
205. Wudhikarn K, Holman CJ, Linan M, et al. Post-transplant lymphoproliferative disorders in lung transplant recipients: 20-yr experience at the University of Minnesota. Clin Transplant 2011; 25 (5): 705-13
206. Filipovich AH, Mathur A, Kamat D, et al. Lymphoproliferative disorders and other tumors complicating immunodeficiencies. Immunodeficiency 1994; 5 (2): 91-112
207. Tran H, Nourse J, Hall S, et al. Immunodeficiency-associated lymphomas. Blood Rev 2008 Sep; 22 (5): 261-81
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
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
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
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
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
213. Salassa JR, Ozgursoy OB, Weindling SM, et al. Computed tomographic angiography with three-dimensional reconstruction for transoral laser microsurgery. Otolaryngol Head Neck Surg 2010 Mar; 142 (3): 351-4
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
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
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
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
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
219. Teachey DT. Autoimmune lymphoproliferative syndrome: New approaches to diagnosis and management. Clin Adv Hematol Oncol 2011; 9 (3): 233-5
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
221. Tommasini A, Valencic E, Piscianz E, et al. Immunomodulatory drugs in autoimmune lymphoproliferative syndrome (ALPS). Pediatr Blood Cancer 2012; 58 (2): 310; reply 311