Targeting the PI3K/mTOR pathway in pediatric hematologic malignancies

Frontiers in Oncology

Volumn 4 MAY, Issue , 2014, Pages

  Tasian, Sarah K ^a   Teachey, David T ^a   Rheingold, Susan R ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

acute lymphoblastic leukemia; acute myeloid leukemia; clinical trial; Hodgkin lymphoma; non Hodgkin lymphoma; pediatric; PI3K mTOR; tyrosine kinase inhibitors

Indexed keywords

CYCLIN D1; CYTARABINE; DASATINIB; DIHYDROFOLATE REDUCTASE; ETOPOSIDE; EVEROLIMUS; FLT3 LIGAND; HISTONE DEACETYLASE INHIBITOR; IMATINIB; INITIATION FACTOR 4E BINDING PROTEIN 1; INTERLEUKIN 7; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOXANTRONE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3, 4, 5 TRISPHOSPHATE 3 PHOSPHATASE; PREDNISONE; PROTEIN MCL 1; PROTEIN TYROSINE KINASE INHIBITOR; RAPAMYCIN; RUXOLITINIB; SOMATOMEDIN; STAT PROTEIN; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; APOPTOSIS; CANCER CHEMOTHERAPY; CELL CYCLE; CELL GROWTH; CELL PROLIFERATION; CELL SURVIVAL; CHRONIC LEUKEMIA; FATIGUE; FOOD AND DRUG ADMINISTRATION; GENE MUTATION; HEMATOLOGIC MALIGNANCY; HEPATIC IMPAIRMENT; HODGKIN DISEASE; HUMAN; HYPERGLYCEMIA; HYPERLIPIDEMIA; INFECTION; INTRACELLULAR SIGNALING; LIVER FAILURE; LYMPHOMA; LYMPHOPROLIFERATIVE DISEASE; METABOLISM; MUCOSA INFLAMMATION; MYELOPROLIFERATIVE NEOPLASM; NONHODGKIN LYMPHOMA; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; T LYMPHOCYTE;

EID: 84904621974     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2014.00108     Document Type: Review

References (75)

1. 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) 145(5):569-80. doi: 10.1111/j.1365-2141.2009.07657.x
2. Janes MR, Fruman DA. Targeting TOR dependence in cancer. Oncotarget (2010) 1(1):69-76.
3. Barrett D, Brown VI, Grupp SA, Teachey DT. Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr Drugs (2012) 14(5):299-316. doi:10.2165/11594740-000000000-00000
4. Hirao A, Hoshii T. Mechanistic/mammalian target protein of rapamycin signaling in hematopoietic stem cells and leukemia. Cancer Sci (2013) 104(8):977-82. doi:10.1111/cas.12189
5. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia (2003) 17(3):590-603. doi:10.1038/sj.leu.2402824
6. Chapuis N, Tamburini J, Cornillet-Lefebvre P, Gillot L, Bardet V, Willems L, et al. Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody. Haematologica (2010) 95(3):415-23. doi:10.3324/haematol.2009.010785
7. Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y, et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood (2009) 114(3):647-50. doi:10.1182/blood-2009-02-206722
8. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov (2011) 10(11):868-80. doi:10.1038/nrd3531
9. Martelli AM, Evangelisti C, Chappell W, Abrams SL, Basecke J, Stivala F, et al. Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway. Leukemia (2011) 25(7):1064-79. doi:10.1038/leu.2011.46
10. Dancey JE. mTOR inhibitors in hematologic malignancies. Clin Adv Hematol Oncol (2003) 1(7):419-23.
11. Teachey DT, Obzut DA, Cooperman J, Fang J, Carroll M, Choi JK, et al. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood (2006) 107(3):1149-55. doi:10.1182/blood-2005-05-1935
12. Houghton PJ, Morton CL, Kolb EA, Gorlick R, Lock R, Carol H, et al. Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer (2008) 50(4):799-805. doi:10.1002/pbc.21214
13. Wei G, Twomey D, Lamb J, Schlis K, Agarwal J, Stam RW, et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell (2006) 10(4):331-42. doi:10.1016/j.ccr.2006.09.006
14. Houghton PJ, Morton CL, Gorlick R, Lock RB, Carol H, Reynolds CP, et al. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther (2010) 9(1):101-12. doi:10.1158/1535-7163.MCT-09-0952
15. Teachey DT, Sheen C, Hall J, Ryan T, Brown VI, Fish J, et al. mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood (2008) 112(5):2020-3. doi:10.1182/blood-2008-02-137141
16. Crazzolara R, Cisterne A, Thien M, Hewson J, Baraz R, Bradstock KF, et al. Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Blood (2009) 113(14):3297-306. doi:10.1182/blood-2008-02-137752
17. Kharas MG, Deane JA, Wong S, O'Bosky KR, Rosenberg N, Witte ON, et al. Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells. Blood (2004) 103(11):4268-75. doi:10.1182/blood-2003-07-2193
18. Hirase C, Maeda Y, Takai S, Kanamaru A. Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: possible clinical application of mTOR inhibitor. Leuk Res (2009) 33(3):450-9. doi:10.1016/j.leukres.2008.07.023
19. Tasian SK, Doral MY, Borowitz MJ, Wood BL, Chen IM, Harvey RC, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood (2012) 120(4):833-42. doi:10.1182/blood-2011-12-389932
20. Tasian SK, Li Y, Ryan T, Vincent T, Teachey DT, Loh ML, et al. In vivo efficacy of PI3K pathway signaling inhibition for Philadelphia chromosome-like acute lymphoblastic leukemia. Blood (2013) 122(21):672.
21. Loh ML, Zhang J, Harvey RC, Roberts K, Payne-Turner D, Kang H, et al. Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project. Blood (2013) 121(3):485-8. doi:10.1182/blood-2012-04-422691
22. Zhang J, Mullighan CG, Harvey RC, Wu G, Chen X, Edmonson M, 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. doi:10.1182/blood-2011-03-341412
23. Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell (2012) 22(2):153-66. doi:10.1016/j.ccr.2012.06.005
24. Brown VI, Fang J, Alcorn K, Barr R, Kim JM, Wasserman R, 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) 100(25):15113-8. doi:10.1073/pnas.2436348100
25. Brown VI, Hulitt J, Fish J, Sheen C, Bruno M, Xu Q, 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) 67(20):9963-70. doi:10.1158/0008-5472.CAN-06-4704
26. Maude SL, Tasian SK, Vincent T, Hall JW, Sheen C, Roberts KG, et al. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood (2012) 120(17):3510-8. doi:10.1182/blood-2012-03-415448
27. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med (2007) 13(10):1203-10. doi:10.1038/nm1636
28. Chiarini F, Fala F, Tazzari PL, Ricci F, Astolfi A, Pession A, 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) 69(8):3520-8. doi:10.1158/0008-5472.CAN-08-4884
29. Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengline E, et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a group for research in adult acute lymphoblastic leukemia study. J Clin Oncol (2013) 31(34):4333-42. doi:10.1200/JCO.2012.48.5292
30. Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet (2011) 43(10):932-9. doi:10.1038/ng.924
31. Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature (2012) 481(7380):157-63. doi:10.1038/nature10725
32. Willems L, Jacque N, Jacquel A, Neveux N, Maciel TT, Lambert M, et al. Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. Blood (2013) 122(20):3521-32. doi:10.1182/blood-2013-03-493163
33. Altman JK, Sassano A, Platanias LC. Targeting mTOR for the treatment of AML. New agents and new directions. Oncotarget (2011) 2(6):510-7.
34. Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood (2008) 111(1):379-82. doi:10.1182/blood-2007-03-080796
35. Janes MR, Fruman DA. The in vivo evaluation of active-site TOR inhibitors in models of BCR-ABL+ leukemia. Methods Mol Biol (2012) 821:251-65. doi:10.1007/978-1-61779-430-8_15
36. Vu C, Fruman DA. Target of rapamycin signaling in leukemia and lymphoma. Clin Cancer Res (2010) 16(22):5374-80. doi:10.1158/1078-0432.CCR-10-0480
37. Jeong JY, Kim KS, Moon JS, Song JA, Choi SH, Kim KI, et al. Targeted inhibition of phosphatidyl inositol-3-kinase p110beta, but not p110alpha, enhances apoptosis and sensitivity to paclitaxel in chemoresistant ovarian cancers. Apoptosis (2013) 18(4):509-20. doi:10.1007/s10495-013-0807-9
38. Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol (2013) 10(3):143-53. doi:10.1038/nrclinonc.2013.10
39. Health USNIo. Clinical Trials (2013). Available from: www.clinicaltrials.gov
40. Melo JV, Chuah C. Novel agents in CML therapy: tyrosine kinase inhibitors and beyond. Hematology Am Soc Hematol Educ Program (2008) 2008(1):427-35. doi:10.1182/asheducation-2008.1.427
41. Burchert A, Wang Y, Cai D, von Bubnoff N, Paschka P, Muller-Brusselbach S, et al. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia (2005) 19(10):1774-82. doi:10.1038/sj.leu.2403898
42. Bogani C, Bartalucci N, Martinelli S, Tozzi L, Guglielmelli P, Bosi A, et al. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PLoS One (2013) 8(1):e54826. doi:10.1371/journal.pone.0054826
43. Bartalucci N, Tozzi L, Bogani C, Martinelli S, Rotunno G, Villeval JL, et al. Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms. J Cell Mol Med (2013) 17(11):1385-96. doi:10.1111/jcmm.12162
44. Witzig TE, Gupta M. Signal transduction inhibitor therapy for lymphoma. Hematology Am Soc Hematol Educ Program (2010) 2010:265-70. doi:10.1182/asheducation-2010.1.265
45. Gupta M, Hendrickson AE, Yun SS, Han JJ, Schneider PA, Koh BD, et al. Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies. Blood (2012) 119(2):476-87. doi:10.1182/blood-2011-04-346601
46. Witzig TE, Reeder CB, LaPlant BR, Gupta M, Johnston PB, Micallef IN, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia (2011) 25(2):341-7. doi:10.1038/leu.2010.226
47. Spender LC, Inman GJ. Developments in Burkitt's lymphoma: novel cooperations in oncogenic MYC signaling. Cancer Manage Res (2014) 6:27-38. doi:10.2147/CMAR.S37745
48. Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature (2012) 490(7418):116-20. doi:10.1038/nature11378
49. Zhao MY, Auerbach A, D'Costa AM, Rapoport AP, Burger AM, Sausville EA, et al. Phospho-p70S6K/p85S6K and cdc2/cdk1 are novel targets for diffuse large B-cell lymphoma combination therapy. Clin Cancer Res (2009) 15(5):1708-20. doi:10.1158/1078-0432.CCR-08-1543
50. Zhao XF, Gartenhaus RB. Phospho-p70S6K and cdc2/cdk1 as therapeutic targets for diffuse large B-cell lymphoma. Expert Opin Ther Targets (2009) 13(9):1085-93. doi:10.1517/14728220903103833
51. Gupta M, Ansell SM, Novak AJ, Kumar S, Kaufmann SH, Witzig TE. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood (2009) 114(14):2926-35. doi:10.1182/blood-2009-05-220889
52. Vega F, Medeiros LJ, Leventaki V, Atwell C, Cho-Vega JH, Tian L, 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) 66(13):6589-97. doi:10.1158/0008-5472.CAN-05-3018
53. Johnston PB, Inwards DJ, Colgan JP, Laplant BR, Kabat BF, Habermann TM, et al. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol (2010) 85(5):320-4. doi:10.1002/ajh.21664
54. Batlevi CL, Younes A. Novel therapy for Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program (2013) 2013:394-9. doi:10.1182/asheducation-2013.1.394
55. Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller LL, et al. PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood (2012) 119(8):1897-900. doi:10.1182/blood-2011-10-386763
56. Lemoine M, Derenzini E, Buglio D, Medeiros LJ, Davis RE, Zhang J, et al. The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines. Blood (2012) 119(17):4017-25. doi:10.1182/blood-2011-01-331421
57. Andres AM, Lopez Santamaria M, Ramos E, Hernandez F, Prieto G, Encinas J, et al. The use of sirolimus as a rescue therapy in pediatric intestinal transplant recipients. Pediatr Transplant (2010) 14(7):931-5. doi:10.1111/j.1399-3046.2010.01363.x
58. Manuelli M, De Luca L, Iaria G, Tatangelo P, Sforza D, Perrone L, et al. Conversion to rapamycin immunosuppression for malignancy after kidney transplantation. Transplant Proc (2010) 42(4):1314-6. doi:10.1016/j.transproceed.2010.03.051
59. Rheingold SR, Sacks N, Chang YJ, Brown VI, Teachey DT, Lange BJ, et al. A phase I trial of sirolimus (rapamycin) in pediatric patients with relapsed/refractory leukemia. Blood (2007) 110(11):2834.
60. Schlis KD, Stubbs M, DeAngelo DJ, Neuberg D, Dahlberg SE, Sallan SE, et al. A pilot trial of rapamycin with glucocorticoids in children and adults with relapsed ALL. ASH Annual Meeting Abstracts 116(21):3244.
61. Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet (2010) 376(9757):2009-17. doi:10.1016/S0140-6736(10)62002-8
62. Teachey DT, Vincent T, Smith-Whitley K, Lambert MP, Seif AE, Casper JT, et al. Targeting mTOR signaling leads to complete and durable responses in children with multi-lineage autoimmune cytopenias, including ALPS, SLE, Evans and CVID. Blood (2013) 122(21):330.
63. Yee KW, Zeng Z, Konopleva M, Verstovsek S, Ravandi F, Ferrajoli A, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res (2006) 12(17):5165-73. doi:10.1158/1078-0432.CCR-06-0764
64. Perl AE, Kasner MT, Tsai DE, Vogl DT, Loren AW, Schuster SJ, 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) 15(21):6732-9. doi:10.1158/1078-0432.CCR-09-0842
65. Wei AH, Sadawarte S, Catalano J, Hills R, Avery S, Patil S, et al. A phase Ib study combining the mTOR inhibitor everolimus (RAD001) with low-dose cytarabine in untreated elderly AML. Blood (2010) 116:3299.
66. Park S, Chapuis N, Saint Marcoux F, Recher C, Prebet T, Chevallier P, et al. A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse. Leukemia (2013) 27(7):1479-86. doi:10.1038/leu.2013.17
67. Guglielmelli P, Barosi G, Rambaldi A, Marchioli R, Masciulli A, Tozzi L, et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood (2011) 118(8):2069-76. doi:10.1182/blood-2011-01-330563
68. Ansell SM, Inwards DJ, Rowland KM Jr, Flynn PJ, Morton RF, Moore DF Jr, et al. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer (2008) 113(3):508-14. doi:10.1002/cncr.23580
69. Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol (2005) 23(23):5347-56. doi:10.1200/JCO.2005.13.466
70. Oki Y, Buglio D, Fanale M, Fayad L, Copeland A, Romaguera J, et al. Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin Cancer Res (2013) 19(24):6882-90. doi:10.1158/1078-0432.CCR-13-1906
71. Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov (2014) 13(2):140-56. doi:10.1038/nrd4204
72. Goodwin CB, Li XJ, Mali RS, Chan G, Kang M, Liu Z, et al. PI3K p110delta uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. Blood (2014) 123(18):2838-42. doi:10.1182/blood-2013-10-535104
73. Gritsman K, Yuzugullu H, Von T, Yan H, Clayton L, Fritsch C, et al. Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110alpha. J Clin Invest (2014) 124(4):1794-809. doi:10.1172/JCI69927
74. Badura S, Tesanovic T, Pfeifer H, Wystub S, Nijmeijer BA, Liebermann M, et al. Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia. PLoS One (2013) 8(11):e80070. doi:10.1371/journal.pone.0080070
75. Younes AXIV. The rationale for combining targeted and biological anti-lymphoma drugs. Hematol Oncol (2013) 31(Suppl 1):81-3. doi:10.1002/hon.2072