Utility of mTOR inhibition in hematologic malignancies

Oncologist

Volumn 16, Issue 6, 2011, Pages 730-741

  Younes, Anas ^a   Samad, Nousheen ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

Hematologic malignancy; Leukemia; Lymphoma; Mammalian target of rapamycin; Multiple myeloma; Waldenstr m macroglobulinemia

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; 2 MORPHOLINO 8 PHENYLCHROMONE; BORTEZOMIB; CIXUTUMUMAB; CYTARABINE; DASATINIB; DOXORUBICIN; ETOPOSIDE; EVEROLIMUS; IMATINIB; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MIDOSTAURIN; MITOXANTRONE; NILOTINIB; PACLITAXEL; PANOBINOSTAT; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; PP 242; PROTEIN KINASE B; RAPAMYCIN; RIDAFOROLIMUS; RITUXIMAB; TEMSIROLIMUS; TIPIFARNIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VINCRISTINE; VORINOSTAT;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; ACUTE LYMPHOCYTIC LEUKEMIA; ADVANCED CANCER; ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; ARTICLE; B CELL LYMPHOMA; BONE MARROW SUPPRESSION; CANCER CELL CULTURE; CANCER RESISTANCE; CELL GROWTH; CELL METABOLISM; CELL PROLIFERATION; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; DRUG BINDING; DRUG CYTOTOXICITY; DRUG POTENTIATION; DRUG RESPONSE; DRUG TARGETING; DRUG UTILIZATION; ENZYME ACTIVATION; ENZYME INHIBITION; HEMATOLOGIC MALIGNANCY; HODGKIN DISEASE; HUMAN; IN VITRO STUDY; LARGE CELL LYMPHOMA; LEUKEMIA RELAPSE; LOW DRUG DOSE; MANTLE CELL LYMPHOMA; MONOCYTIC LEUKEMIA; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; MYELODYSPLASTIC SYNDROME; NONHODGKIN LYMPHOMA; OVERALL SURVIVAL; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; SIGNAL TRANSDUCTION; UNSPECIFIED SIDE EFFECT; WALDENSTROEM MACROGLOBULINEMIA;

CELL LINE, TUMOR; CELL PROLIFERATION; CLINICAL TRIALS AS TOPIC; DISEASE-FREE SURVIVAL; DOWN-REGULATION; HEMATOLOGIC NEOPLASMS; HUMANS; LEUKEMIA; LYMPHOMA, NON-HODGKIN; MULTIPLE MYELOMA; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; UP-REGULATION; WALDENSTROM MACROGLOBULINEMIA;

EID: 79959610128     PISSN: 10837159     EISSN: 1549490X     Source Type: Journal    
DOI: 10.1634/theoncologist.2010-0318     Document Type: Article

References (80)

1. Altman JK, Platanias LC. Exploiting the mammalian target of rapamycin pathway in hematologic malignancies. Curr Opin Hematol 2008;15:88-94.
2. Teachey DT, Grupp SA, Brown VI. Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematologi-cal malignancies. Br J Haematol 2009;145:569-580.
3. Kopelovich L, Fay JR, Sigman CC et al. The mammalian target of rapamy-cin pathway as a potential target for cancer chemoprevention. Cancer Epidemiol Biomarkers Prev 2007;16:1330-1340.
4. Le Tourneau C, Faivre S, Serova M. et al. mTORC1 inhibitors: Is temsiroli-mus in renal cancer telling us how they really work? Br J Cancer 2008;99: 1197-1203.
5. Manning BD. Balancing Akt with S6K: Implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004;167:399-403.
6. Witzig TE, Kaufmann SH. Inhibition of the phosphatidylinositol 3-kinase/ mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol 2006;7:285-294.
7. Costa LJ. AspectsofmTOR biology and the useofmTOR inhibitorsinnon-Hodgkin's lymphoma. Cancer Treat Rev 2007;33:78-84.
8. Gingras AC, Kennedy SG, O'Leary MA. et al. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 1998;12:502-513.
9. Meyuhas O. Synthesis of the translational apparatus is regulated at the translational level. Eur J Biochem 2000;267:6321-6330.
10. 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;115:4455-4463.
11. Sarbassov DD, Guertin DA, Ali SM et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-1101.
12. Engelman JA. Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550-562.
13. Guertin DA, Sabatini DM. The pharmacologyof mTOR inhibition. Sci Signal 2009;2:pe24.
14. Bhagwat SV, Crew AP. Novel inhibitors of mTORC1 and mTORC2. Curr Opin Investig Drugs 2010;11:638-645.
15. Kojima K, Shimanuki M, Shikami M et al. The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 2008;22:1728-1736.
16. Fan QW, Knight ZA, Goldenberg DD et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006;9:341-349.
17. Janes MR, Limon JJ, So L et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 2010;16:205-213.
18. Feldman ME, Apsel B, Uotila A. et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009; 7:e38.
19. Gupta M, Ansell SM, Novak AJ et al. Histone deacetylase inhibition with LBH589 inhibits the rapamycin insensitive rictor-mTOR (mTORC2) complex and translation initiation factor eIF4E activation in diffuse large B-cell lymphoma [abstract 603]. Presentedatthe Annual Meetingof the American Society of Hematology, San Francisco, CA, December 6-9, 2008.
20. Roccaro AM, Sacco A, Husu EN et al. Dual targeting of the PI3K/Akt/ mTOR pathway as an antitumor strategy in Waldenstrom macroglobuline-mia. Blood 2010;115:559-569.
21. Kornblau SM, Womble M, Qiu YH et al. Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelog-enous leukemia. Blood 2006;108:2358-2365.
22. Kharas MG, Okabe R, Ganis JJ et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 2010;115: 1406-1415.
23. 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;118:3762-3774.
24. Récher C, Dos Santos C, Demur C. et al. mTOR, a new therapeutic target in acute myeloid leukemia. Cell Cycle 2005;4:1540-1549.
25. Zeng Z, Sarbassov dos D, Samudio IJ et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 2007;109: 3509-3512.
26. Chiarini F, Falí F, Tazzari PL et al. Dual inhibition of class IA phosphati-dylinositol 3-kinase and mammalian target of rapamycin as new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res 2009;69: 3520-3528.
27. Tamburini J, Chapuis N, Bardet V 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;111:379-382.
28. Xu Q, Simpson SE, Scialla TJ et al. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003;102:972-980.
29. 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;20:693-701.
30. VanderWeele DJ, Zhou R, Rudin CM. Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin. Mol Cancer Ther 2004;3:1605-1613.
31. Saunders PO, Bradstock KF, Bendall LJ. Combining RAD001 (everoli-mus) with proteasome inhibitors bortezomib (Velcade) or MG132 significantly enhances pre-B ALL cell death in vitro [abstract 2743]. Presented at the Annual Meeting ofthe American Society of Hematology, New Orleans, LA, December 5-8, 2009.
32. Mancini M, Petta S, Martinelli G et al. RAD 001 (everolimus) prevents mTOR and Akt late re-activation inresponsetoimatinib in chronic myeloid leukemia. J Cell Biochem 2010;109:320-328.
33. 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;34:641-648.
34. Minami Y, Minami M, Kuwatsuka Y. et al. Treatment with mTOR inhibitor, everolimus (RAD001) overcomes resistance to imatinib in Ph-leukemia quiescent or T315I-mutated cells [abstract 3277]. Presented at the Annual Meeting of the American Society of Hematology, New Orleans, LA, December 5-8, 2009.
35. Nagai T, Ohmine K, Fujiwara S et al. Combination of tipifarnib and rapa-mycin synergistically inhibits the growth of leukemia cells and overcomes resistance to tipifarnib via alteration of cellular signaling pathways. Leuk Res 2010;34:1057-1063.
36. Boehm A, Mayerhofer M, Herndlhofer S et al. Evaluation of in vivo anti-neoplastic effects of rapamycin in patients with chemotherapy-refractory AML. Eur J Intern Med 2009;20:775-778.
37. Perl AE, Kasner MT, Tsai DE. et al. A phaseI study ofthe mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clin Cancer Res 2009;15:6732-6739.
38. Yee KW, Zeng Z, Konopleva M et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2006;12: 5165-5173.
39. Zent CS, LaPlant BR, Johnston PB et al. The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer 2010;116:2201-2207.
40. Rizzieri DA, Feldman E, Dipersio JF et al. A phase 2 clinical trial of defo-rolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2008;14:2756-2762.
41. Dal Col J, Zancai P, Terrin L et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 2008; 111:5142-5151.
42. Peponi E, Drakos E, Reyes G et al. Activation of mammalian target of rapa-mycin signaling promotes cell cycle progression and protects cells from ap-optosis in mantle cell lymphoma. Am J Pathol 2006;169:2171-2180.
43. 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;205:498-506.
44. Mavrakis KJ, Zhu H, Silva RLA. et al. Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev 2008;22:2178-2188.
45. Hipp S, Ringshausen I, Oelsner M et al. Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica 2005;90:1433-1434.
46. 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;114: 2926-2935.
47. Wanner K, Hipp S, Oelsner M et al. Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitizes DLBCL cells to rituximab. Br J Haematol 2006;134: 475-484.
48. Haritunians T, Mori A, O'Kelly J et al. Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 2007;21:333-339.
49. Jundt F, Raetzel N, Mller C et al. A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein /3 and NF-kB activity in Hodgkin and anaplastic large cell lymphomas. Blood 2005;106:1801-1807.
50. Witzig TE, Geyer SM, Ghobrial I et al. Phase II trial of single-agent tem-sirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005; 23:5347-5356.
51. Ansell SM, Inwards DJ, Rowland KM Jr et al. Low-dose, single-agent tem-sirolimus for relapsed mantle cell lymphoma: A phase 2 trial in the North Central Cancer Treatment Group. Cancer 2008;113:508-514.
52. Hess G, Herbrecht R, Romaguera J et al. Phase III study to evaluate tem-sirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 2009;27:3822-3829.
53. Ogura M, Uchida T, Maruyama D et al. Phase I and pharmacokinetic (PK) study of everolimus (RAD001) in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) [abstract 1712]. Presented at the Annual Meeting of the American Society of Hematology, New Orleans, LA, December 5-8, 2009.
54. Witzig T, Habermann T, Reeder C et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) [abstract 1081]. Presented at the Congressofthe European Hematology Association, Berlin, Germany, June 4-7, 2009.
55. 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; 85:320-324.
56. Pene F, Claessens YE, Muller O et al. Role of the phosphatidylinositol 3-ki-nase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apo-ptosis in multiple myeloma. Oncogene 2002;21:6587-6597.
57. Frost P, Shi Y, Hoang B et al. Regulation of D-cyclin translation inhibition in myeloma cells treated with mammalian target of rapamycin inhibitors: Rationale for combined treatment with extracellular signal-regulated kinase inhibitors and rapamycin. Mol Cancer Ther 2009;8:83-93.
58. Frost P, Moatamed F, Hoang B et al. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 2004;104:4181-4187.
59. Mitsiades N, McMullan C, Poulaki V et al. The mTOR inhibitor RAD001 (everolimus) is active against multiple myeloma cells in vitro and in vivo [abstract 1496]. Blood 2004;104:418a.
60. Guenther A, Baumann P, Burger R et al. Single-agent everolimus (RAD001) in patients with relapsed or refractory multiple myeloma: Final results of a phase I study [abstract 8137]. J Clin Oncol 2010;28:7s.
61. Leleu X, Gay J, Roccaro AM et al. Update on therapeutic options in Waldenström macroglobulinemia. Eur J Haematol 2009;82:1-12.
62. Leleu X, Jia X, Runnels J et al. The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia. Blood 2007;110:4417-4426.
63. Ghobrial IM, Gertz M, LaPlant B et al. Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenström macroglobulinemia. J Clin Oncol 2010;28:1408-1414.
64. 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;16:1033-1041.
65. Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J Chem Biol 2008;1:27-36.
66. ClinicalTrials.gov. Panobinostat and Everolimus in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma. ClinicalTrials. gov Identifier, NCT00962507. Available at http://www.clinicaltrials.gov/ct2/show/NCT00962507?term=NCT00962507&rank=1, accessed February 23, 2010.
67. ClinicalTrials.gov. Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma. ClinicalTrials.gov Identifier, NCT00918333. Available at http://www.clinicaltrials.gov/ct2/show/NCT00918333?term=NCT00918333&rank = 1, accessed February 23, 2010.
68. ClinicalTrials.gov. A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer. ClinicalTrials.gov Identifier, NCT00620594. Available at http://www.clinicaltrials.gov/ct2/show/NCT00620594?term=NCT00620594&rank = 1, accessed September 8, 2010.
69. Gharbi SI, Zvelebil MJ, Shuttleworth SJ et al. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J 2007;404:15-21.
70. ClinicalTrials.gov. RAD001 in Combination With PKC412 in Patients With Relapsed, Refractory or Poor Prognosis AML or MDS. ClinicalTrials. gov Identifier, NCT00819546. Available at http://www.clinicaltrials.gov/ct2/show/NCT00819546?term=NCT00819546&rank=1, accessed February 23, 2010.
71. ClinicalTrials.gov. Sirolimus in Combination With MEC in High Risk Myeloid Leukemias (UPCC 02407). ClinicalTrials.gov Identifier, NCT00780104. Available at http://www.clinicaltrials.gov/ct2/show/NCT00780104?term=NCT00780104&rank= 1, accessed February 23, 2010.
72. ClinicalTrials.gov. Combination of Nilotinib (AMN107) and RAD001 in Patients With Acute Myeloid Leukemia. ClinicalTrials.gov Identifier, NCT00762632. Available at http://www.clinicaltrials.gov/ct2/show/NCT00762632?term=NCT00762632&rank= 1, accessed February 23, 2010.
73. ClinicalTrials.gov. CCI-779 in B-Cell Lymphoma and Chronic Lymphocytic Leukemia (CLL). ClinicalTrials.gov Identifier, NCT00290472. Available at http://www.clinicaltrials.gov/ct2/show/NCT00290472?term=NCT00290472&rank= 1, accessed February 23, 2010.
74. ® Therapy (PILLAR-1). ClinicalTrials.gov Identifier, NCT00702052. Available at http://www.clinicaltrials.gov/ct2/show/NCT00702052?term=PILLAR-1&rank= 1, accessed February 23, 2010.
75. ClinicalTrials.gov. Phase III Study of RAD001 Adjuvant Therapy in Poor Risk Patients With Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 Versus Matching Placebo After Patients Have Achieved Complete Response With First-Line Rituximab-Chemotherapy (PILLAR-2). ClinicalTrials.gov Identifier, NCT00790036. Available at http://www. clinicaltrials.gov/ct2/show/NCT00790036?term = PILLAR&rank=5, accessed February 23, 2010.
76. ClinicalTrials.gov. Everolimus Plus Rituximab for Relapsed/Refractory Diffuse Large B Cell Lymphoma. ClinicalTrials.gov Identifier, NCT00869999. Available at http://www.clinicaltrials.gov/ct2/show/NCT00869999?term=NCT00869999&rank=1, accessed February 23, 2010.
77. ClinicalTrials.gov. Everolimus in Treating Older Patients With Mantle Cell Lymphoma Previously Treated With First-Line or Second-Line Chemotherapy. ClinicalTrials.gov Identifier, NCT00727207. Available at http://www.clinicaltrials.gov/ct2/show/NCT00727207?term=NCT00727207&rank =1, accessed February 23, 2010.
78. ClinicalTrials.gov. IMC-A12 in Combination withTemsirolimus (CCI-779) in Patients with Advanced Cancers. ClinicalTrials.gov Identifier, NCT00678769. Available at http://www.clinicaltrials.gov/ct2/show/NCT00678769?term=NCT00678769&rank=1, accessed April 6, 2011.
79. ClinicalTrials.gov. Sorafenib and Everolimus in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma. ClinicalTrials.gov Identifier, NCT00474929. Available at http://www.clinicaltrials.gov/ct2/show/NCT00474929?term=NCT00474929&rank=1, accessed February 23, 2010.
80. ClinicalTrials.gov. Everolimus in Treating Patients With Lymphoma That Has Relapsed or Not Responded to Previous Treatment. ClinicalTrials.gov Identifier, NCT00436618. Available at http://www.clinicaltrials.gov/ct2/show/NCT00436618?term=NCT00436618&rank=1, accessed February 23, 2010.