Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway

Anti-Cancer Drugs

Volumn 17, Issue 5, 2006, Pages 487-494

  Smolewski, Piotr ^a  

^a MEDICAL UNIVERSITY OF LODZ   (Poland)

Author keywords

Cancer; Leukemia; Mammalian target of rapamycin; mTOR; mTOR inhibitor; mTOR kinase; Treatment

Indexed keywords

ALPHA INTERFERON; AP 23573; EVEROLIMUS; FK 506 BINDING PROTEIN; IMMUNOSUPPRESSIVE AGENT; INITIATION FACTOR 4E BINDING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; RAPAMYCIN; S6 KINASE; TEMSIROLIMUS;

ANEMIA; BREAST CANCER; CANCER CHEMOTHERAPY; CELL CYCLE G1 PHASE; CELL CYCLE S PHASE; CLINICAL TRIAL; DIARRHEA; DRUG TARGETING; ENZYME ACTIVATION; ENZYME INHIBITION; GENE MUTATION; GLIOBLASTOMA; HEMATOLOGIC MALIGNANCY; HUMAN; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTRIGLYCERIDEMIA; HYPOCALCEMIA; HYPOKALEMIA; HYPONATREMIA; KIDNEY CARCINOMA; LIVER TOXICITY; LUNG CANCER; MELANOMA; MUCOSA INFLAMMATION; NEUTROPENIA; NONHUMAN; PRIORITY JOURNAL; RASH; REVIEW; SARCOMA; SEPSIS; SIGNAL TRANSDUCTION; SKIN MANIFESTATION; SOLID TUMOR; STOMATITIS; THROMBOCYTOPENIA;

EID: 33748194240     PISSN: 09594973     EISSN: None     Source Type: Journal    
DOI: 10.1097/00001813-200606000-00001     Document Type: Review

References (77)

1. Mita MM, Mita A, Rowinsky EK. The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Ther 2003; 2:169-177.
2. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4:335-348.
3. Panwalkar A, Verstovsek S, Giles FJ. Mammalian target of rapamycin as therapy for hematologic malignancies. Cancer 2004; 100:657-666.
4. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110:163-175.
5. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003; 11:895-904.
6. Borlado LR, Redondo C, Alvarez B. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J 2000; 14:895-903.
7. Vose JM, Chiu BCH, Cheson D, Dancey J, Wright J. Update on epidemiology and therapeutics for non-Hodgkin's lymphoma. Hematology (Am Soc Hematol Educ Program) 2002; 241-262.
8. Jimenez C, Jones DR, Rodrguez-Viciana P, Gonzalez-Garcia A, Leonardo E, Wennsrtom S, et al. Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J 1998; 17:743-753.
9. Raftopoulou M, Etienne-Manneville S, Self A, Nicholls S, Hall A. Regulation of cell migration by the tumor suppressor PTEN. Science 2004; 303:1179-1181.
10. Royl HK, Olusolal BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT, et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 2002; 23:201-205.
11. David O, Jett J, LeBeau H, Dy G, Hughes J, Friedman M, et al. Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage. Clin Cancer Res 2004; 10:6865-6871.
12. Zhou X, Tan M, Stone Hawthorne V, Klos KS, Lan KH, Yang Y, et al. Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 2004; 10:6779-6788.
13. De Benedetti A, Harris AL. eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol 1999; 31:59-72.
14. De Benedetti A, Graff JR. eIF4E expression and its role in malignancies and metastases. Oncogene 2004; 23:3189-3199.
15. Jiang H, Coleman J, Miskimins R, Miskimins WK. Expression of constitutively active 4EBP-1 enhances p27Kip1 expression and inhibits proliferation of MCF7 breast cancer cells. Cancer Cell Int 2003; 3:2.
16. Altomare 2005. Perturbations of the Akt signaling pathway in human cancer. Oncogene 2005; 24:7455-7464.
17. Altomare DA, You H, Xiao GH, Ramos-Nino ME, Skele KL, De Rienzo A, et al. Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene 2005; 24:6080-6089.
18. Asano T, Yao Y, Zhu J, Li D, Abbruzzese JL, Reddy SA. The rapamycin analog CCI-779 is a potent inhibitor of pancreatic cancer cell proliferation. Biochem Biophys Res Commun 2005; 331:295-302.
19. Ito D, Fujimoto K, Mori T, Kami K, Koizumi M, Toyoda E, et al. In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. Int J Cancer 2005; [Epub ahead of print]
20. Slupianek A, Nieborowska-Skorska M, Hoser G, Morrione A, Majewski M, Xue L, et al. Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res 2001; 61:2194-2199.
21. Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C, et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 2004; 10:484-486.
22. Pene F, Claessens YE, Muller O, Viguie F, Mayeux P, Dreyfus F, et al. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 2002; 43:6587-6597.
23. Lentzsch S, Chatterjee M, Gries M, Bommert K, Gollasch H, Dorken B, et al. PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. Leukemia 2004; 18:1883-1890.
24. Vega F, Mediros LJ, Atwell C, Cho JH, Tian L, Claret F-X, et al. Activation of mTOR signaling pathway contributes to lymphoma cell survival in ALK-positive anaplastic large cell lymphoma. Blood 2005; 106:abstr 2419.
25. Peponi E, Drakos E, Reyes G, Leventaki V, Medeiros LJ. Inhibition of Akt/mTOR signalling pathway induces cell cycle arrest and apoptosis in mantle cell lymphoma. Blood 2005; 106:abstr 2415.
26. Topisirovic I, Guzman ML, McConnel MJ, Licht JD, Culjkovic B, Neering SJ, et al. Aberrant eukaryotic translation initiation factor 4E-dependent mRNA impedes hematopoietic differentiation and contributes to leukemogenesis. Mol Cell Biol 2003; 23:8992-9002.
27. Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003; 102:972-980.
28. Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK. Constitutive phosphorylation of AktPKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia 2003; 17:995-997.
29. Kubota Y, Ohnishi H, Kitanaka A, Ishida T, Tanaka T. Constitutive activation of PI3K is involved in the spontaneous proliferation of primary acute myeloid leukemia cells:direct evidence of PI3K activation. Leukemia 2004; 18:1438-1440.
30. Chen W, Grammatikakis I, Li J, Leventaki V, Medieros LJ, Rassidakis GZ. Inhibition of Akt/mTOR signalling pathway induces cell cycle arrest and apoptosis in acute myelogenous leukaemia. Blood 2005; 106:abstr 2355.
31. Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas JA, Sanchez A, Martin-Saavedra FM, et al. A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia 2004; 18:1391-1400.
32. Barragan M, Bellosillo B, Campas C, Colomer D, Pons G, Gil J. Involvement of protein kinase C and phosphatidylinositol 3-kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells. Blood 2002; 15:2969-2976.
33. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989) a new antifungal antibiotic. Taxonomy of the producing streptomycyte and isolation of the active principle. J Antibiot (Tokyo) 1975; 10:721.
34. Gu J, Ruppen ME, Cai P. Lipase-catalyzed regioselective esterification of rapamycin: synthesis of temsirolimus (CCI-779). Org Lett 2005; 7:3945-3948.
35. Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000; 27:6680-6686.
36. Rowinsky EK. Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 2004; 16:564-575.
37. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol 2003; 4:75-85.
38. Blagosklonny MV, Darzynkiewicz Z. Four birds with one stone: RAPA as potential anticancer therapy. Cancer Biol Ther 2002; 1:359-361.
39. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000; 15:1541-1545.
40. Smolewski P, Janus A, Cebula B, Linke A, Jamroziak K, Robak T. Inhibition of mTOR kinase pathway selectively sensitizes acute myeloid leukemia cells to cytarabine-induced apoptosis. Blood 2005; 106:abstr 2474.
41. 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 2005; 107:1149-1155.
42. Teachey DT, Axsom K, Brown VI, Obzut D, Grupp A. Murine ultrasonography confirms that rapamycin is effective against autoimmune lymphoproliferative syndrome (ALPS). Blood 2005; 106:abstr 2386.
43. Mayerhofer M, Boehm A, Aichberger KJ, Esterbauer H, Derdak S, Piekl WF, et al. In vitro and in vivo antileukemic effects of the mTOR-targeting drug rapamycin in patients with imatinib-resistant CML. Blood 2005; 106:abstr 4834.
44. Dudkin L, Dilling MB, Cheshire PJ, Harwood FC, Hollingshead M, Arbuck S, et al. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 2001; 7:1758-1764.
45. Gibbons JJ, Discafani C, Peterson R, Hernandez R, Skotnicki J, Frost J. The effect of CCI-779, a novel macrolide antitumor agent on the growth of human tumor cells in vitro and in nude mouse xenograft in vivo. Proc Am Assoc Cancer Res 1999; 40:abstr 2000.
46. Georger B, Kerr K, Tang CB, Fung KM, Powell B, Sutton LN, et al. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 2001; 61:1572-1532.
47. Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 2004; 15:2336-2347.
48. Hidalgo M, Rowinsky E, Erlichman C, Drengler R, Marshall B, Marks R, et al. Phase 1 and pharmacologic study of CCI-779, a cell cycle inhibitor. Presented at: 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy, Amsterdam; 2000. abstr 545.
49. Boni JP, Leister C, Bender G, Fitzpatrick V, Twine N, Stover J, et al. Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin Pharmacol Ther 2005; 77:76-89.
50. Peralba JM, DeGraffenried L, Friedrichs W, Fulcher L, Grunwald V, Weiss G, et al. Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 2003; 9:2887-2892.
51. Smith JW, Ko Y-J, Duthcer G, Hudes B, Escudier R, Motzer S, et al. Update of a phase 1 study of intravenous CCI-779 given in combination with interferon-a to patients with advanced renal cell carcinoma. J Clin Oncol 2004; 22:abstr 4513.
52. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004; 22:909-918.
53. Pandya KJ, Levy DE, Hidalgo M, Cohen RB, Lee MW, Schiller JH, et al. A randomized, phase II ECOG trial of two dose levels of temsirolimus (CCI-779) in patients with extensive stage small cell lung cancer in remission after induction chemotherapy. J Clin Oncol 2005; 23:abstr 7005.
54. Chan S, Scheulen ME, Johnston S, Mross K, Piccart M, Hess D, et al. Phase 2 study of two dose levels of CCI-779 in locally advanced or metastatic breast cancer (MBC) failing prior anthracycline and/or taxane regimens. J Clin Oncol 2005; 23:5314-5322.
55. Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005; 23:5294-5304.
56. Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, et al. North American Brain Tumor Consortium and the National Cancer Institute. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 2005; 23:357-361.
57. Galanis E, Buckner JC, Maurer MJ, Hidalgo M, Kreisberg JI, Peralba J, et al. N997B: phase II trial of CCI-779 in recurrent glioblastoma multiforme (GBM): updated results and correlative laboratory analysis. J Clin Oncol 2005; 23:abstr 1505.
58. Margolin K, Longmate J, Baratta T, Synold T, Christensen S,Weber J, et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer 2005; 104:1045-1048.
59. 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; 23:5347-5356.
60. Witzig TE, Ansell SM, Geyer SM, Kurtin PJ, Rowland KM, Flynn PJ, et al. Anti-tumor activity of low-dose single agent CCI-779 for relapsed mantle cell lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 2005; 23:abstr 6504.
61. Yee KWL, Garcia-Manero G, Thomas D, Ravandi-Kashani F, Verstovsek S, Andreeff M, et al. A phase II study of temsirolimus (CCI-779) in patients with advanced leukemias. Blood 2004; 104:abstr 4523.
62. O'Donnell S, Faivre I, Judson C, Delbado C, Brock H, Lane N, et al. A phase I study of the oral mTOR inhibitor RAD001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in patients with solid tumors. Proc Am Soc Clin Oncol 2003; 74:200 (abstr 803).
63. Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004; 64:252-261.
64. Tabernero J, Rojo F, Burris H, Casado E, Macarulla T, Jones S, et al. A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR-inhibitor Everolimus (RAD001) in patients (pts) with advanced solid tumors. J Clin Oncol 2005; 23:abstr 3007.
65. Lerut E, Roskams T, Goossens E, Bootle D, Dimitrijevic S, Stumm M, et al. Molecular pharmacodynamic (MPD) evaluation of dose and schedule of RAD001 (everolimus) in patients with operable prostate carcinoma (PC). J Clin Oncol 2005; 23:abstr 3071.
66. Majewski M, Korecka M, Kossev P, Li S, Goldman J, Moore J, et al. The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: a potential approach to prevention and treatment of posttransplant lymphoproliferative disorders. Proc Natl Acad Sci U S A 2000; 97:4285-4290.
67. Yee KWL, Wierda W, O'Brien S, Thomas D, Kurzrock R, Fayad LE, et al. A phase I/II study of the oral mTOR inhibitor RAD001 in patients with advanced hematologic malignancies. Blood 2004; 104:abstr 4818.
68. Rivera VM, Kreisberg JI, Mita MM, Goldston M, Knowles HL, Herson J, et al. Pharmacodynamic study of skin biopsy specimens in patients (pts) with refractory or advanced malignancies following administration of AP23573, an mTOR inhibitor. J Clin Oncol 2005; 23:abstr 3033.
69. Desai AA, Mita M, Fetterly GJ, Chang C, Netsch M, Knowles HL, et al. Development of a pharmacokinetic (PK) model and assessment of patient (pt) covariate effects on dose-dependent PK following different dosing schedules in two phase I trials of AP23573 (AP), a mTOR inhibitor. J Clin Oncol 2005; 23:abstr 3043.
70. Mita MM, Rowinsky EK, Goldston ML, Mita AC, Chu Q, Syed S, et al. Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily x 5 every other week in patients (pts) with refractory or advanced malignancies. J Clin Oncol 2004; 22:abstr 3076.
71. Desai AA, Janisch LL, Berk R, Knowles HL, Rivera VM, Bedrosian CL, et al. A phase 1 trial of a novel mTOR inhibitor AP23573 administered weekly in patients with refractory or advanced malignancies: a pharmacokinetic and pharmacodynamic analysis. J Clin Oncol 2004; 22:abstr 3150.
72. Clackson T, Metcalf CA, Rivera VM, Konwles HL, Tang H, Burns KD, et al. Broad anti-tumor activity of AP23573, an mTOR inhibitor in clinical development. [abstract] Proc Am Soc Clin Oncol 2003; 22:882A.
73. Nelms JL, Goldlust SA, Kanner A, Vogelbaum MA. A novel mTOR inhibitor (AP23573) produces cell loss and apoptosis in glioblastoma multiforme independent of EGFR status. [abstract] Neuro-Oncology 2003; 5:29A.
74. Chawla SP, Sankhala KK, Chua V, Menendez LR, Eilber FC, Eckardt JJ, et al. A phase II study of AP23573 (an mTOR inhibitor) in patients (pts) with advanced sarcomas. [abstract] J Clin Oncol 2005; 23:9068A.
75. 18F]2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan. J Clin Oncol 2005; 23:abstr 9028.
76. Rizzieri DA, Feldman E, Moore JO, Roboz GJ, DiPersio J, Gabrail N, et al. A phase 2 clinical trial of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies. Blood 2005; 106:abstr 2980.
77. Feldman E, Giles F, Roboz G, Yee K, Curcio T, Rivera VM, et al. A phase 2 clinical trial of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies. J Clin Oncol 2005; 23:abstr 6631.