The biology behind mTOR inhibition in sarcoma

Oncologist

Volumn 12, Issue 8, 2007, Pages 1007-1018

  Wan, Xiaolin ^a   Helman, Lee J ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

Clinical trial; mTOR; Rapamycin; Sarcoma

Indexed keywords

ALPHA INTERFERON; ANTINEOPLASTIC AGENT; AP 23573; EVEROLIMUS; IMMUNOSUPPRESSIVE AGENT; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; RAPAMYCIN; TEMSIROLIMUS;

ANOREXIA; BREAST CARCINOMA; CANCER GROWTH; CANCER SURVIVAL; CLINICAL TRIAL; DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG INHIBITION; DRUG SCREENING; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; FATIGUE; GENE CONTROL; HEADACHE; HUMAN; HYPERLIPIDEMIA; HYPOCALCEMIA; KIDNEY CARCINOMA; LUNG CARCINOMA; MUCOSA INFLAMMATION; PATIENT SELECTION; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RASH; REVIEW; SARCOMA; SIDE EFFECT; SIGNAL TRANSDUCTION; SKIN MANIFESTATION; THROMBOCYTOPENIA; TREATMENT RESPONSE; VOMITING;

1-PHOSPHATIDYLINOSITOL 3-KINASE; CLINICAL TRIALS; HUMANS; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; PROTO-ONCOGENE PROTEINS C-AKT; SARCOMA; SIROLIMUS;

EID: 34548427415     PISSN: 10837159     EISSN: 1549490X     Source Type: Journal    
DOI: 10.1634/theoncologist.12-8-1007     Document Type: Review

References (89)

1. Helman LJ, Meltzer P. Mechanisms of sarcoma development. Nat Rev Cancer 2003;3:685-694.
2. Raney RB, Anderson JR, Barr FG et al. Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: A selective review of Intergroup Rhabdomyosarcoma Study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 2001;23:215-220.
3. Miser JS, Pappo AS, Triche TJ et al. Other soft tissue sarcomas of childhood. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. Philadelphia, PA: Lippincott Williams & Wilkins, 2002; 1017-1050.
4. Marina N, Gebhardt M, Teot L et al. Biology and therapeutic advances for pediatric osteosarcoma. The Oncologist 2004;9:422- 441.
5. Grier HE, Krailo MD, Tarbell NJ et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694-701.
6. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991;253:905-909.
7. Sabatini DM, Erdjument-Bromage H, Lui M et al. RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994;78:35-43.
8. Sabers CJ, Martin MM, Brunn GJ et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995;270:815-822.
9. Brown EJ, Albers MW, Shin TB et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994;369:756-758.
10. Chiu MI, Katz H, Berlin V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci U S A 1994;91:12574-12578.
11. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-1657.
12. Franke TF, Kaplan DR, Cantley LC et al. Direct regulation of the Akt protooncogene product by phosphatidylinositol-3,4-bisphosphate. Science 1997;275:665-668.
13. Stokoe D, Stephens LR, Copeland T et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 1997;277:567-570.
14. Stephens L, Anderson K, Stokoe D et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 1998;279:710-714.
15. Toker A, Newton AC. Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site. J Biol Chem 2000;275:8271-8274.
16. Fingar DC, Blenis J. Target of rapamycin (TOR): An integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 2004;23:3151-3171.
17. Inoki K, Li Y, Zhu T et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648-657.
18. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002;4:658-665.
19. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004;18:1926-1945.
20. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577-590.
21. Kim DH, Sarbassov DD, Ali SM et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002;110:163-175.
22. Kim DH, Sarbassov DD, Ali SM 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.
23. Sarbassov DD, Guertin DA, Ali SM et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-1101.
24. Sarbassov DD, Ali SM, Kim DH et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14:1296-1302.
25. Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol 2005;17:158-166.
26. Mamane Y, Petroulakis E, Rong L et al. elF4E - from translation to transformation. Oncogene 2004;23:3172-3179.
27. Ferrari S, Bandi HR, Hofsteenge J et al. Mitogen activated 70K S6 kinase. Identification of in vitro 40 S ribosomal S6 phosphorylation sites. J Biol Chem 1991;266:22770-22775.
28. Holz MK, Ballif BA, Gygi SP et al. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 2005;123:569-580.
29. Redpath NT, Foulstone EJ, Proud CG. Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway. EMBO J 1996;15:2291-2297.
30. Baserga R. The insulin-like growth factor-I receptor as a target for cancer therapy. Expert Opin Ther Targets 2005;9:753-768.
31. Penault-Llorca F, Bertucci F, Adelaide J et al. Expression of FGF and FGF receptor genes in human breast cancer. Int J Cancer 1995;61:170-176.
32. Bange J, Prechtl D, Cheburkin Y et al. Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer Res 2002;62:840-847.
33. Holbro T, Hynes NE. ErbB receptors: Directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol 2004;44:195-217.
34. Xie Y, Skytting B, Nilsson G et al. Expression of insulin-like growth factor-1 receptor in synovial sarcoma: Association with an aggressive phenotype. Cancer Res 1999;59:3588-3591.
35. Girnita L, Girnita A, WangMet al. A link between basic fibroblast growth factor (bFGF) and EWS/FLI-1 in Ewing's sarcoma cells. Oncogene 2000;19:4298-4301.
36. Hughes DP, Thomas DG, Giordano TJ et al. Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. Cancer Res 2004;64:2047-2053.
37. Baird K, Davis S, Antonescu CR et al. Gene expression profiling of human sarcomas: Insights into sarcoma biology. Cancer Res 2005;65:9226-9235.
38. Ganti R, Skapek SX, Zhang J et al. Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma. Mod Pathol 2006;19:1213-1220.
39. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-619.
40. Hill MM, Hemmings BA. Inhibition of protein kinase B/Akt: Implications for cancer therapy. Pharmacol Ther 2002;93:243-251.
41. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 2005;37:19-24.
42. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006;5:671-688.
43. Neshat MS, Mellinghoff IK, Tran C et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 2001;98:10314-10319.
44. Podsypanina K, Lee RT, Politis C et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice. Proc Natl Acad Sci U S A 2001;98:10320-10325.
45. Shaw RJ, Bardeesy N, Manning BD et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004;6:91-99.
46. Mamane Y, Petroulakis E, LeBacquer O et al. mTOR, translation initiation and cancer. Oncogene 2006;25:6416-6422.
47. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature 1990;345:544-547.
48. De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene 2004;23:3189-3199.
49. Jiang H, Coleman J, Miskimins R et al. Expression of constitutively active 4EBP-1 enhances p27Kip1 expression and inhibits proliferation of MCF7 breast cancer cells. Cancer Cell Int 2003;3:2.
50. Avdulov S, Li S, Michalek V et al. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 2004;5:553-563.
51. Polunovsky VA, Gingras AC, Sonenberg N et al. Translational control of the antiapoptotic function of Ras. J Biol Chem 2000;275:24776-24780.
52. Herbert TP, Fahraeus R, Prescott A et al. Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E. Curr Biol 2000;10:793-796.
53. Petricoin EF, Espina V, Araujo RP et al. Phosphorylation pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival. Cancer Res 2007;67:3431-3440.
54. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975;28:721-726.
55. Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 2003;3:371-377.
56. Humar R, Kiefer FN, Berns H et al. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 2002;16:771-780.
57. Mayerhofer M, Valent P, Sperr WR et al. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 2002;100:3767-3775.
58. Guba M, von Breitenbuch P, Steinbauer M et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nature Med 2002;8:128-135.
59. Wan X, Shen N, Mendoza A et al. CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia 2006;8:394-401.
60. Wan X, Mendoza A, Khanna C et al. Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma. Cancer Res 2005;65:2406-2411.
61. Hidalgo M, Rowinsky E, Erlichman C et al. Phase 1 and pharmacologic study of CCI-779, a cell cycle inhibitor. Presented at the 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy, Amsterdam, The Netherlands, November 7-10, 2000.
62. Raymond E, Alexandre J, Faivre S 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;22:2336-2347.
63. Atkins MB, Hidalgo M, Stadler WM 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.
64. Chan S, Scheulen ME, Johnston S et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005;23:5314-5322.
65. Witzig TE, Geyer SM, Ghobrial I et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005;23:5347-5356.
66. Galanis E, Buckner JC, Maurer MJ 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.
67. Hudes G, Carducci M, Tomczak P et al. A phase III, randomised, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFR in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma. J Clin Oncol 2006;24(suppl 18):LBA4a.
68. O'Donnell A, Faivre S, Judson I et al. A phase I study of the oral mTOR inhibitors 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;22:803a.
69. Amato RJ, Misellati A, Khan M et al. A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). J Clin Oncol 2006;24(suppl 18):4530a.
70. Mita M, Rowinsky E, Mita A et al. AP23573, and mTOR, administered IV daily x 5 every other week in patients with refractory or advanced malignancies - a phase 1, pharmacokinetic (PK), and pharmacodynamic (PD) study. Presented at the 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Geneva, September 28-October 1, 2004.
71. Mita M, Rowinsky E, Mita A et al. A Phase 1, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (patients) with refractory or advanced malignancies. J Clin Oncol 2004;22(suppl 14):3076a.
72. Desai AA, Janisch L, Berk L et al. A phase 1 trial of weekly AP23573, a novel mTOR inhibitor, in patients with advanced or refractory malignancies: A pharmacokinetic (PK) and pharmacodynamic (PD) analysis. Presented at the 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Geneva, September 28-October 1, 2004.
73. Desai AA, Mita M, Fetterly GJ et al. Development of a pharmacokinetic (PK) model and assessment of patient (patient) covariate effects on dose-dependent PK following different dosing schedules in two phase 1 trials of AP23573 (AP23573), a mTOR inhibitor. Presented at the 2005 American Society of Clinical Oncology Annual Meeting, Orlando, FL, May 13-17, 2005.
74. Chawla SP, Tolcher AW, Staddon AP et al. Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcoma. J Clin Oncol 2006;24(suppl 18):9505a.
75. Sankhala KK, Chawla SP, LagaruAet al. Early response evaluation of therapy with AP23573 (an mTOR inhibitor) in sarcoma using [18F]2-fluoro-2-deoxy- D-glucose (FDG) positron emission tomography (PET) scan. J Clin Oncol 2005;23(suppl 16):9028a.
76. Chawla SP. Sankhala KK, Chua V et al. A phase II study of AP23573 (an mTOR inhibitor) in patients (pts) with advanced sarcomas. J Clin Oncol 2005;23(suppl 16):9068a.
77. Chawla SP, Sankhala KK, Mida MM et al. AP23573: A review of recent results. Available at http://www.liddyshriversarcomainitiative.org/News-letters/ V02N04/AP23573/ap23573.htm. Accessed March 29, 2007.
78. Dancey JE. Therapeutic targets: MTOR and related pathways. Cancer Biol Ther 2006;5:1065-1073.
79. Rizzieri DA, Feldman E, Moore JQ et al. A phase II clinical trial of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies. Blood 2005;106:2980a.
80. Feldman E, Giles F, Roboz G et al. A Phase 2 clinical trials of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies. J Clin Oncol 2005;23(suppl 16):6631a.
81. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase Akt pathway in human cancer. Nat Rev Cancer 2002;2:489-501.
82. 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;65:7052-7058.
83. O'Reilly KE, Rojo F, She QB et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-1508.
84. Wan X, Harkavy B, Shen N et al. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 2007;26:1932-1940.
85. Yao JC, Phan AT, Chang DZ et al. Phase II study of RAD001 (everolimus) and depot octreotide (Sandostatin LAR) in patients with advanced low grade neuroendocrine carcinoma (LGNET). J Clin Oncol 2006;24(Post-Meeting Edition):4042a.
86. Dutcher IP, Hudes G, Motzer R et al. Preliminary report of a phase I study of a phase I study of intravenous (IV) CCI-779 given in combination with interferon- (INF) to patients with advanced renal cell carcinoma (RCC). Proc Am Soc Clin Oncol 2003;22:854a.
87. Punt CJ, Boni J, Bruntsch U et al. Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol 2003;14:931-937.
88. Pacey S, Rea D, Steven N et al. Results of a phase I clinical trial investigating a combination of the oral mTOR-inhibitor everolimus (E, RAD001) and gemcitabine (GEM) in patients (pts) with advanced cancers. Proc Am Soc Clin Oncol 2004;22(Post-Meeting Edition):3120a.
89. Milton DT, Kris MG, Azzoli CG et al. Phase I/II trial of gefitinib and RAD001 (everolimus) in patients (pts) with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2005;24:7104a.