1. Brown EJ, Albers MW, Shin TB et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994; 369: 756–8.
2. Chiu MI, Katz H, Berlin V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA 1994; 91: 12574–8.
3. 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: 815–22.
4. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004 18: 1926–45.
5. Jacinto E, Loewith R, Schmidt A et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6: 1122–8.
6. 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: 1296–302.
7. Jiang BH, Liu LZ. Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist 2008; 11: 63–76.
8. Proud CG. Signalling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem J 2007; 403: 217–34.
9. Jastrzebski K, Hannan KM, Tchoubrieva EB et al. Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 2007; 25: 209–26.
10. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655–7.
11. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006; 7: 606–19.
12. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008; 27: 5486–96.
13. Skolnik EY, Margolis B, Mohammadi M et al. Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 1991; 65: 83–90.
14. Dhand R, Hiles I, Panayotou G et al. PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J 1994; 13: 522–33.
15. Foukas LC, Beeton CA, Jensen J et al. Regulation of phosphoinositide 3-kinase by its intrinsic serine kinase activity in vivo. Mol Cell Biol 2004; 24: 966–75.
16. Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 1997; 275: 665–8.
17. Corvera S, Czech MP. Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Cell Biol 1998; 8: 442–6.
18. Alessi DR, James SR, Downes CP et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7: 261–9.
19. Alessi DR, Kozlowski MT, Weng QP et al. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. Curr Biol 1998; 8: 69–81.
20. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098–101.
21. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 13375–8.
22. Myers MP, Pass I, Batty IH et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA 1998; 95: 13513–8.
23. Stambolic V, Suzuki A, de la Pompa JL et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998; 95: 29–39.
24. Blanco-Aparicio C, Renner O, Leal JF, Carnero A. PTEN, more than the AKT pathway. Carcinogenesis 2007; 28: 1379–86.
25. Inoki K, Li Y, Zhu T et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4: 648–57.
26. Manning BD, Tee AR, Logsdon MN et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10: 151–62.
27. Kovacina KS, Park GY, Bae SS et al. Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 2003; 278: 10189–94.
28. Govindarajan B, Mizesko MC, Miller MS et al. Tuberous sclerosis-associated neoplasms express activated p42/44 mitogen-activated protein (MAP) kinase, and inhibition of MAP kinase signaling results in decreased in vivo tumor growth. Clin Cancer Res 2003; 9: 3469–75.
29. Han S, Santos TM, Puga A et al. Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions. Cancer Res 2004; 64: 812–6.
30. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004; 14: 1650–6.
31. Um SH, Frigerio F, Watanabe M et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431: 200–5.
32. Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004; 167: 399–403.
33. Harrington LS, Findlay GM, Lamb RF. Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem Sci 2005; 30: 35–42.
34. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115: 577–90.
35. Kimura N, Tokunaga C, Dalal S et al. A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 2003; 8: 65–79.
36. Inoki K, Ouyang H, Zhu T et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006; 126: 955–68.
37. Brugarolas J, Lei K, Hurley RL et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18: 2893–904.
38. DeYoung MP, Horak P, Sofer A et al. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008; 22: 239–51.
39. Jiang BH, Liu LZ. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta 2008; 1784: 150–8.
40. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009; 9: 550–62.
41. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8: 627–44.
42. Sawyers CL. Will mTOR inhibitors make it as cancer drugs? Cancer Cell 2003; 4: 343–8.
43. Ligresti G, Militello L, Steelman LS et al. PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches. Cell Cycle 2009; 8: 1352–8.
44. Stiles BL. Phosphatase and tensin homologue deleted on chromosome 10: extending its PTENtacles. Int J Biochem Cell Biol 2009; 41: 757–61.
45. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27: 5497–510.
46. Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 2008; 27: 5477–85.
47. Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 2009; 4: 127–50.
48. Qiao M, Sheng S, Pardee AB. Metastasis and AKT activation. Cell Cycle 2008; 7: 2991–6.
49. Shtilbans V, Wu M, Burstein DE. Current overview of the role of Akt in cancer studies via applied immunohistochemistry. Ann Diagn Pathol 2008; 12: 153–60.
50. Dai DL, Martinka M, Li G. Prognostic significance of activated Akt expression in melanoma: a clinicopathologic study of 292 cases. J Clin Oncol 2005; 23: 1473–82.
51. Schlieman MG, Fahy BN, Ramsamooj R et al. Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br J Cancer 2003; 89: 2110–5.
52. Nakanishi K, Sakamoto M, Yamasaki S et al. Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma. Cancer 2005; 103: 307–12.
53. Yamamoto S, Tomita Y, Hoshida Y et al. Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res 2004; 10: 2846–50.
54. Perez-Tenorio G, Stal O. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 2002; 86: 540–5.
55. Kreisberg JI, Malik SN, Prihoda TJ et al. Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res 2004; 64: 5232–6.
56. Nam SY, Lee HS, Jung GA. Akt/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis. APMIS 2003; 111: 1105–13.
57. Terakawa N, Kanamori Y, Yoshida S. Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer. Endocr Relat Cancer 2003; 10: 203–8.
58. Ermoian RP, Furniss CS, Lamborn KR et al. Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clin Cancer Res 2002; 8: 1100–6.
59. Bellacosa A, de Feo D, Godwin AK et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 1995; 64: 280–5.
60. Ruggeri BA, Huang L, Wood M et al. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog 1998; 21: 81–6.
61. Merritt JL, 2nd, Davis DM, Pittelkow MR, Babovic-Vuksanovic D. Extensive acrochordons and pancreatic islet-cell tumors in tuberous sclerosis associated with TSC2 mutations. Am J Med Genet A 2006; 140: 1669–72.
62. Yeung RS, Xiao GH, Jin F et al. Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci USA 1994; 91: 11413–6.
63. Pacheco-Rodriguez G, Steagall WK, Crooks DM et al. TSC2 loss in lymphangioleiomyomatosis cells correlated with expression of CD44v6, a molecular determinant of metastasis. Cancer Res 2007; 67: 10573–81.
64. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4: 335–48.
65. Couch FJ, Wang XY, Wu GJ et al. Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer Res 1999; 59: 1408–11.
66. 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; 15: 1708–20.
67. Surace EI, Lusis E, Haipek CA, Gutmann DH. Functional significance of S6K overexpression in meningioma progression. Ann Neurol 2004; 56: 295–8.
68. Ehrbrecht A, Muller U, Wolter M et al. Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. J Pathol 2006; 208: 554–63.
69. Pende M, Um SH, Mieulet V et al. S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 2004; 24: 3112–24.
70. Trinh XB, Tjalma WA, Vermeulen PB et al. The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer. Br J Cancer 2009; 100: 971–8.
71. Rojo F, Najera L, Lirola J et al. 4E-binding protein 1, a cell signaling hallmark in breast cancer that correlates with pathologic grade and prognosis. Clin Cancer Res 2007; 13: 81–9.
72. Castellvi J, Garcia A, Rojo F. Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer 2006; 107: 1801–11.
73. Defatta RJ, De Benedetti A. Translational upregulation of yes accompanies eIF4E-mediated oncogenic transformation. Int J Oncol 2003; 23: 1709–13.
74. Sorrells DL, Ghali GE, Meschonat C et al. Competitive PCR to detect eIF4E gene amplification in head and neck cancer. Head Neck 1999; 21: 60–5.
75. McClusky DR, Chu Q, Yu H et al. A prospective trial on initiation factor 4E (eIF4E) overexpression and cancer recurrence in node-positive breast cancer. Ann Surg 2005; 242: 584–90.
76. Rosenwald IB, Chen JJ, Wang S et al. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 1999; 18: 2507–17.
77. Salehi Z, Mashayekhi F. Expression of the eukaryotic translation initiation factor 4E (eIF4E) and 4E-BP1 in esophageal cancer. Clin Biochem 2006; 39: 404–9.
78. Chen CN, Hsieh FJ, Cheng YM et al. Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J Surg Oncol 2004; 86: 22–7.
79. West KA, Castillo SS, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist 2002; 5: 234–48.
80. Tazzari PL, Cappellini A, Ricci F et al. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia 2007; 21: 427–38.
81. Lee JT, Jr., Steelman LS, McCubrey JA. Phosphatidylinositol 3'-kinase activation leads to multidrug resistance protein-1 expression and subsequent chemoresistance in advanced prostate cancer cells. Cancer Res 2004; 64: 8397–404.
82. Vanderweele DJ, Rudin CM. Mammalian target of rapamycin promotes vincristine resistance through multiple mechanisms independent of maintained glycolytic rate. Mol Cancer Res 2005; 3: 635–44.
83. Berns K, Horlings HM, Hennessy BT et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007; 12: 395–402.
84. Maleddu A, Pantaleo MA, Nannini M et al. Mechanisms of secondary resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumours (Review). Oncol Rep 2009; 21: 1359–66.
85. Marinov M, Fischer B, Arcaro A. Targeting mTOR signaling in lung cancer. Crit Rev Oncol Hematol 2007; 63: 172–82.
86. Konings IR, Verweij J, Wiemer EA, Sleijfer S. The applicability of mTOR inhibition in solid tumors. Curr Cancer Drug Targets 2009; 9: 439–50.
87. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 2008; 11: 32–50.
88. Yuan R, Kay A, Berg WJ, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2009; 2: 45.
89. Thompson RH, Hill JR, Babayev Y et al. Metastatic renal cell carcinoma risk according to tumor size. J Urol 2009; 182: 41–5.
90. 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: 5294–304.
91. 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: 5314–22.
92. Sarkaria JN, Schwingler P, Schild SE et al. Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer. J Thorac Oncol 2007; 2: 751–7.
93. Baselga J, Semiglazov V, van Dam P et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009; 27: 2630–7.
94. Chollet P, Abrial C, Tacca O et al. Mammalian target of rapamycin inhibitors in combination with letrozole in breast cancer. Clin Breast Cancer 2006; 7: 336–8.
95. Neshat MS, Mellinghoff IK, Tran C et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 2001; 98: 10314–9.
96. Rowinsky EK. Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 2004; 16: 564–75.
97. Molhoek KR, Brautigan DL, Slingluff CL Jr. Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin. J Transl Med 2005; 3: 39.
98. Omuro AM. Exploring multi-targeting strategies for the treatment of gliomas. Curr Opin Investig Drugs 2008; 9: 1287–95.
99. Reardon DA, Quinn JA, Vredenburgh JJ et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 2006; 12: 860–8.
100. Omuro AM, Faivre S, Raymond E. Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther 2007; 6: 1909–19.
101. Kreisl TN, Lassman AB, Mischel PS et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol 2009; 92: 99–105.
102. La Monica S, Galetti M, Alfieri RR et al. Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem Pharmacol 2009; 78: 460–8.
103. Milton DT, Riely GJ, Azzoli CG et al. Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer 2007; 110: 599–605.
104. Ma WW, Hidalgo M. Exploiting novel molecular targets in gastrointestinal cancers. World J Gastroenterol 2007; 13: 5845–56.
105. Morgan TM, Koreckij TD, Corey E. Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets 2009; 9: 237–49.
106. George S, Bukowski RM. Role of everolimus in the treatment of renal cell carcinoma. Ther Clin Risk Manag 2009; 5: 699–706.
107. Sosman J, Puzanov I. Combination targeted therapy in advanced renal cell carcinoma. Cancer 2009; 115: 2368–75.
108. DeGraffenried LA, Fulcher L, Friedrichs WE et al. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann Oncol 2004; 15: 1510–6.
109. Cloughesy TF, Yoshimoto K, Nghiemphu P et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 2008; 5: e8.
110. Margolin K, Longmate J, Baratta T et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer 2005; 104: 1045–8.
111. Thimmaiah KN, Easton J, Huang S et al. Insulin-like growth factor I-mediated protection from rapamycin-induced apoptosis is independent of Ras-Erk1-Erk2 and phosphatidylinositol 3'-kinase-Akt signaling pathways. Cancer Res 2003; 63: 364–74.
112. Duran I, Kortmansky J, Singh D, Hirte H et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 2006, 95: 1148–54.
113. Yao J, Phan A, Chang D, Wolff R et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- and intermediate-grade neuroendocrine tumors: results of phase II study. J Clin Oncol 2008, 26: 4311–8.
114. Yao J, Lombard-Boha C, Baudin E et al. RADIANT-1 Study Group: Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2009.
115. NCT00863655 Everolimus in combination with exemestane in the treatment of postmenopausal women with esrrogene receptor positive locally advanced or metastatic breast cancer who are refractory to letrozole or anastrosole (BOLERO II). http://www.clinicaltrials.gov Accessed July 15, 2009.
116. NCT00876395 Everolimus in combination with trastuzumab and paclitaxel in the treatment of HER2 positive locally advanced or metastatic breast cancer (BOLERO-1) http://www.clinicaltrials.gov Accessed July 15, 2009.
117. Chawla S, Tolcher A, Staddon A et al. Survival results with AP23573, a novel mTOR inhibitor, in patients with advanced soft tissue or bone sarcomas: update of phase II trial. J Clin Oncol 2007; 25: Abstr 10076.
118. Colombo N, McMeekin S, Schwartz P et al. A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer. J Clin Oncol 2007; 25: Abstr 5516.
119. Oza A, Elit L, Chapman W et al. Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer – NCICIND 160. J Clin Oncol 2006; 24: Abstr 3003.
120. Slomovitz BM, Lu K, Johnston T et al. A phase II study of oral mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), in patients with recurrent endometrial carcinoma (EC). J Clin Oncol 2008; 26: Abstr 5502.
121. Yuan R, Kay A, Berg W, Lebwohl D. Targeting tumorogenesis: development and use of mTOR inhibitors in cancer therapy. J Hem Oncol 2009; 2: 45–57.
122. Oudard S, Medioni J, Ayllon J et al. Expert Rev. Anticancer Therapy 2009; 9 (6): 705–17.
123. Coppin C. Biologics: Targets and Therapy 2010; 4: 91–101.
Авторы
М.А.Красильников1, Н.В.Жуков2
1 Лаборатория молекулярной эндокринологии НИИ канцерогенеза РОНЦ им. Н.Н.Блохина РАМН;
2 Отделение химиотерапии ФГУ ФНКЦ ДГОИ, Москва