Cancer and Metastasis Reviews

, Volume 26, Issue 3–4, pp 611–621

Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis

  • Hendrik Seeliger
  • Markus Guba
  • Axel Kleespies
  • Karl-Walter Jauch
  • Christiane J. Bruns
Article

Abstract

The mammalian target of rapamycin (mTOR) is a controller of cell growth with multiple effects on cancer development and progression. Being closely linked to key oncogenic pathways that regulate tumor cell growth and cell cycle progression, mTOR integrates the cellular response to mitogenic and growth stimuli. Rapamycin and its analogs temsirolimus and everolimus are specific inhibitors of mTOR that exert suppressive effects on proliferation, invasion, and metastasis and induce apoptosis of tumor cells. Apart from the direct effects of mTOR inhibitors on tumor cells, rapamycin and its analogs have potent antiangiogenic properties related to the suppression of vascular endothelial growth factor signal transduction. While the use of mTOR inhibitors as a monotherapy seems to be insufficient to effectively control tumor progression in most tumor entities, combination with tyrosine kinase inhibitors or cytotoxic agents might potentiate the antitumoral effects of mTOR inhibition. In a clinical setting, mTOR inhibitors show an acceptable safety profile over a wide dose range. Currently, mTOR inhibitors are tested in multiple trials in combination with other agents in various cancer entities in intermittent schedules to avoid immunosuppression. However, lacking adequate surrogate and response parameters, the most effective biological dosing schedules remain to be defined. Considering these apparent limitations, the full clinical potential of this promising class of drugs is at risk to be missed by applying them inadequately.

Keywords

mTOR Rapamycin Angiogenesis Solid tumors 

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References

  1. 1.
    Easton, J. B., & Houghton, P. J. (2006). mTOR and cancer therapy. Oncogene, 25, 6436–446.PubMedCrossRefGoogle Scholar
  2. 2.
    Heitman, J., Movva, N. R., & Hall, M. N. (1991). Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science, 253, 905–09.PubMedCrossRefGoogle Scholar
  3. 3.
    Schmelzle, T., & Hall, M. N. (2000). TOR, a central controller of cell growth. Cell, 103, 253–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Del Bufalo, D., Ciuffreda, L., Trisciuoglio, D., Desideri, M., Cognetti, F., Zupi, G., et al. (2006). Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Research, 66, 5549–54.PubMedCrossRefGoogle Scholar
  5. 5.
    Guba, M., von Breitenbuch, P., Steinbauer, M., Koehl, G., Flegel, S., Hornung, M., et al. (2002). Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Medicine, 8, 128–35.PubMedCrossRefGoogle Scholar
  6. 6.
    Shinohara, E. T., Cao, C., Niermann, K., Mu, Y., Zeng, F., Hallahan, D. E., et al. (2005). Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene, 24, 5414–422.PubMedCrossRefGoogle Scholar
  7. 7.
    Bjornsti, M. A., & Houghton, P. J. (2004). The TOR pathway: a target for cancer therapy. Nature Reviews, Cancer, 4, 335–48.CrossRefGoogle Scholar
  8. 8.
    Wullschleger, S., Loewith, R., & Hall, M. N. (2006). TOR signaling in growth and metabolism. Cell, 124, 471–84.PubMedCrossRefGoogle Scholar
  9. 9.
    Fingar, D. C., Salama, S., Tsou, C., Harlow, E., & Blenis, J. (2002). Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes & Development, 16, 1472–487.CrossRefGoogle Scholar
  10. 10.
    Murakami, M., Ichisaka, T., Maeda, M., Oshiro, N., Hara, K., Edenhofer, F., et al. (2004). mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Molecular and Cellular Biology, 24, 6710–718.PubMedCrossRefGoogle Scholar
  11. 11.
    Neshat, M. S., Mellinghoff, I. K., Tran, C., Stiles, B., Thomas, G., Petersen, R., et al. (2001). Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proceedings of the National Academy of Sciences of the United States of America, 98, 10314–0319.PubMedCrossRefGoogle Scholar
  12. 12.
    Wullschleger, S., Loewith, R., Oppliger, W., & Hall, M. N. (2005). Molecular organization of target of rapamycin complex 2. Journal of Biological Chemistry, 280, 30697–0704.PubMedCrossRefGoogle Scholar
  13. 13.
    Jacinto, E., Loewith, R., Schmidt, A., Lin, S., Ruegg, M. A., Hall, A., et al. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biology, 6, 1122–128.PubMedCrossRefGoogle Scholar
  14. 14.
    Sarbassov, D. D., Ali, S. M., Kim, D. H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., et al. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current Biology, 14. 1296–302.PubMedCrossRefGoogle Scholar
  15. 15.
    Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor’mTOR complex. Science, 307, 1098–101.PubMedCrossRefGoogle Scholar
  16. 16.
    Zeng, Z., Sarbassov dos, D., Samudio, I. J., Yee, K. W., Munsell, M. F., Ellen Jackson, C., et al. (2007). Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood, 109, 3509–512.PubMedCrossRefGoogle Scholar
  17. 17.
    Inoki, K., Li, Y., Xu, T., & Guan, K. L. (2003). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes & Development, 17, 1829–834.CrossRefGoogle Scholar
  18. 18.
    Long, X., Lin, Y., Ortiz-Vega, S., Busch, S., & Avruch, J. (2007). The Rheb switch 2 segment is critical for signaling to TOR complex 1. Journal of Biological Chemistry, 282(25), 18542–8551.PubMedCrossRefGoogle Scholar
  19. 19.
    Jefferies, H. B., Fumagalli, S., Dennis, P. B., Reinhard, C., Pearson, R. B., & Thomas, G. (1997). Rapamycin suppresses 5-TOP mRNA translation through inhibition of p70s6k. EMBO Journal, 16, 3693–704.PubMedCrossRefGoogle Scholar
  20. 20.
    Stolovich, M., Tang, H., Hornstein, E., Levy, G., Cohen, R., Bae, S. S., et al. (2002). Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation. Molecular and Cellular Biology, 22, 8101–813.PubMedCrossRefGoogle Scholar
  21. 21.
    Nourse, J., Firpo, E., Flanagan, W. M., Coats, S., Polyak, K., Lee, M. H., et al. (1994). Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature, 372, 570–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Kato, J. Y., Matsuoka, M., Polyak, K., Massague, J., & Sherr, C. J. (1994). Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell, 79, 487–96.PubMedCrossRefGoogle Scholar
  23. 23.
    Chow, L. M., & Baker, S. J. (2006). PTEN function in normal and neoplastic growth. Cancer Letters, 241, 184–96.PubMedCrossRefGoogle Scholar
  24. 24.
    Nakayama, K., Nakayama, N., Kurman, R. J., Cope, L., Pohl, G., Samuels, Y., et al. (2006). Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biology & Therapy, 5, 779–85.CrossRefGoogle Scholar
  25. 25.
    Bertelsen, B. I., Steine, S. J., Sandvei, R., Molven, A., & Laerum, O. D. (2006). Molecular analysis of the PI3K’AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation. International Journal of Cancer, 118, 1877–883.CrossRefGoogle Scholar
  26. 26.
    Gao, X., Zhang, Y., Arrazola, P., Hino, O., Kobayashi, T., Yeung, R. S., et al. (2002). Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nature Cell Biology, 4, 699–04.PubMedCrossRefGoogle Scholar
  27. 27.
    Astrinidis, A., & Henske, E. P. (2005). Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease. Oncogene, 24, 7475–481.PubMedCrossRefGoogle Scholar
  28. 28.
    Zacharek, S. J., Xiong, Y., & Shumway, S. D. (2005). Negative regulation of TSC1’TSC2 by mammalian D-type cyclins. Cancer Research, 65, 11354–1360.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang, H., Cicchetti, G., Onda, H., Koon, H. B., Asrican, K., Bajraszewski, N., et al. (2003). Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K’Akt signaling through downregulation of PDGFR. Journal of Clinical Investigation, 112, 1223–233.PubMedGoogle Scholar
  30. 30.
    Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Zhang, X., et al. (2006). TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell, 126, 955–68.PubMedCrossRefGoogle Scholar
  31. 31.
    Feng, Z., Hu, W., de Stanchina, E., Teresky, A. K., Jin, S., Lowe, S., et al. (2007). The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Research, 67, 3043–053.PubMedCrossRefGoogle Scholar
  32. 32.
    Feng, Z., Zhang, H., Levine, A. J., & Jin, S. (2005). The coordinate regulation of the p53 and mTOR pathways in cells. Proceedings of the National Academy of Sciences of the United States of America, 102, 8204–209.PubMedCrossRefGoogle Scholar
  33. 33.
    Levine, A. J., Feng, Z., Mak, T. W., You, H., & Jin, S. (2006). Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes & Development, 20, 267–75.CrossRefGoogle Scholar
  34. 34.
    Shaw, R. J., Bardeesy, N., Manning, B. D., Lopez, L., Kosmatka, M., DePinho, R. A., et al. (2004). The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell, 6, 91–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Mabuchi, S., Altomare, D. A., Connolly, D. C., Klein-Szanto, A., Litwin, S., Hoelzle, M. K., et al. (2007). RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Research, 67, 2408–413.PubMedCrossRefGoogle Scholar
  36. 36.
    Skeen, J. E., Bhaskar, P. T., Chen, C. C., Chen, W. S., Peng, X. D., Nogueira, V., et al. (2006). Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell, 10, 269–80.PubMedCrossRefGoogle Scholar
  37. 37.
    Wu, Q., Kiguchi, K., Kawamoto, T., Ajiki, T., Traag, J., Carbajal, S., et al. (2007). Therapeutic effect of rapamycin on gallbladder cancer in a transgenic mouse model. Cancer Research, 67, 3794–800.PubMedCrossRefGoogle Scholar
  38. 38.
    Namba, R., Young, L. J., Abbey, C. K., Kim, L., Damonte, P., Borowsky, A. D., et al. (2006). Rapamycin inhibits growth of premalignant and malignant mammary lesions in a mouse model of ductal carcinoma in situ. Clinical Cancer Research, 12, 2613–621.PubMedCrossRefGoogle Scholar
  39. 39.
    Majumder, P. K., Febbo, P. G., Bikoff, R., Berger, R., Xue, Q., McMahon, L. M., et al. (2004). mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Medicine, 10, 594–01.PubMedCrossRefGoogle Scholar
  40. 40.
    Wimmer, C. D., Rentsch, M., Crispin, A., Illner, W. D., Arbogast, H., Graeb, C., et al. (2007). The janus face of immunosuppression –de novo malignancy after renal transplantation: the experience of the Transplantation Center Munich. Kidney International, 71, 1271–278.PubMedCrossRefGoogle Scholar
  41. 41.
    Sieghart, W., Fuereder, T., Schmid, K., Cejka, D., Werzowa, J., Wrba, F., et al. (2007). Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation, 83, 425–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Huang, S., Shu, L., Easton, J., Harwood, F. C., Germain, G. S., Ichijo, H., et al. (2004). Inhibition of mammalian target of rapamycin activates apoptosis signal-regulating kinase 1 signaling by suppressing protein phosphatase 5 activity. Journal of Biological Chemistry, 279, 36490–6496.PubMedCrossRefGoogle Scholar
  43. 43.
    Huang, S., Shu, L., Dilling, M. B., Easton, J., Harwood, F. C., Ichijo, H., et al. (2003). Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1). Molecular Cell, 11, 1491–501.PubMedCrossRefGoogle Scholar
  44. 44.
    Hosoi, H., Dilling, M. B., Shikata, T., Liu, L. N., Shu, L., Ashmun, R. A., et al. (1999). Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Research, 59, 886–94.PubMedGoogle Scholar
  45. 45.
    Thimmaiah, K. N., Easton, J., Huang, S., Veverka, K. A., Germain, G. S., Harwood, F. C., et al. (2003). 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 Research, 63, 364–74.PubMedGoogle Scholar
  46. 46.
    Buck, E., Eyzaguirre, A., Brown, E., Petti, F., McCormack, S., Haley, J. D., et al. (2006). Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Molecular Cancer Therapeutics, 5, 2676–684.PubMedCrossRefGoogle Scholar
  47. 47.
    Raje, N., Kumar, S., Hideshima, T., Ishitsuka, K., Chauhan, D., Mitsiades, C., et al. (2004). Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood, 104, 4188–193.PubMedCrossRefGoogle Scholar
  48. 48.
    Beuvink, I., Boulay, A., Fumagalli, S., Zilbermann, F., Ruetz, S., O’Reilly T., et al. (2005). The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell, 120, 747–59.PubMedCrossRefGoogle Scholar
  49. 49.
    Bruns, C. J., Koehl, G. E., Guba, M., Yezhelyev, M., Steinbauer, M., Seeliger, H., et al. (2004). Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer. Clinical Cancer Research, 10, 2109–119.PubMedCrossRefGoogle Scholar
  50. 50.
    Seeliger, H., Guba, M., Koehl, G. E., Doenecke, A., Steinbauer, M., Bruns, C. J., et al. (2004). Blockage of 2-deoxy-d-ribose-induced angiogenesis with rapamycin counteracts a thymidine phosphorylase-based escape mechanism available for colon cancer under 5-fluorouracil therapy. Clinical Cancer Research, 10, 1843–852.PubMedCrossRefGoogle Scholar
  51. 51.
    Cao, C., Subhawong, T., Albert, J. M., Kim, K. W., Geng, L., Sekhar, K. R., et al. (2006). Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Research, 66, 10040–0047.PubMedCrossRefGoogle Scholar
  52. 52.
    Kim, K. W., Mutter, R. W., Cao, C., Albert, J. M., Freeman, M., Hallahan, D. E., et al. (2006). Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling. Journal of Biological Chemistry, 281, 36883–6890.PubMedCrossRefGoogle Scholar
  53. 53.
    Paglin, S., Lee, N. Y., Nakar, C., Fitzgerald, M., Plotkin, J., Deuel, B., et al. (2005). Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Research, 65, 11061–1070.PubMedCrossRefGoogle Scholar
  54. 54.
    Iwamaru, A., Kondo, Y., Iwado, E., Aoki, H., Fujiwara, K., Yokoyama, T., et al. (2007). Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells. Oncogene, 26, 1840–851.PubMedCrossRefGoogle Scholar
  55. 55.
    Zhang, D., Bar-Eli, M., Meloche, S., & Brodt, P. (2004). Dual regulation of MMP-2 expression by the type 1 insulin-like growth factor receptor: the phosphatidylinositol 3-kinase/Akt and Raf/ERK pathways transmit opposing signals. Journal of Biological Chemistry, 279, 19683–9690.PubMedCrossRefGoogle Scholar
  56. 56.
    Zhang, D., & Brodt, P. (2003). Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling. Oncogene, 22, 974–82.PubMedCrossRefGoogle Scholar
  57. 57.
    Hornberger, T. A., & Chien, S. (2006). Mechanical stimuli and nutrients regulate rapamycin-sensitive signaling through distinct mechanisms in skeletal muscle. Journal of Cellular Biochemistry, 97, 1207–216.PubMedCrossRefGoogle Scholar
  58. 58.
    Hornberger, T. A., Chu, W. K., Mak, Y. W., Hsiung, J. W., Huang, S. A., & Chien, S. (2006). The role of phospholipase D and phosphatidic acid in the mechanical activation of mTOR signaling in skeletal muscle. Proceedings of the National Academy of Sciences of the United States of America, 103, 4741–746.PubMedCrossRefGoogle Scholar
  59. 59.
    Hui, L., Rodrik, V., Pielak, R. M., Knirr, S., Zheng, Y., & Foster, D. A. (2005). mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells. Journal of Biological Chemistry, 280, 35829–5835.PubMedCrossRefGoogle Scholar
  60. 60.
    Zheng, Y., Rodrik, V., Toschi, A., Shi, M., Hui, L., Shen, Y., et al. (2006). Phospholipase D couples survival and migration signals in stress response of human cancer cells. Journal of Biological Chemistry, 281, 15862–5868.PubMedCrossRefGoogle Scholar
  61. 61.
    Meng, Q., Xia, C., Fang, J., Rojanasakul, Y., & Jiang, B. H. (2006). Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signalling, 18, 2262–271.PubMedCrossRefGoogle Scholar
  62. 62.
    Krishnamachary, B., Berg-Dixon, S., Kelly, B., Agani, F., Feldser, D., Ferreira, G., et al. (2003). Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Research, 63, 1138–143.PubMedGoogle Scholar
  63. 63.
    Lang, S. A., Gaumann, A., Koehl, G. E., Seidel, U., Bataille, F., Klein, D., et al. (2007). Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. International Journal of Cancer, 120, 1803–810.CrossRefGoogle Scholar
  64. 64.
    Liu, L., Li, F., Cardelli, J. A., Martin, K. A., Blenis, J., & Huang, S. (2006). Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene, 25, 7029–040.PubMedCrossRefGoogle Scholar
  65. 65.
    Hudson, C. C., Liu, M., Chiang, G. G., Otterness, D. M., Loomis, D. C., Kaper, F., et al. (2002). Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Molecular and Cellular Biology, 22, 7004–014.PubMedCrossRefGoogle Scholar
  66. 66.
    Pugh, C. W., & Ratcliffe, P. J. (2003). Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Medicine, 9. 677–84.PubMedCrossRefGoogle Scholar
  67. 67.
    Zhong, H., Chiles, K., Feldser, D., Laughner, E., Hanrahan, C., Georgescu, M. M., et al. (2000). 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 Research, 60, 1541–545.PubMedGoogle Scholar
  68. 68.
    Huber, S., Bruns, C. J., Schmid, G., Hermann, P. C., Conrad, C., Niess, H., et al. (2007). Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis. Kidney International, 71, 771–77.PubMedCrossRefGoogle Scholar
  69. 69.
    Kobayashi, S., Kishimoto, T., Kamata, S., Otsuka, M., Miyazaki, M., & Ishikura, H. (2007). Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis. Cancer Science, 98, 726–33.PubMedCrossRefGoogle Scholar
  70. 70.
    Baluk, P., Morikawa, S., Haskell, A., Mancuso, M., & McDonald, D. M. (2003). Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. American Journal of Pathology, 163, 1801–815.PubMedGoogle Scholar
  71. 71.
    Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature, 407, 249–57.PubMedCrossRefGoogle Scholar
  72. 72.
    Morikawa, S., Baluk, P., Kaidoh, T., Haskell, A., Jain, R. K., & McDonald, D. M. (2002). Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. American Journal of Pathology, 160, 985–000.PubMedGoogle Scholar
  73. 73.
    Folkman, J. (1971). Tumor angiogenesis: therapeutic implications. New England Journal of Medicine, 285, 1182–186.PubMedCrossRefGoogle Scholar
  74. 74.
    Ilan, N., Mahooti, S., & Madri, J. A. (1998). Distinct signal transduction pathways are utilized during the tube formation and survival phases of in vitro angiogenesis. Journal of Cell Science, 111(Pt 24), 3621–631.PubMedGoogle Scholar
  75. 75.
    Yu, Y., & Sato, J. D. (1999). MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. Journal of Cellular Physiology, 178, 235–46.PubMedCrossRefGoogle Scholar
  76. 76.
    Moon, S. O., Kim, W., Kim, D. H., Sung, M. J., Lee, S., Kang, K. P., et al. (2005). Angiopoietin-1 reduces iopromide-induced endothelial cell apoptosis through activation of phosphatidylinositol 3–kinase/p70 S6 kinase. International Journal of Tissue Reactions, 27, 115–24.PubMedGoogle Scholar
  77. 77.
    Panka, D. J., & Mier, J. W. (2003). Canstatin inhibits Akt activation and induces Fas-dependent apoptosis in endothelial cells. Journal of Biological Chemistry, 278, 37632–7636.PubMedCrossRefGoogle Scholar
  78. 78.
    Guba, M., Yezhelyev, M., Eichhorn, M. E., Schmid, G., Ischenko, I., Papyan, A., et al. (2005). Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF. Blood, 105, 4463–469.PubMedCrossRefGoogle Scholar
  79. 79.
    Steffel, J., Latini, R. A., Akhmedov, A., Zimmermann, D., Zimmerling, P., Luscher, T. F., et al. (2005). Rapamycin, but not FK-506, increases endothelial tissue factor expression: implications for drug-eluting stent design. Circulation, 112, 2002–011.PubMedCrossRefGoogle Scholar
  80. 80.
    Zhu, S., Viswambharan, H., Gajanayake, T., Ming, X. F., & Yang, Z. (2005). Sirolimus increases tissue factor expression but not activity in cultured human vascular smooth muscle cells. BMC Cardiovascular Disorders, 5, 22.PubMedCrossRefGoogle Scholar
  81. 81.
    Butzal, M., Loges, S., Schweizer, M., Fischer, U., Gehling, U. M., Hossfeld, D. K., et al. (2004). Rapamycin inhibits proliferation and differentiation of human endothelial progenitor cells in vitro. Experimental Cell Research, 300, 65–1.PubMedCrossRefGoogle Scholar
  82. 82.
    Chen, T. G., Chen, J. Z., & Wang, X. X. (2006). Effects of rapamycin on number activity and eNOS of endothelial progenitor cells from peripheral blood. Cell Proliferation, 39, 117–25.PubMedCrossRefGoogle Scholar
  83. 83.
    Miriuka, S. G., Rao, V., Peterson, M., Tumiati, L., Delgado, D. H., Mohan, R., et al. (2006). mTOR inhibition induces endothelial progenitor cell death. American Journal of Transplantation, 6, 2069–079.PubMedCrossRefGoogle Scholar
  84. 84.
    Sodhi, A., Chaisuparat, R., Hu, J., Ramsdell, A. K., Manning, B. D., Sausville, E. A., et al. (2006). The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell, 10, 133–43.PubMedCrossRefGoogle Scholar
  85. 85.
    Di Paolo, S., Teutonico, A., Leogrande, D., Capobianco, C., & Schena, P. F. (2006). Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: A crossroad between cancer and diabetes? Journal of the American Society of Nephrology, 17, 2236–244.PubMedCrossRefGoogle Scholar
  86. 86.
    Klos, K. S., Wyszomierski, S. L., Sun, M., Tan, M., Zhou, X., Li, P., et al. (2006). ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Cancer Research, 66, 2028–037.PubMedCrossRefGoogle Scholar
  87. 87.
    Zhou, X., Tan, M., Stone Hawthorne, V., Klos, K. S., Lan, K. H., Yang, Y., et al. (2004), Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clinical Cancer Research, 10, 6779–788.PubMedCrossRefGoogle Scholar
  88. 88.
    Pantuck, A. J., Seligson, D. B., Klatte, T., Yu, H., Leppert, J. T., Moore, L., et al. (2007). Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer, 109(11), 2257–267.Google Scholar
  89. 89.
    Burczynski, M. E., Twine, N. C., Dukart, G., Marshall, B., Hidalgo, M., Stadler, W. M., et al. (2005). Transcriptional profiles in peripheral blood mononuclear cells prognostic of clinical outcomes in patients with advanced renal cell carcinoma. Clinical Cancer Research, 11, 1181–189.PubMedGoogle Scholar
  90. 90.
    Hidalgo, M., Buckner, J. C., Erlichman, C., Pollack, M. S., Boni, J. P., Dukart, G., et al. (2006). A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clinical Cancer Research, 12, 5755–763.PubMedCrossRefGoogle Scholar
  91. 91.
    Raymond, E., Alexandre, J., Faivre, S., Vera, K., Materman, E., Boni, J., et al. (2004). Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. Journal of Clinical Oncology, 22, 2336–347.PubMedCrossRefGoogle Scholar
  92. 92.
    Doherty, L., Gigas, D. C., Kesari, S., Drappatz, J., Kim, R., Zimmerman, J., et al. (2006). Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology, 67, 156–58.PubMedCrossRefGoogle Scholar
  93. 93.
    Reardon, D. A., Quinn, J. A., Vredenburgh, J. J., Gururangan, S., Friedman, A. H., Desjardins, A., et al. (2006). Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clinical Cancer Research, 12, 860–68.PubMedCrossRefGoogle Scholar
  94. 94.
    Goudar, R. K., Shi, Q., Hjelmeland, M. D., Keir, S. T., McLendon, R. E., Wikstrand, C. J., et al. (2005). Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Molecular Cancer Therapeutics, 4, 101–12.PubMedGoogle Scholar
  95. 95.
    Punt, C. J., Boni, J., Bruntsch, U., Peters, M., & Thielert, C. (2003). 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. Annals of Oncology, 14, 931–37.PubMedCrossRefGoogle Scholar
  96. 96.
    Atkins, M. B., Hidalgo, M., Stadler, W. M., Logan, T. F., Dutcher, J. P., Hudes, G. R., et al. (2004). 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. Journal of Clinical Oncology, 22, 909–18.PubMedCrossRefGoogle Scholar
  97. 97.
    Chang, S. M., Wen, P., Cloughesy, T., Greenberg, H., Schiff, D., Conrad, C., et al. (2005). Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Investigational New Drugs, 23, 357–61.PubMedCrossRefGoogle Scholar
  98. 98.
    Galanis, E., Buckner, J. C., Maurer, M. J., Kreisberg, J. I., Ballman, K., Boni, J., et al. (2005). Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. Journal of Clinical Oncology, 23, 5294–304.PubMedCrossRefGoogle Scholar
  99. 99.
    Chan, S., Scheulen, M. E., Johnston, S., Mross, K., Cardoso, F., Dittrich, C., et al. (2005). Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. Journal of Clinical Oncology, 23, 5314–322.PubMedCrossRefGoogle Scholar
  100. 100.
    Duran, I., Kortmansky, J., Singh, D., Hirte, H., Kocha, W., Goss, G., et al. (2006). A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. British Journal of Cancer, 95, 1148–154.PubMedCrossRefGoogle Scholar
  101. 101.
    Margolin, K., Longmate, J., Baratta, T., Synold, T., Christensen, S., Weber, J., et al. (2005). CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer, 104, 1045–048.PubMedCrossRefGoogle Scholar
  102. 102.
    Andrassy, J., Graeb, C., Rentsch, M., Jauch, K. W., & Guba, M. (2005). mTOR inhibition and its effect on cancer in transplantation. Transplantation, 80, S171’S174.PubMedCrossRefGoogle Scholar
  103. 103.
    Dudkin, L., Dilling, M. B., Cheshire, P. J., Harwood, F. C., Hollingshead, M., Arbuck, S. G., et al. (2001). Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clinical Cancer Research, 7, 1758–764.PubMedGoogle Scholar
  104. 104.
    Peralba, J. M., DeGraffenried, L., Friedrichs, W., Fulcher, L., Grunwald, V., Weiss, G., et al. (2003). Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clinical Cancer Research, 9, 2887–892.PubMedGoogle Scholar
  105. 105.
    Willett, C. G., Boucher, Y., di Tomaso, E., Duda, D. G., Munn, L. L., Tong, R. T., et al. (2004). Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Medicine, 10, 145–47.PubMedCrossRefGoogle Scholar
  106. 106.
    Willett, C. G., Boucher, Y., Duda, D. G., di Tomaso, E., Munn, L. L., Tong, R. T., et al. (2005). Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. Journal of Clinical Oncology, 23, 8136–139.PubMedCrossRefGoogle Scholar
  107. 107.
    Hidalgo, M. (2004). New target, new drug, old paradigm. Journal of Clinical Oncology, 22, 2270–272.PubMedCrossRefGoogle Scholar
  108. 108.
    Wan, X., Shen, N., Mendoza, A., Khanna, C., & Helman, L. J. (2006). CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling. Neoplasia, 8, 394–01PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Hendrik Seeliger
    • 1
  • Markus Guba
    • 1
  • Axel Kleespies
    • 1
  • Karl-Walter Jauch
    • 1
  • Christiane J. Bruns
    • 1
  1. 1.Department of SurgeryMunich University –Grosshadern CampusMunichGermany

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