Investigating mammalian target of rapamycin inhibitors for their anticancer properties

Bibliography

• HANNAN KM, BRANDENBURGER Y, JENKINS A et al.: mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol. Cell Biol. (2003) 23(23):8862-8877.
   PubMed Web of Science ®Google Scholar
• RICHTER JD, SONENBERG N: Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature (2005) 433(7025):477-480.
   PubMed Web of Science ®Google Scholar
• PENG T, GOLUB TR, SABATINI DM: The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol. Cell Biol. (2002) 22(15):5575-5584.
   PubMed Web of Science ®Google Scholar
• MEIJER AJ, CODOGNO P: Regulation and role of autophagy in mammalian cells. Int. J. Biochem. Cell Biol. (2004) 36(12):2445-2462.
   PubMed Web of Science ®Google Scholar
• MITA MM, MITA A, ROWINSKY EK: The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol. Ther. (2003) 2(Suppl. 1):169-177.
   PubMed Web of Science ®Google Scholar
• VEZINA C, KUDELSKI A, SEHGAL SN: Rapamycin (AY-22,989) a new antifungal antibiotic. Taxonomy of the producing streptomycyte amd isolation of the active principle. J. Antibiot. (Tokyo) (1975) 28(10):721-726.
   PubMed Web of Science ®Google Scholar
• BJORNSTI MA, HOUGHTON PJ: The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer (2004) 4(5):335-348.
   PubMed Web of Science ®Google Scholar
• ANRADE MA, BORK P: HEAT repeats in the Huntington’s disease protein. Nat. Gen. (1995) 11(2):115-116.
   PubMed Web of Science ®Google Scholar
• PANWALKAR A, VERSTOVSEK S, GILES FJ: Mammalian target of rapamycin as therapy for hematologic malignancies. Cancer (2004) 100(4):657-666.
   PubMed Web of Science ®Google Scholar
• 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(2):163-175.
   PubMed Web of Science ®Google Scholar
• KIM DH, SARBASSOV DD, ALI SM et al.: GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell (2003) 11(4):895-904.
   PubMed Web of Science ®Google Scholar
• SARBASSOV DD, GUERTIN DA, ALI SM, SABATINI DM: Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science (2005) 307(5712):1098-1101.
   PubMed Web of Science ®Google Scholar
• SARBASSOV DD, SABATINI DM: Redox regulation of the nutrient-sensitive raptor–mTOR pathway and complex. J. Biol. Chem. (2005) 280(47):39505-39509.
   PubMed Web of Science ®Google Scholar
• WULLSCHLEGER S, LOEWITH R, OPPLIGER W, HALL MN: Molecular organization of TOR complex 2. J. Biol. Chem. (2005) 280(35):30697-30704.
   PubMed Web of Science ®Google Scholar
• SARBASSOW 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(14):1296-1302.
   PubMed Web of Science ®Google Scholar
• JACINTO E, LOEWITH R, SCHMIDT A et al.: Mammalian mTOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. (2004) 6(11):1122-1128.
   PubMed Web of Science ®Google Scholar
• LOEWITH R, JACINTO E, WULLSCHLEGER S et al.: Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell (2002) 10(3):457-468.
   PubMed Web of Science ®Google Scholar
• MANNING BD: Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J. Cell Biol. (2004) 167(3):399-403.
   PubMed Web of Science ®Google Scholar
• LIN HJ, HSIEH FC, SONG H, LIN J: Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer. Br. J. Cancer (2005) 93(12):1372-1381.
   PubMed Web of Science ®Google Scholar
• JOZWIAK J, JOZWIAK S, GRZELA T, LAZARCZYK M: Positive and negative regulation of TSC2 activity and its effects on downstream effectors of the mTOR pathway. Neuromolecular Med. (2005) 7(4):287-296.
   PubMed Web of Science ®Google Scholar
• KWIATKOWSKI DJ, MANNING BD: Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum. Mol. Genet. (2005) 14(2):R251-R258.
   PubMed Web of Science ®Google Scholar
• LI Y, CORRADETTI MN, INOKI K, GUAN KL: TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem. Sci. (2004) 29(1):32-38.
   PubMed Web of Science ®Google Scholar
• INOKI K, ZHU T, GUAN KL: TSC2 mediates cellular energy response to control cell growth and survival. Cell (2003) 115(5):577-590.
   PubMed Web of Science ®Google Scholar
• LONG X, LIN Y, ORTIZ-VEGA S, YONEZAWA K, AVRUCH J: Rheb binds and regulates the mTOR kinase. Curr. Biol. (2005) 15(8):702-713.
   PubMed Web of Science ®Google Scholar
• JOHANNESSEN CM, RECZEK EE, JAMES MF, BREMS H, LEGIUS E, CICHOWSKI K: The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl. Acad. Sci. USA (2005) 102(24):8573-8578.
   PubMed Web of Science ®Google Scholar
• DASGUPTA B, YI Y, CHEN DY, WEBER JD, GUTMANN DH: Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. (2005) 65(7):2755-2760.
   PubMed Web of Science ®Google Scholar
• ROYL HK, OLUSOLA BF, CLEMENS DL et al.: AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis (2002) 23(1):201-205.
   PubMed Web of Science ®Google Scholar
• AOKI M, BLAZEK E, VOGT PK: A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc. Natl. Acad. Sci. USA (2001) 98(1):136-141.
   PubMed Web of Science ®Google Scholar
• SONG K, WANG H, KREBS TL, DANIELPOUR D: Novel roles of Akt and mTOR in suppressing TGF-β/ALK5-mediated Smad3 activation. EMBO J. (2006) 25(1):58-69.
   PubMed Web of Science ®Google Scholar
• BIANCO R, MELISIS D, CIARDIELLO F, TORTORA G: Key cancer cell signal transduction pathways as therapeutic targets. Eur. J. Cancer (2006) 42(3):290-294.
   PubMed Web of Science ®Google Scholar
• TAKAOKA M, SMITH CE, MASHIBA MK et al.: EGF-mediated regulation of IGFBP-3 determines oesophageal epithelial cellular response to IGF-I. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) 290(2):G404-G416.
   Google Scholar
• LO HW, HUNG MC: Nuclear EGFR signaling network in cancers: linking EGFR pathway and patient survival. Br. J. Cancer (2006) 94(2):184-188.
   PubMed Web of Science ®Google Scholar
• SHAW RJ, BARDEESY N, MANNING BD et al.: The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell (2004) 6(1):91-99.
   PubMed Web of Science ®Google Scholar
• CORRADETTI MN, INOKI K, BARDEESY N, DEPINHO RA, GUAN KL: Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. (2004) 18(13):1533-1538.
   PubMed Web of Science ®Google Scholar
• HAHN-WINDGASSEN A, NOGUEIRA V, CHEN CC, SKEEN JE, SONENBERG N, HAY N: Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J. Biol. Chem. (2005) 280(37):32081-3289.
   PubMed Web of Science ®Google Scholar
• ELLISEN LW: Growth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell Cycle (2005) 4(11):1500-1502.
   PubMed Web of Science ®Google Scholar
• FENG Z, ZHANG H, LEVINE AJ, JIN S: The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl. Acad. Sci. USA (2005) 102(23):8204-8209.
   PubMed Web of Science ®Google Scholar
• EDINGER AL, THOMPSON CB: Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol. Biol. Cell (2002) 13(7):2276-2288.
   PubMed Web of Science ®Google Scholar
• HAY N, SONENBERG N: Upstream and downstream of mTOR. Genes Dev. (2004) 18(16):1926-1945.
   PubMed Web of Science ®Google Scholar
• GAO X, ZHANG Y, ARRAZOLA P et al.: Tsc tumour suppressor proteins antagonize aminoacid-TOR signalling. Nat. Cell Biol. (2002) 4(9):699-704.
   PubMed Web of Science ®Google Scholar
• SMITH EM, FINN SG, TEE AR, BROWNE GJ, PROUD CG: The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J. Biol. Chem. (2005) 280(19):18717-18727.
   PubMed Web of Science ®Google Scholar
• GARAMI A, ZWARTKRUIS FJ, NOBUKUNI T et al.: Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling is inhibited by TSC1 and 2. Mol. Cell (2003) 11(6):1457-1466.
   PubMed Web of Science ®Google Scholar
• SAUCEDO LJ, GAO X, CHIARELLI DA, LI L, PAN D, EDGAR BA: Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat. Cell Biol. (2003) 5:566-571.
   PubMed Web of Science ®Google Scholar
• LONG X, ORTIZ-VEGA S, LIN Y, AVRUCH J: Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J. Biol. Chem. (2005) 280:23433-23436.
   PubMed Web of Science ®Google Scholar
• NOBUKUNI T, JOAQUIN M, ROCCIO M et al.: Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol3OH-kinase. Proc. Natl. Acad. Sci. USA (2005) 102(40):14238-14243.
   PubMed Web of Science ®Google Scholar
• BYFIELD MP, MURRAY JT, BACKER JM: hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J. Biol. Chem. (2005) 280(38):33076-33082.
   PubMed Web of Science ®Google Scholar
• DAMES SA, MULET JM, RATHGEB-SZABO K, HALL MN, GRZESIEK S: The solution structure of the FATC domain of the protein kinase target of rapamycin suggests a role for redox-dependent structural and cellular stability. J. Biol. Chem. (2005) 280(38):20558-20564.
   PubMed Web of Science ®Google Scholar
• RAFTOPOULOU M, ETIENNE-MANNEVILLE S, SELF A, NICHOLLS S, HALL A: Regulation of cell migration by the tumor suppressor PTEN. Science (2004) 303(5661):1179-1181.
   PubMed Web of Science ®Google Scholar
• CHIANG GG, ABRAHAM RT: Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J. Biol. Chem. (2005) 280(27):25485-25490.
   PubMed Web of Science ®Google Scholar
• HOLZ MK, BALLIF BA, GYGI SP, BLENIS J: mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell (2005) 123(4):569-580.
   PubMed Web of Science ®Google Scholar
• HOLZ MK, BLENIS J: Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J. Biol. Chem. (2005) 280(28):26089-26093.
   PubMed Web of Science ®Google Scholar
• CRUZ R, HEDDEN L, BOYER D, KHARAS MG, FRUMAN DA, LEE-FRUMAN KK: S6 kinase 2 potentiates interleukin-3-driven cell proliferation. J. Leukoc. Biol. (2005) 78(6):1378-1385.
   PubMed Web of Science ®Google Scholar
• DAVID O, JETT J, LEBEAU H et al.: Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage. Clin. Cancer Res. (2004) 10(20):6865-6871.
   PubMed Web of Science ®Google Scholar
• ZHOU X, TAN M, STONE HAWTHORNE V 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(20):6779-6788.
   PubMed Web of Science ®Google Scholar
• DE BENEDETTI A, HARRIS AL: eIF4E expression in tumors: its possible role in progression of malignancies. Int. J. Biochem. Cell Biol. (1999) 31(1):59-72.
   PubMed Web of Science ®Google Scholar
• DE BENEDETTI A, GRAFF JR: eIF4E expression and its role in malignancies and metastases. Oncogene (2004) 23(18):3189-3199.
   PubMed Web of Science ®Google Scholar
• 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(1):2.
   PubMedGoogle Scholar
• ALTOMARE DA, TESTA JR: Perturbations of the Akt signaling pathway in human cancer. Oncogene (2005) 24(50):7455-7464.
   PubMed Web of Science ®Google Scholar
• 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) 14:1650-1656.
   PubMed Web of Science ®Google Scholar
• VIGNOT S, FAIVRE S, AGUIRRE D, RAYMOND E: mTOR-targeted therapy of cancer with rapamycin derivatives. Ann. Oncol. (2005) 16(4):525-537.
   PubMed Web of Science ®Google Scholar
• 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. USA (2001) 98(18):10320-10325.
   PubMed Web of Science ®Google Scholar
• SHI Y, GERA J, HU L et al.: Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. (2002) 62(17):5027-5034.
   PubMed Web of Science ®Google Scholar
• 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(18):10314-10319.
   PubMed Web of Science ®Google Scholar
• DEGRAFFENRIED LA, FULCHER L, FRIEDRICHS WE, GRUNWALD V, RAY RB, HIDALGO M: Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann. Oncol. (2004) 15(10):1510-1516.
   PubMed Web of Science ®Google Scholar
• 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(1):295-302.
   PubMed Web of Science ®Google Scholar
• ALTOMARE DA, YOU H, XIAO GH et al.: Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene (2005) 24(40):6080-6089.
   PubMed Web of Science ®Google Scholar
• PENE F, CLAESSENS YE, MULLER O et al.: Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene (2002) 21(43):6587-6597.
   PubMed Web of Science ®Google Scholar
• LENTZSCH S, CHATTERJEE M, GRIES M 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(11):1883-1890.
   PubMed Web of Science ®Google Scholar
• VEGA F, MEDIROS LJ, ATWELL C et al.: Activation of mTOR signaling pathway contributes to lymphoma cell survival in ALK-positive anaplastic large cell lymphoma.47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11)::2419 (Abstract).
   Google Scholar
• XU Q, SIMPSON SE, SCIALLA TJ, BAGG A, CARROLL M: Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood (2003) 102(3):972-980.
   PubMed Web of Science ®Google Scholar
• MIN YH, EOM JI, CHEONG JW, MAENG HO, KIM JY, JEUNG HK: Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia (2003) 17(5):995-997.
   PubMed Web of Science ®Google Scholar
• 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(8):1438-1440.
   PubMed Web of Science ®Google Scholar
• DUTTON A, REYNOLDS GM, DAWSON CW, YOUNG LS, MURRAY PG: 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(4):498-506.
   PubMed Web of Science ®Google Scholar
• SLUPIANEK A, NIEBOROWSKA-SKORSKA M, HOSER G et al.: Role of phosphatidyloinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res. (2001) 61(5):2194-2199.
   PubMed Web of Science ®Google Scholar
• CHEN W, GRAMMATIKAKIS I, LI J, LEVENTAKI V, MEDIEROS LJ, RASSIDAKIS GZ: Inhibition of Akt/mTOR signaling pathway induces cell cycle arrest and apoptosis in acute myelogenous leukaemia. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):2355 (Abstract).
   Google Scholar
• PEPONI E, DRAKOS E, REYES G, LEVENTAKI V, MEDEIROS LJ: Inhibition of Akt/mTOR signaling pathway induces cell cycle arrest and apoptosis in mantle cell lymphoma. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):2415 (Abstract).
   Google Scholar
• CUNI S, PEREZ-ACIEGO P, PEREZ-CHACON G et al.: A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia (2004) 18(8):1391-1400.
   PubMed Web of Science ®Google Scholar
• 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) 99(8):2969-2976.
   PubMed Web of Science ®Google Scholar
• ITO D, FUJIMOTO K, MORI T et al.: In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. Int. J. Cancer (2006) 118(9):2337-2343.
   PubMed Web of Science ®Google Scholar
• LY C, ARECHIGA AF, MELO JV, WALSH CM, ONG ST: Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res. (2003) 63(18):5716-5722.
   PubMed Web of Science ®Google Scholar
• KLOS KS, WYSZOMIERSKI SL, SUN M et al.: 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 Res. (2006) 66(4):2028-2037.
   PubMed Web of Science ®Google Scholar
• OHGUCHI K, BANNO Y, NAKAGAWA Y, AKAO Y, NOZAWA Y: Negative regulation of melanogenesis by phospholipase D1 through mTOR/p70 S6 kinase 1 signaling in mouse B16 melanoma cells. J. Cell Physiol. (2005) 205(3):444-451.
   PubMed Web of Science ®Google Scholar
• HUI L, RODRIK V, PIELAK RM, KNIRR S, ZHENG Y, FOSTER DA: mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells. J. Biol. Chem. (2005) 280(43):35829-35835.
   PubMed Web of Science ®Google Scholar
• RUGGERO D, MONTANARO L, MA L et al.: The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat. Med. (2004) 10:484-486.
   PubMed Web of Science ®Google Scholar
• TOPISIROVIC I, GUZMAN ML, MCCONNELL MJ et al.: Aberrant eukaryotic translation initiation factor 4E-dependent mRNA impedes hematopoietic differentiation and contributes to leukemogenesis. Mol. Cell. Biol. (2003) 23(24):8992-9002.
   PubMed Web of Science ®Google Scholar
• HIDALGO M, ROWINSKY EK: The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene (2000) 19(56):6680-6686.
   PubMed Web of Science ®Google Scholar
• ROWINSKY EK: Targeting the molecular target of rapamycin (mTOR). Curr. Opin. Oncol. (2004) 16(6):564-575.
   PubMed Web of Science ®Google Scholar
• 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(2):75-85.
   PubMed Web of Science ®Google Scholar
• BLAGOSKLONNY MV, DARZYNKIEWICZ Z: Four birds with one stone: RAPA as potential anticancer therapy. Cancer Biol. Ther. (2002) 1(4):359-361.
   PubMed Web of Science ®Google Scholar
• ZHONG H, CHILES K, FELDSER D et al.: Modulation of hypoxia-inducible factor 1α 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) 60(6):1541-1545.
   PubMed Web of Science ®Google Scholar
• COSTA LF, BALCELLS M, EDELMAN ER, NADLER LM, CARDOSO AA: Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-κB. Blood (2006) 107(1):285-292.
   PubMed Web of Science ®Google Scholar
• KWON YS, HONG HS, KIM JC, SHIN JS, SON Y: Inhibitory effect of rapamycin on corneal neovascularization in vitro and in vivo. Invest. Ophthalmol. Vis. Sci. (2005) 46(2):454-460.
   PubMed Web of Science ®Google Scholar
• SCHEIDENHELM DK, CRESSWELL J, HAIPEK CA, FLEMING TP, MERCER RW, GUTMANN DH: Akt-dependent cell size regulation by the adhesion molecule on glia occurs independently of phosphatidylinositol 3-kinase and Rheb signaling. Mol. Cell Biol. (2005) 25(8):3151-3162.
   PubMed Web of Science ®Google Scholar
• FUMAROLA C, LA MONICA S, ALFIERI RR, BORRA E, GUIDOTTI GG: Cell size reduction induced by inhibition of the mTOR/S6K-signaling pathway protects Jurkat cells from apoptosis. Cell Death Differ. (2005) 12(10):1344-1357.
   PubMed Web of Science ®Google Scholar
• MISAWA A, HOSOI H, TSUCHIYA K, SUGIMOTO T: Rapamycin inhibits proliferation of human neuroblastoma cells without suppression of MycN. Int. J. Cancer (2003) 104(2):233-237.
   PubMed Web of Science ®Google Scholar
• ZHOU C, GEHRIG PA, WHANG YE, BOGGESS JF: Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells. Mol. Cancer Ther. (2003) 2(8):789-795.
   PubMed Web of Science ®Google Scholar
• MATEO-LOZANO S, TIRADO OM, NOTARIO V: Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing’s sarcoma cell proliferation. Oncogene (2003) 22(58):9282-9287.
   PubMed Web of Science ®Google Scholar
• RIZELL M, LINDNER P: Inhibition of mTOR suppresses experimental liver tumours. Anti-Cancer Res. (2005) 25(2A):789-793.
   PubMed Web of Science ®Google Scholar
• DECKER T, HIPP S, RINGSHAUSEN I et al.: Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin. Blood (2003) 101(1):278-285.
   PubMed Web of Science ®Google Scholar
• ZANESI N, AQEILAN R, DRUSCO A et al.: Effect of rapamycin on mouse chronic lymphocytic leukemia and the development of nonhematopoietic malignancies in Emu-TCL1 transgenic mice. Cancer Res. (2006) 66(2):915-920.
   PubMed Web of Science ®Google Scholar
• LIU M, HOWES A, LESPERANCE J et al.: Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer. Cancer Res. (2005) 65(12):5325-5236.
   PubMed Web of Science ®Google Scholar
• SHI Y, FRANKEL A, RADVANYI LG, PENN LZ, MILLER RG, MILLS GB: Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res. (1995) 55(9):1982-1988.
   PubMed Web of Science ®Google Scholar
• AMORNPHIMOLTHAM P, PATEL V, SODHI A et al.: Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res. (2005) 65(21):9953-9961.
   PubMed Web of Science ®Google Scholar
• HOSOI H, DILLING MB, SHIKATA T et al.: Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res. (1999) 59(4):886-894.
   PubMed Web of Science ®Google Scholar
• HUANG S, LIU LN, HOSOI H, DILLING MB, SHIKATA T, HOUGHTON PJ: p53/p21CIP1 cooperate in enforcing rapamycin-induced G1 arrest and determine the cellular response to rapamycin. Cancer Res. (2001) 61(8):3373-3381.
   PubMed Web of Science ®Google Scholar
• HOUGHTON PJ, HUANG S: mTOR as a target for cancer therapy. Curr. Top. Microbiol. Immunol. (2004) 279:339-359.
   PubMed Web of Science ®Google Scholar
• 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. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):2474 (Abstract).
   Google Scholar
• AVELLINO R, ROMANO S, PARASOLE R et al.: Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood (2005) 106(4):1400-1406.
   PubMed Web of Science ®Google Scholar
• MUTHUKKUMAR S, RAMESH TM, BONDADA S: Rapamycin, a potent immunosuppressive drug, causes programmed cell death in B lymphoma cells. Transplantation (1995) 60(3):264-270.
   PubMed Web of Science ®Google Scholar
• BROWN VI, FANG J, ALCORN K et al.: Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc. Natl. Acad. Sci. USA (2003) 100(25):15113-15118.
   PubMed Web of Science ®Google Scholar
• 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(8):771-780.
   PubMed Web of Science ®Google Scholar
• GUBA M, VON BREITENBUCH P, STEINBAUER M et al.: Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat. Med. (2002) 8(2):128-135.
   PubMed Web of Science ®Google Scholar
• TEACHEY DT, OBZUT DA, COOPERMAN J et al.: The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood (2006) 107(3):1149-1155.
   PubMed Web of Science ®Google Scholar
• O’REILLY T, VAXELAIRE J, MULLER M et al.: In vivo activity of RAD 001, an orally active rapamycin derivative, in experimental tumor models. Proc. Am. Assoc. Cancer Res. (2002) 43:359 (Abstract).
   Google Scholar
• LANE H, SCHNELL C, THEUER A et al.: Antiangiogenetic activity of RAD 001, an orally active anticancer agent. Proc. Am. Assoc. Cancer Res. (2002) 43:922 (Abstract).
   Google Scholar
• MAJEWSKI M, KORECKA M, KOSSEV P 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. USA (2000) 97(8):4285-4290.
   PubMed Web of Science ®Google Scholar
• MAJEWSKI M, KORECKA M, JOERGENSEN J et al.: Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation (2003) 75(10):1710-1717.
   PubMed Web of Science ®Google Scholar
• JUNDT F, RAETZEL N, MULLER C et al.: A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein β and NF-κB activity in Hodgkin and anaplastic large cell lymphomas. Blood (2005) 106(5):1801-1807.
   PubMed Web of Science ®Google Scholar
• GEORGAKIS GV, YAZBECK VY, LI Y, YOUNES A: Preclinical rationale for therapeutic targeting of mTOR by CC-I779 and rapamycin in Hodgkin lymphoma. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):10070 (Abstract).
   Google Scholar
• KUO SH, HSU CH, YEH PY et al.: RAD001 (everolimus) down-regulates cyclin D3 and c-Myc and is particularly effective in the treatment of aggressive B-cell lymphomas. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):17573 (Abstract).
   Google Scholar
• DUDKIN L, DILLING MB, CHESHIRE PJ et al.: Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin. Cancer Res. (2001) 7(6):1758-1764.
   PubMed Web of Science ®Google Scholar
• GIBBONS JJ, DISCAFANI C, PETERSON R: The effect of CCI-779, a novel macrolide anti-tumor agent, on the growth of human tumor cells in vitro and in nude mouse xenograft in vivo. Proc. Am. Assoc. Cancer Res. (2000) 40:301.
   Google Scholar
• ITO D, FUJIMOTO K, DOI R et al.: mTOR, a novel target in pancreatic cancer: the effect of CCI-779 in preclinical models. Proc. Am. Assoc. Cancer Res. (2004) 45:3886 (Abstract).
   Google Scholar
• WU L, BIRLE D, TANNOCK IF: Effects of the mTOR inhibitor CCI-779 used alone or during chemotherapy on human prostate cancer xenografts. Cancer Res. (2005) 65(7):2825-2831.
   PubMed Web of Science ®Google Scholar
• NATHAN C-A, AMIRGHAHARI N, SIBLEY D et al.: In vivo and in vitro effect of CCI-779 a rapamycin analogue on HNSCC. Proc. Am. Assoc. Cancer Res. (2004) 45:3688 (Abstract).
   Google Scholar
• YU K, TORAL-BARZA L, DISCAFANI C et al.: mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr. Relat. Cancer (2001) 8(3):249-258.
   PubMed Web of Science ®Google Scholar
• GEOERGER B, KERR K, TANG CB et al.: Antitumour activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumour/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res. (2001) 61(4):1527-1532.
   PubMed Web of Science ®Google Scholar
• DEL BUFALO D, CIUFFREDA L, TRISCIUOGLIO D et al.: Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. (2006) 66(11):5549-5554.
   PubMed Web of Science ®Google Scholar
• YAZBECK VY, GEORGAKIS GV, LI Y, YOUNES A: The mTOR inhibitor CCI-779 (temsirolimus) downregulates p21 and induces cell cycle arrest and autophagy in mantle cell lymphoma (MCL). 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):7573 (Abstract).
   Google Scholar
• 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(13):4181-4187.
   PubMed Web of Science ®Google Scholar
• POLLOCK R, KEATS JA, TANG H et al.: Cell shrinkage, cell arrest and anti-angiogenesis underline the anti-tumor activity of the mTOR inhibitor AP23573. 15th EORT-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. (2003):B160 (Abstract).
   Google Scholar
• METCALF CA III, BOHACEK R, ROZAMUS LW et al.: Structure-based design of AP23573, a phospho- rous-containing analog of rapamycin for anti-tumor therapy. Proc. Am. Assoc. Cancer Res. (2004) 45:2476 (Abstract).
   Google Scholar
• RIVERA V, TANG H, METCALF C et al.: Anti-proliferative activity of the mTOR inhibitor AP23573 in combination with cytotoxic and targeted agents. Proc. Am. Assoc. Cancer Res. (2004) 45:3887 (Abstract).
   Google Scholar
• CLACKSON T, CA MI, ROZAMUS L et al.: Regression of tumor xenografts in mice after oral administration of AP23573, a novel mTOR inhibitor that induces tumor starvation. Proc. Am. Assoc. Cancer Res. (2002) 43:LB95 (Abstract).
   Google Scholar
• CLACKSON T, METCALF CA, RIVERA VM et al.: Broad anti-tumor activity of AP23573, an mTOR inhibitor in clinical development. Proc. Am. Soc. Clin. Oncol. (2003) 22(220):882 (Abstract).
   Google Scholar
• JIMENO A, KULESZA P, CUSAIS G et al.: Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):3020 (Abstract).
   PubMedGoogle Scholar
• MAYERHOFER M, BOEHM A, AICHBERGER KJ et al.: In vitro and in vivo antileukemic effects of the mTOR-targeting drug rapamycin in patients with immatinib-resistant CML. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):4834 (Abstract).
   Google Scholar
• RIZELL M, CAHLIN C, OLAUSSON M, HAFSTROM L, ANDERSSON M, LINDNER P: mTOR inhibition affects primary liver cancer. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):14106 (Abstract).
   Google Scholar
• SHAREF S, JAC J, KHAN M, AMATO R: Rapamycin for androgen-independent prostrate cancer (AIPC). 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):14584 (Abstract).
   Google Scholar
• FRANZ DN, LEONARD J, TUDOR C et al.: Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. (2006) 59(3):49049-49048.
   Google Scholar
• 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(12):2336-2347.
   PubMed Web of Science ®Google Scholar
• HIDALGO M, ROWINSKY E, ERLICHMAN C et al.: Phase I and pharmacologic study of CCI-779, a cell cycle inhibitor. 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy. Amsterdam, The Netherlands (7 – 10 November 2000) Abstract 545.
   Google Scholar
• 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(5):909-918.
   PubMed Web of Science ®Google Scholar
• CHAN S, SCHEULEN ME, JOHNSTON S et al.: Phase II 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(23):5314-5322.
   PubMed Web of Science ®Google Scholar
• PANDYA KJ, LEVY DE, HIDALGO M 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. A preliminary report. 2005 ASCO Annual Meeting Proceedings (post-meeting edition) J. Clin. Oncol. (2005) 23(16S):7005 (Abstract).
   Google Scholar
• OZA MD AM, ELIT L, BIAGI J et al.: Molecular correlates associated with a Phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer-NCIC IND 160. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):3003 (Abstract).
   PubMedGoogle Scholar
• GALANIS E, BUCKNER JC, MAURER MJ et al.: North Central Cancer Treatment Group. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol. (2005) 23(23):5294-5304.
   PubMed Web of Science ®Google Scholar
• CHANG SM, WEN P, CLOUGHESY T 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(4):357-361.
   PubMed Web of Science ®Google Scholar
• OKUNO SH, MAHONEY MR, BAILEY HH et al.: A multicenter Phase II consortium (P2C) study of the mTOR inhibitor CCI-779 in advanced soft tissue sarcomas (STS). 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):9504 (Abstract).
   Google Scholar
• 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(5):1045-1048.
   PubMed Web of Science ®Google Scholar
• YEE KWL, GARCIA-MANERO G, THOMAS D et al.: A Phase II study of temsirolimus (CCI-779) in patients with advanced leukemias. 46th Annual Meeting of American Society of Hematology. Blood (2004) 104(11):4523 (Abstract).
   Google Scholar
• 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(23):5347-5356.
   PubMed Web of Science ®Google Scholar
• WITZIG TE, ANSELL SM, GEYER SM et al.: Anti-tumor activity of mTOR inhibitor temsirolimus (CCI-779) for relapsed mantle cell lymphoma: a Phase II trial in the North Central Cancer Treatment Group. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):7532 (Abstract).
   Google Scholar
• FARAG SS, ZHANG S, MILLER M et al.: Phase II trial of temsirolimus (CCI-779) in patients with relapsed or refractory multiple myeloma (MM): Preliminary results. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):7616 (Abstract).
   Google Scholar
• O’DONNELL S, FAIVRE I, JUDSON C 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 tumours. Proc. Am. Soc. Clin. Oncol. (2003) 74:803 (Abstract).
   Google Scholar
• TABERNERO J, ROJO F, BURRIS H 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. 2005 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2005) 23(16S):3007 (Abstract).
   Google Scholar
• LERUT E, ROSKAMS T, GOOSSENS E et al.: Molecular pharmacodynamic (MPD) evaluation of dose and schedule of RAD001 (everolimus) in patients with operable prostate carcinoma (PC). 2005 ASCO Annual Meeting Proceedings (post-meeting edition) J. Clin. Oncol. (2005) 23(16S):3071 (Abstract).
   Google Scholar
• PORTER LL, BURRIS HA, JONES SF et al.: Summary of results in patients with metastatic renal cell cancer (RCC) from Phase I studies of RAD001 (everolimus). 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):14599 (Abstract).
   Google Scholar
• YEE KWL, WIERDA W, O’BRIEN S et al.: A Phase I/II study of the oral mTOR inhibitor RAD001 in patients with advanced hematologic malignancies. 46th Annual Meeting of American Society of Hematology, San Diego 4 – 7 December 2004. Blood (2004) 104(11):4818 (Abstract).
   Google Scholar
• RAO RD, WINDSCHITL HE, ALLRED JB et al.: Phase II trial of the mTOR inhibitor everolimus (RAD-001) in metastatic melanoma. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):8043 (Abstract).
   Google Scholar
• AMATO RJ, MISELLATI A, KHAN M, CHIANG S. A Phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):4530 (Abstract).
   PubMedGoogle Scholar
• MITA MM, ROWINSKY EK, GOLDSTON ML et al.: Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily × 5 every other week in patients (pts) with refractory or advanced malignancies. 2004 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2004) 22(15S):3076 (Abstract).
   Google Scholar
• RIVERA VM, KREISBERG JI, MITA MM et al.: Pharmacodynamic study of skin biopsy specimens in patients (pts) with refractory or advanced malignancies following administration of AP23573, an mTOR inhibitor. 2005 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2005) 23(16S):3033 (Abstract).
   PubMedGoogle Scholar
• DESAI AA, MITA M, FETTERLY GJ et al.: Development of pharmacokinetic (PK) model of assessment of patient (patient) covariate effects on dose-dependent PK following different dosing schedules in two Phase I trials of AP23573 (AP23573), a mTOR inhibitor. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):3043 (Abstract).
   Google Scholar
• DESAI AA, JANISCH LL, BERK R et al.: A Phase I trial of a novel mTOR inhibitor AP23573 administered weekly in patients with refractory or advanced malignancies: a pharmacokinetic and pharmacodynamic analysis. 2004 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2004) 22(15S):3150 (Abstract).
   Google Scholar
• CHAWLA SP, TOLCHER AW, STADDON AP et al.: for the AP23573 Sarcoma Study Group. Updated results of a Phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 23(16S):9505 (Abstract).
   Google Scholar
• SANKHALA KK, CHAWLA SP, IAGARU A et al.: for the AP23573 Sarcoma Study Group. 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. 2005 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2005) 23(16S):9028 (Abstract).
   Google Scholar
• RIVERA VM, BERK L, CHAWLA SP et al.: Analysis of potential biomarkers of AP23573 activity in sarcoma patients. Clin. Cancer Res. (2005) 11(24):9077 (Abstract B181).
   Google Scholar
• VAN GLABBEKE M, VERWEIJ J, JUDSON I et al.: Progression-free survival as the principal end-point for Phase II trials in sft-tissue sarcomas. Eur. J. Cancer (2002) 38(4):543-549.
   PubMed Web of Science ®Google Scholar
• RIZZIERI DA, FELDMAN E, MOORE JO et al.: A Phase II clinical trial of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):2980 (Abstract).
   Google Scholar
• 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(16):7052-7058.
   PubMed Web of Science ®Google Scholar
• O’REILLY KE, ROJO F, SHE QB et al.: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. (2006) 66(3):1500-1508.
   PubMed Web of Science ®Google Scholar
• SHI Y, YAN H, FROST P, GERA J, LICHTENSTEIN A: Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol. Cancer Ther. (2005) 4(10):1533-1540.
   PubMed Web of Science ®Google Scholar
• FROST P, HOANG B, SHI Y, YAN H, LICHTENSTEIN A: Anti-angiongenic effects of mTOR-inhibitors is regulated by AKT activity in multiple myeloma cells. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):3406 (Abstract).
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• KASUKABE T, OKABE-KADO J, KATO N, SASSA T, HONMA Y: Effects of combined treatment with rapamycin and cotylenin A, a novel differentiation-inducing agent, on human breast carcinoma MCF-7 cells and xenografts. Breast Cancer Res. (2005) 7(6):1097-2110.
   PubMed Web of Science ®Google Scholar
• GEMMILL RM, ZHOU M, COSTA L, KORCH C, BUKOWSKI RM, DRABKIN: A. Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma. Br. J. Cancer (2005) 92(12):2266-2277.
   PubMed Web of Science ®Google Scholar
• STEPHAN S, DATTA K, WANG E, LI J et al.: Effect of rapamycin alone and in combination with antiangiogenesis therapy in an orthotopic model of human pancreatic cancer. Clin. Cancer Res. (2004) 10(20):6993-7000.
   PubMed Web of Science ®Google Scholar
• TAKEUCHI H, KONDO Y, FUJIWARA K et al.: Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res. (2005) 65(8):3336-3346.
   PubMed Web of Science ®Google Scholar
• HAHN M, LI W, YU C, RAHMANI M, DENT P, GRANT S: Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. Mol. Cancer Ther. (2005) 4(3):457-470.
   PubMed Web of Science ®Google Scholar
• XU Q, THOMPSON JE, CARROLL M: mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood (2005) 106(13):4261-4268.
   PubMed Web of Science ®Google Scholar
• XU RH, PELICANO H, ZHANG H, GILES FJ, KEATING MJ, HUANG P: Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. Leukemia (2005) 19(12):2153-2158.
   PubMed Web of Science ®Google Scholar
• ALTMAN JK, YOON PJ, SASSANO A et al.: The combination of arsenic trioxide and rapamycin has potent inhibitory effects on acute myeloid leukemia (AML) cells. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):13101 (Abstract).
   Google Scholar
• SMOLEWSKI P, CEBULA B, WIERZBICKA D et al.: Rapamycin, inhibitor of mTOR kinase, sensitizes leukemia cells to fludarabine-induced apoptosis, but protects survival of normal lymphocytes. 46th Annual Meeting of American Society of Hematology, San Diego December, 2004. Blood (2004) 104(11):4497.
   Google Scholar
• YU C, MAO X, LI WX: Inhibition of the PI3K pathway sensitizes fludarabine-induced apoptosis in human leukemic cells through an inactivation of MAPK-dependent pathway. Biochem. Biophys. Res. Commun. (2005) 331(2):391-397.
   PubMed Web of Science ®Google Scholar
• ARMSTRONG SA, WEI G, LAM JB et al.: gene expression connectivity map identifies rapamycin as a glucocorticoid resistance reversal agent in lymphoblastic leukemia. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):108 (Abstract).
   Google Scholar
• MOHI MG, BOULTON C, GU TL et al.: Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc. Natl. Acad. Sci. USA (2004) 101(9):3130-3135.
   PubMed Web of Science ®Google Scholar
• PARMAR S, SMITH J, SASSANO A et al.: Differential regulation of the p70 S6 kinase pathway by interferon α (IFNα) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells. Blood (2005) 106(7):2436-2443.
   PubMed Web of Science ®Google Scholar
• ARANHA O, KAUR S, SMITH J, SASSANO A, PLATANIAS LC: Regulation of pathways downstream of mTOR by imatinib mesylate in CML cells. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):6595 (Abstract).
   Google Scholar
• BURCHERT A, WANG Y, CAI D et al.: Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia (2005) 19(10):1774-1782.
   PubMed Web of Science ®Google Scholar
• RAJE N, KUMAR S, HIDESHIMA T et al.: Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood (2004) 104(13):4188-93.
   PubMed Web of Science ®Google Scholar
• STROMBERG T, DIMBERG A, HAMMARBERG A et al.: Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood (2004) 103(8):3138-3147.
   PubMed Web of Science ®Google Scholar
• BAKKER F, OTT A, RICHTER K et al.: Synergistic Inhibition of myeloma cell growth by combinations of dexamethasone with other anti-myeloma agents. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):5105 (Abstract).
   PubMedGoogle Scholar
• YAN H, FROST P, SHI Y et al.: Mechanism by which mTOR inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):1582 (Abstract).
   Google Scholar
• KASDAN LA, LU G, SINGHA U, LENTZSCH S, ROODMAN GD, GHOBRIAL IM: Combination of the mTOR inhibitor Rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxy geldanamycin (17AAG) inhibits proliferation and induces apoptosis in multiple myeloma (MM). 2005 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2005) 23(16S):9609 (Abstract).
   Google Scholar
• ALSAYED Y, SINGHA U, FRANCIS L et al.: Combination of the mTOR inhibitor rapamycin with the HSP90 inhibitor 17-AAG has synergistic activity in EBV positive post transplant lymphoproliferative disorders (PTLD). 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):2414 (Abstract).
   Google Scholar
• ZENG Z, ESTROV Z, HARRIS D, GILES F, ANDREEFF M, KONOPLEVA M: Intra-pathway inhibition of upstream (pi3k) and downstream (mTor) kinases synergistically induces apoptosis in AML. 47th Annual Meeting of American Society of Hematology, San Diego December, 2004. Blood (2005) 106(11):2477 (Abstract).
   Google Scholar
• CAI D, WANG Y, OTTMANN OG, BARTH PJ, NEUBAUER A, BURCHERT A: FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment. Blood (2006) 107(5):2094-2097.
   PubMed Web of Science ®Google Scholar
• BOULAY A, RUDLOFF J, YE J et al.: Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin. Cancer Res. (2005) 11(14):5319-5328.
   PubMed Web of Science ®Google Scholar
• BEUVINK I, BOULAY A, FUMAGALLI S et al.: The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell. (2005) 120(6):747-759.
   PubMed Web of Science ®Google Scholar
• TREECK O, WACKWITZ B, HAUS U, ORTMANN O: Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells. Gynecol. Oncol. (2006) 102(2):292-299.
   PubMed Web of Science ®Google Scholar
• RAO RD, MLADEK AC, LAMONT JD et al.: Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. Neoplasia (2005) 7(10):921-929.
   PubMed Web of Science ®Google Scholar
• GOUDAR RK, SHI Q, HJELMELAND MD et al.: 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. Mol. Cancer Ther. (2005) 4(1):101-112.
   PubMed Web of Science ®Google Scholar
• PANNER A, JAMES CD, BERGER MS, PIEPER RO: mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol. Cell. Biol. (2005) 25(20):8809-8823.
   PubMed Web of Science ®Google Scholar
• SHINOHARA ET, CAO C, NIERMANN K et al.: Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene (2005) 24(35):5414-5422.
   PubMed Web of Science ®Google Scholar
• ALBERT JM, KIM KW, CAO C, LU B: Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol. Cancer Ther. (2006) 5(5):1183-1189.
   PubMed Web of Science ®Google Scholar
• DAS A, BADRUDDOJA M, TRYCIECKY D, YU J, BLACK K: Phase I study of gefitinib and rapamycin in patients with recurrent or progressive glioblastoma (Gbm). 2005 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2005) 23(16S):1572 (Abstract).
   PubMedGoogle Scholar
• REARDON DA, QUINN JA, VREDENBURGH JJ et al.: Phase I trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin. Cancer Res. (2006) 12(3):860-868.
   PubMed Web of Science ®Google Scholar
• PUNT CJ, BONI J, BRUNTSCH U, PETERS M, THIELERT C: 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(6):931-937.
   PubMed Web of Science ®Google Scholar
• HAAS NB, LEWIS N, COHEN RB et al.: Phase I study of intravenous CCI-779 in combination with bryostatin-1 in solid tumors. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):3067 (Abstract).
   Google Scholar
• SMITH JW, KO Y-J, DUTHCER G et al.: Update of a Phase I study of intravenous CCI-779 given in combination with interferon-α to patients with advanced renal cell carcinoma. 2005 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2005) 23(16S):4513 (Abstract).
   Google Scholar
• CARPENTER T, ROCHÉ H, CAMPONE M et al.: Randomized 3-arm, Phase II study of temsirolimus (CCI-779) in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer. 47th Annual Meeting of American Society of Hematology. Blood (2005) 106(11):564 (Abstract).
   PubMedGoogle Scholar
• HUDES G, CARDUCCI M, TOMCZAK P et al.: A Phase III, randomized, 3-arm study of temsirolismus (TEMSR) or interferon-α (IFN) or the combination TEMSR + IFN in the treatment of first line, poor-risk patients with advanced renal cell carcinoma (adv RCC). 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):AbstractLBA4.
   PubMedGoogle Scholar
• PACCEY S, REA D, STEVEN N et al.: Results of Phase I clinical trial investigating a combination of the oral mTOR-inhibitor Everolismus (E, RAD001) and gemcitabine (GEM) in patients (pts) with advanced cancers. 2004 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2004) 22(15S):3120 (Abstract).
   Google Scholar
• REARDON D, QUINN JA, RICH JN, VREDENBURGH JJ et al.: A Phase I trial of imatinib, hydroxyurea and RAD001 for patients with recurrent malignant glioma. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):1580 (Abstract).
   Google Scholar
• VAN OOSTEROM AT, DUMEZ H, DESAI J et al.: Combination signal transduction inhibition: A Phase I/II trial of the oral mTOR-inhibitor everolismus (E, RAD001) and imatinib mesylate (IM) in patients (pts) with gastrointestinal tumor (GIST) refractory to IM. 2004 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2004) 22(15S):3002 (Abstract).
   Google Scholar
• MILLTON DT, KRIS MG, AZZOLI CG et al.: Phase I/II clinical trial of gefitinib and RAD001 (everolismus) in patients (pts) with advanced non-small cell lung cancer (NSCLC). 2005 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2005) 23(16S):7104 (Abstract).
   Google Scholar
• PAPADIMITRAKOPOULOU V, BLUMENSCHEIN G, ROLLINS M et al.: A Phase I/II study investigating the combination of RAD001(R) (everolimus) and erlotinib (E) as 2nd /3rd line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy. 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):17039 (Abstract).
   PubMedGoogle Scholar
• 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). 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):4042 (Abstract).
   Google Scholar
• PEROTTI A, MAUR M, VIGANÒ L et al.: Phase Ib pharmacokinetic (PK) and pharmacodynamic (PD) study to define the optimal dose for combining the mTOR inhibitor AP23573 with capecitabine (CAPE). 2006 ASCO Annual Meeting Proceedings (post-meeting edition). J. Clin. Oncol. (2006) 24(18S):3065 (Abstract).
   Google Scholar
• BLAGOSKLONNY MV, DARZYNKIEWICZ Z: Cyclotherapy: protection of normal cells and unshielding of cancer cells. Cell Cycle (2002) 1(6):375-382.
   PubMed Web of Science ®Google Scholar
• KAHAN BD, YAKUPOGLU YK, SCHOENBERG L et al.: Low incidence of malignancy among sirolimus/cyclosporine- treated renal transplant recipients. Transplantation (2005) 80(6):749-758.
   PubMed Web of Science ®Google Scholar
• KAUFFMAN HM, CHERIKH WS, CHENG Y, HANTO DW, KAHAN BD: Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation (2005) 80(7):883-889.
   PubMed Web of Science ®Google Scholar
• LAW M, FORRESTER E, CHYTIL A et al.: Rapamycin disrupts cyclin/cyclin-dependent kinase/p21/proliferating cell nuclear antigen complexes and cyclin D1 reverses rapamycin action by stabilizing these complexes. Cancer Res. (2006) 66(2):1070-1080.
   PubMed Web of Science ®Google Scholar
• AGUIRRE D, BOYA P, BELLET D et al.: Bcl-2 and CCND1/CDK4 as molecular markers of the cellular effects of mTOR inhibitors in human ovarian carcinomas cells. Apoptosis (2004) 9(6):797-805.
   PubMed Web of Science ®Google Scholar
• LUO Y, MARX SO, KIYOKAWA H et al.: Rapamycin resistance tied to defective regulation of p27Kip1. Mol. Cell Biol. (1996) 16(12):6744-6751.
   PubMed Web of Science ®Google Scholar
• DIJKERS PF, MEDEMA RH, PALS C et al.: Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol. Cell Biol. (2000) 20(28):9138-9148.
   PubMed Web of Science ®Google Scholar
• DILLING MB, GERMAIN GS, DUDKIN L et al.: 4E-binding proteins, the suppressors of eukaryotic initiation factor 4E, are down-regulated in cells with acquired or intrinsic resistance to rapamycin. J. Biol. Chem. (2002) 277(16):13907-13917.
   PubMed Web of Science ®Google Scholar
• MAJUMDER PK, FEBBO PG, BIKOFF R et al.: mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat. Med. (2004) 10(6):594-601.
   PubMed Web of Science ®Google Scholar
• Mondesire WH, Jian W, Zhang Het al.: Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin. Cancer Res. (2004) 10(20):7031-7042.
   PubMed Web of Science ®Google Scholar