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Combinations of Cytotoxic Drugs, Ionizing Radiation, and Mammalian Target of Rapamycin (mTOR) Inhibitors

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Multimodal Concepts for Integration of Cytotoxic Drugs

Part of the book series: Medical Radiology ((Med Radiol Radiat Oncol))

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9.7 Conclusion

Rapamycin and its analogs are versatile drugs with proven efficacy in cardiovascular and transplant medicine and with promising results in early cancer clinical trials. In specific tumor types, a select minority of patients likely will benefit from monotherapy. The challenge for the future will be to dissect further the molecular signaling pathways modulated by rapamycin in order to appreciate fully the molecular mechanisms underpinning sensitivity or resistance to mTOR inhibition. This understanding will provide insight into rational combinations of mTOR inhibitors with classic cytotoxic agents, radiation, and other molecularly targeted therapies.

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References

  • Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Devel 15:2177–2196

    Article  PubMed  CAS  Google Scholar 

  • Abraham RT (2004) mTOR as a positive regulator of tumor cell responses to hypoxia. Curr Topics Microbiol Immunol 279:299–319

    CAS  Google Scholar 

  • Atkins MB, Hidalgo M, Stadler WM 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. J Clin Oncol 22:909–918

    Article  PubMed  CAS  Google Scholar 

  • Benedetti A de, Harris AL (1999) eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol 31:59–72

    Article  PubMed  Google Scholar 

  • Bentzen SM (2003) Repopulation in radiation oncology: perspectives of clinical research. Int J Radiat Biol 79:581–585

    Article  PubMed  CAS  Google Scholar 

  • Bertrand FE, Spengemen JD, Shelton JG et al (2005) Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support. Leukemia 19:98–102

    PubMed  CAS  Google Scholar 

  • Beuvink I, Boulay A, Fumagalli S et al (2005) The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120:747–759

    Article  PubMed  CAS  Google Scholar 

  • Boulay A, Rudloff J, Ye J et al (2005) Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 11:5319–5328

    Article  PubMed  CAS  Google Scholar 

  • Brown EJ, Albers MW, Shin TB et al (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:756–758

    Article  PubMed  CAS  Google Scholar 

  • Brunn GJ, Hudson CC, Sekulic A et al (1997) Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277:99–101

    Article  PubMed  CAS  Google Scholar 

  • Burchert A, Wang Y, Cai D et al (2005) Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 19:1774–1782

    Article  PubMed  CAS  Google Scholar 

  • Castro AF, Rebhun JF, Clark GJ et al (2003) Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin-and farnesylation-dependent manner. J Biol Chem 278:32493–32496

    Article  PubMed  CAS  Google Scholar 

  • Chang SM, Wen P, Cloughesy T et al (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23:357–361

    Article  PubMed  CAS  Google Scholar 

  • Corradetti MN, Inoki K, Bardeesy N et al (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18:1533–1538

    Article  PubMed  CAS  Google Scholar 

  • Cutler NS, Heitman J, Cardenas ME (1999) TOR kinase homologs function in a signal transduction pathway that is conserved from yeast to mammals. Mol Cell Endocrinol 155:135–142

    Article  PubMed  CAS  Google Scholar 

  • Dan HC, Sun M, Yang L et al (2002) Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 277:35364–35370

    Article  PubMed  CAS  Google Scholar 

  • De Graffenried LA, Friedrichs WE, Russell DH et al (2004) Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clin Cancer Res 10:8059–8067

    Article  Google Scholar 

  • Dengler J, Bubnoff N von, Decker T et al (2005) Combination of imatinib with rapamycin or RAD001 acts synergistically only in Bcr-Abl-positive cells with moderate resistance to imatinib. Leukemia 19:1835–1838

    Article  PubMed  CAS  Google Scholar 

  • Dudkin L, Dilling MB, Cheshire PJ et al (2001) Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 7:1758–1764

    PubMed  CAS  Google Scholar 

  • Durocher D, Jackson SP (2001) DNA-PK, ATM and ATR as sensors of DNA damage: Variations on a theme? Curr Opinion Cell Biol 13:225–231

    Article  PubMed  CAS  Google Scholar 

  • Edinger AL, Linardic CM, Chiang GG et al (2003) Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res 63:8451–8460

    PubMed  CAS  Google Scholar 

  • Eng CP, Sehgal SN, Vezina C (1984) Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 37:1231–1237

    PubMed  CAS  Google Scholar 

  • Eshleman JS, Carlson BL, Mladek AC et al (2002) Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62:7291–7297

    PubMed  CAS  Google Scholar 

  • Fowler JF (2001) Biological factors influencing optimum fractionation in radiation therapy. Acta Oncol 40:712–717

    Article  PubMed  CAS  Google Scholar 

  • Galanis E, Buckner JC, Maurer MJ et al (2005) Phase II trial of Temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304

    Article  PubMed  CAS  Google Scholar 

  • Garami A, Zwartkruis FJ, Nobukuni T et al (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 11:1457–1466

    Article  PubMed  CAS  Google Scholar 

  • Gemmill RM, Zhou M, Costa L et al (2005) Synergistic growth inhibition by iressa and rapamycin is modulated by VHL mutations in renal cell carcinoma. Br J Cancer 92:2266–2277

    Article  PubMed  CAS  Google Scholar 

  • Geoerger B, Kerr K, Tang CB et al (2001) Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 61:1527–1532

    PubMed  CAS  Google Scholar 

  • Ghosh PM, Malik SN, Bedolla RG et al (2005) Signal transduction pathways in androgen-dependent and-independent prostate cancer cell proliferation. Endocr Relat Cancer 12:119–134

    Article  PubMed  CAS  Google Scholar 

  • Gingras AC, Kennedy SG, O’Leary MA et al (1998) 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Devel 12:502–513

    PubMed  CAS  Google Scholar 

  • Gingras AC, Gygi SP, Raught B et al (1999) Regulation of 4EBP1 phosphorylation: a novel two-step mechanism. Genes Devel 13:1422–1437

    PubMed  CAS  Google Scholar 

  • Goudar RK, Shi Q, Hjelmeland MD 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. Mol Cancer Ther 4:101–112

    PubMed  CAS  Google Scholar 

  • Grant S, Qiao L, Dent P (2002) Roles of ERBB family receptor tyrosine kinases, and downstream signaling pathways, in the control of cell growth and survival. Front Biosci 7:376–389

    Google Scholar 

  • Guba M, Breitenbuch P von, Steinbauer M et al (2002) Rapamycin inhibits primary and metastatic tumor growth by anti-angiogenesis: involvement of vascular endothelial growth factor. Nature Med 8:128–135

    Article  PubMed  CAS  Google Scholar 

  • Hahn M, Li W, Yu C et al (2005) 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 4:457–470

    PubMed  CAS  Google Scholar 

  • Hara K, Maruki Y, Long X et al (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–189

    Article  PubMed  CAS  Google Scholar 

  • Harris AL (2002) Hypoxia: a key regulatory factor in tumour growth. Nature Rev Cancer 2:38–47

    Article  CAS  Google Scholar 

  • Herbert TP, Tee AR, Proud CG (2002) The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites. J Biol Chem 277:11591–11596

    Article  PubMed  CAS  Google Scholar 

  • Holland EC, Celestino J, Dai C et al (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genet 25:55–57

    Article  PubMed  CAS  Google Scholar 

  • Houchens DP, Ovejera AA, Riblet SM et al (1983). Human brain tumor xenografts in nude mice as a chemotherapy model. Eur J Cancer Clin Oncol 19:799–805

    Article  PubMed  CAS  Google Scholar 

  • Hudson CC, Liu M, Chiang GG et al (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014

    Article  PubMed  CAS  Google Scholar 

  • Inoki K, Li Y, Zhu T et al (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol 4:648–657

    Article  PubMed  CAS  Google Scholar 

  • Inoki K, Li Y, Xu T et al (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829–1834

    Article  PubMed  CAS  Google Scholar 

  • Jaakkola P, Mole DR, Tian YM et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472

    PubMed  CAS  Google Scholar 

  • Jefferies HB, Fumagalli S, Dennis PB et al (1997) Rapamycin suppresses 5’TOP mRNA translation through inhibition of p70s6k. EMBO J 16:3693–3704

    Article  PubMed  CAS  Google Scholar 

  • Kim Do H, Sarbassov D, Ali SM et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175

    Article  Google Scholar 

  • Kirkegaard T, Witton CJ, McGlynn LM et al (2005) AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 207:139–146

    Article  PubMed  CAS  Google Scholar 

  • Kozak M (1991) An analysis of vertebrate mRNA sequences: intimations of translational control. J Cell Biol 115:887–903

    Article  PubMed  CAS  Google Scholar 

  • Laughner E, Taghavi P, Chiles K et al (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995–4004

    Article  PubMed  CAS  Google Scholar 

  • Luan FL, Ding R, Sharma VK et al (2003) Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 63:917–926

    Article  PubMed  CAS  Google Scholar 

  • Ly C, Arechiga AF, Melo JV et al (2003) 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 63:5716–5722

    PubMed  CAS  Google Scholar 

  • Majumder PK, Febbo PG, Bikoff R et al (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Med 10:594–601

    Article  PubMed  CAS  Google Scholar 

  • Margolin K, Longmate J, Barattam T et al (2005) CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer 104:1045–1048

    Article  PubMed  CAS  Google Scholar 

  • Mayerhofer M, Valent P, Sperr WR et al (2002) BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 100:3767–3775

    Article  PubMed  CAS  Google Scholar 

  • Mazure NM, Chen EY, Laderoute KR et al (1997) Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90:3322–3331

    PubMed  CAS  Google Scholar 

  • Mohi MG, Boulton C, Gu TL et al (2004) Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 101:3130–3135

    Article  PubMed  CAS  Google Scholar 

  • Mothe-Satney I, Brunn GJ, McMahon LP et al (2000) Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies. J Biol Chem 275:33836–33843

    Article  PubMed  CAS  Google Scholar 

  • Mousses S, Wagner U, Chen Y et al (2001) Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene 20:6718–6723

    Article  PubMed  CAS  Google Scholar 

  • Neshat MS, Mellinghoff IK, Tran C et al (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. PNAS 98:10314–10319

    Article  PubMed  CAS  Google Scholar 

  • Potter CJ, Pedraza LG, Xu T (2002) Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol 4:658–665

    Article  PubMed  CAS  Google Scholar 

  • Rao RD, Buckner JC, Sarkaria JN (2004) Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents. Curr Cancer Drug Targets 4:621–635

    Article  PubMed  CAS  Google Scholar 

  • Rao RD, Mladek AC, Lamont JD et al (2005) Disruption of parallel and converging signaling pathways contribute to the synergistic anti-tumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. Neoplasia 7, epub

    Google Scholar 

  • Raught B, Gingras AC, Sonenberg N (2001) The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA 98:7037–7044

    Article  PubMed  CAS  Google Scholar 

  • Sabatini DM, Erdjument-Bromage H, Lui M et al (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM et al (2005) Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science 307:1098–1101

    Article  PubMed  CAS  Google Scholar 

  • Saucedo LJ, Gao X, Chiarelli DA et al (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. (Erratum in Nat Cell Biol 2003 5:680). Nature Cell Biol 5:566–571

    Article  PubMed  CAS  Google Scholar 

  • Sekulic A, Hudson CC, Homme JL et al (2000) A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 60:3504–3513

    PubMed  CAS  Google Scholar 

  • Shaw RJ, Bardeesy N, Manning BD et al (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6:91–99

    Article  PubMed  CAS  Google Scholar 

  • Shi Y, Frankel A, Radvanyi LG et al (1995) Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res 55:1982–1988

    PubMed  CAS  Google Scholar 

  • Shinohara ET, Cao C, Niermann K et al (2005) Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 24:5414–5422

    Article  PubMed  CAS  Google Scholar 

  • Sun SY, Rosenberg LM, Wang X et al (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65:7052–7058

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi H, Kondo Y, Fujiwara K et al (2005) Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 65:3336–3346

    PubMed  CAS  Google Scholar 

  • Tee AR, Fingar DC, Manning BD et al (2002) Tuberous sclerosis complex-1 and-2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA 99:13571–13576

    Article  PubMed  CAS  Google Scholar 

  • Vinals F, Chambard JC, Pouyssegur J (1999) p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation. J Biol Chem 274:26776–26782

    Article  PubMed  CAS  Google Scholar 

  • Volarevic S, Thomas G (2001) Role of S6 phosphorylation and S6 kinase in cell growth. Prog Nucleic Acid Res Molec Biol 65:101–127

    Article  CAS  Google Scholar 

  • Wan X, Helman LJ (2002) Effect of insulin-like growth factor II on protecting myoblast cells against cisplatin-induced apoptosis through p70 S6 kinase pathway. Neoplasia 4:400–408

    Article  PubMed  CAS  Google Scholar 

  • Witzig TE, Geyer SM, Ghobrial I et al (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23:5347–5356

    Article  PubMed  CAS  Google Scholar 

  • Wu L, Birle DC, Tannock IF (2005) Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. Cancer Res 65:2825–2831

    Article  PubMed  CAS  Google Scholar 

  • Yu F, White SB, Zhao Q et al (2001) HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA 98:9630–9635

    Article  PubMed  CAS  Google Scholar 

  • Zhong H, Chiles K, Feldser D 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 Res 60:1541–1545

    PubMed  CAS  Google Scholar 

  • Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439

    Article  PubMed  CAS  Google Scholar 

  • Zundel W, Schindler C, Haas-Kogan D et al (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Devel 14:391–396

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, 200 First Street SW, Rochester, MN, 55905, USA

    Jann N. Sarkaria MD (Assistant Professor)

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  1. Jann N. Sarkaria MD
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Editors and Affiliations

  1. Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford School of Medicine, 269 Campus Drive Center for Clinical Science and Research, Rm 1255, Stanford, CA, 94305-5152, USA

    J. Martin Brown PhD

  2. Department of Human Oncology, University of Wisconsin Hospital Medical School, 600 Highland Ave., K4 312-3684, Madison, WI, 53792, USA

    Minesh P. Mehta MD

  3. Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Strasse 22, 81675, München, Germany

    Carsten Nieder MD

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Sarkaria, J.N. (2006). Combinations of Cytotoxic Drugs, Ionizing Radiation, and Mammalian Target of Rapamycin (mTOR) Inhibitors. In: Brown, J.M., Mehta, M.P., Nieder, C. (eds) Multimodal Concepts for Integration of Cytotoxic Drugs. Medical Radiology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-35662-2_9

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