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Développement des inhibiteurs de mTOR en oncologie

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Les thérapies ciblées

Part of the book series: Oncologie pratique ((ONCOLPRAT))

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Abstrait

La voie de la phosphatidyl-inositol-3-kinase (PI3K) joue un rôle majeur dans les cellules, en régulant notamment la croissance cellulaire, la progression du cycle cellulaire et la survie cellulaire. La dérégulation de cette voie est impliquée dans de nombreux processus tumoraux, et représente une cible particulièrement intéressante pour les traitements anticancéreux. En aval de la PI3K, mTOR (mammalian target of rapamycin) est une kinase jouant un rôle de commutateur du métabolisme cellulaire. Cette kinase est la cible ďun antibiotique, la rapamycine, qui est doté de propriétés intéressantes pour traiter les cellules présentant des anomalies de cette voie de signalisation.

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Références

  1. Edinger AL, Thompson CB (2002) Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 13: 2276–88

    Article  PubMed  CAS  Google Scholar 

  2. Dennis PB, Jaeschke A, Saitoh M, et al. (2001) Mammalian TOR: a homeostatic ATP sensor. Science 294: 1102–5

    Article  PubMed  CAS  Google Scholar 

  3. Guertin DA, Sabatini DM (2005) An expanding role for mTOR in cancer. Trends Mol Med 11: 353–61

    Article  PubMed  CAS  Google Scholar 

  4. Martin DE, Hall MN (2005) The expanding TOR signaling network. Curr Opin Cell Biol 17: 158–66

    Article  PubMed  CAS  Google Scholar 

  5. Easton JB, Kurmasheva RT, Houghton PJ (2006) IRS-1: auditing the effectiveness of mTOR inhibitors. Cancer Cell 9: 153–5

    Article  PubMed  CAS  Google Scholar 

  6. 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 Dev 12: 502–13

    Article  PubMed  CAS  Google Scholar 

  7. Heesom KJ, Denton RM (1999) Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR associated kinase. FEBS lett 457: 489–93

    Article  PubMed  CAS  Google Scholar 

  8. Hara K, Yonezawa K, Weng QP, et al. (1998) Amino acid sufficiency and mTOR regulate p70S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273: 14484–94

    Article  PubMed  CAS  Google Scholar 

  9. McLeod LE, Proud CG (2002) ATP depletion increases phosphorylation of elongation factor eEF2 in adult cardiomyocytes independently of inhibition of mTOR signalling. FEBS lett 531: 448–52

    Article  PubMed  CAS  Google Scholar 

  10. Okumura E, Fukuhara T, Yoshida H (2002) Akt inhibits Myt1 in the signalling pathway that leads to meiotic G2/M-phase transition. Nat Cell Biol 4: 111–6

    Article  PubMed  CAS  Google Scholar 

  11. Li B, Desai SA, MacCorkle-Chosnek RA, et al. (2002) A novel conditional Akt “survival switch” reversibly protects cells from apoptosis. Gene Ther 9: 233–44

    Article  PubMed  CAS  Google Scholar 

  12. Brunet A, Bonni A, Zigmond MJ, et al. (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–68

    Article  PubMed  CAS  Google Scholar 

  13. Rodriguez-Viciana P (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370: 527–32

    Article  PubMed  CAS  Google Scholar 

  14. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nature 5: 671–88

    CAS  Google Scholar 

  15. Vezina C, Kudelski A, Sehgal SN (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot 28: 721–726

    PubMed  CAS  Google Scholar 

  16. Kahan BD (2003) Optimization of cyclosporine therapy. Transplant Proc 25: 5–9

    Google Scholar 

  17. Sousa JE, Sousa AG, Costa MA, et al. (2003) Use of rapamycin-impregnated stents in coronary arteries. Transplant Proc 35: 165S–170S

    Article  PubMed  CAS  Google Scholar 

  18. Hosoi H, Dilling MB, Shikata T, et al. (1999) Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res 59: 886–94

    PubMed  CAS  Google Scholar 

  19. Shi Y, Frankel A, Radvanyi LG, et al. (1995) Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res 55: 1982–8

    PubMed  CAS  Google Scholar 

  20. Raymond R, Alexandre J, Faivre S, et al. (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J. Clin Oncol 16: 2336–47

    Article  Google Scholar 

  21. Hidalgo M, Rowinsky E, Erlichman C, et al. (2000) CCI-779, a rapamycin analog and multifaceted inhibitor of signal transduction: a phase I study. Proc Am Soc Clin Oncol 19: 187a, A726

    Google Scholar 

  22. O’Donnell A, Faivre S, Judson I, et al. (2003) 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 tumors. Proc Am Soc Clin Oncol 22: A803

    Google Scholar 

  23. Mita M, Rowinsky E, Goldston M, et al. (2004) Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily5 every other week in patients (pts) with refractory or advanced malignancies. Proc Am Soc Clin Onco 46: A3076

    Google Scholar 

  24. Desai AA, Janisch L, Berk LR, et al. (2004) A phase I trial of a novel mTOR inhibitor AP23573 administered weekly (wkly) in patients (pts) with refractory or advanced malignancies: A pharmacokinetic (PK) and pharmacodynamic (PD) analysis. Proc Am Soc Clin Onco 46: A3150

    Google Scholar 

  25. Sehgal SN, Baker H, Vezina C (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot 28: 727–32

    PubMed  CAS  Google Scholar 

  26. Seufferlein T, Rozengurt E (1996) Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res 56: 3895–7

    PubMed  CAS  Google Scholar 

  27. Wiederrecht GJ, Sabers CJ, Brunn GJ, et al. (1995) Mechanism of action of rapamycin: new insights into the regulation of G1-phase progression in eukaryotic cells. Prog Cell Cycle Res 1: 53–71

    PubMed  CAS  Google Scholar 

  28. Huang S, Liu LN, Hosoi H, et al. (2001) P53/p21 (CIP1) cooperate in enforcing rapamycin-induced G (1) arrest and determine the cellular response to rapamycin. Cancer Res 61: 3373–81

    PubMed  CAS  Google Scholar 

  29. Guba, M, von Breitenbuch P, Steinbauer M, et al. (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Med 8: 128–35

    Article  PubMed  CAS  Google Scholar 

  30. Humar R, Kiefer FN, Berns H, et al. (2002) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 16: 771–80

    Article  PubMed  CAS  Google Scholar 

  31. Arsham AM, Plas, DR, Thompson CB, et al. (2002) Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1α nor sufficient for HIF-1-dependent target gene transcription. J Biol Chem 277: 15162–70

    Article  PubMed  CAS  Google Scholar 

  32. Oza AM (2005) A phase II study or tensirolimus (CCI-779) in patients with metastatic and/or locally recurrent endometrial cancer. Proc 17th Symp Mol Targets Cancer Thera 197: 269

    Google Scholar 

  33. 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: 5347–56

    Article  PubMed  CAS  Google Scholar 

  34. Hudes G, Carducci M, Tomczak P, et al. (2007) Tensirolimus, interferon alpha, or both in advanced Renal-cell carcinoma. N Eng J Med 31; 356(22): 2271–81

    Article  Google Scholar 

  35. 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: 357–61

    Article  PubMed  CAS  Google Scholar 

  36. Chan S, Scheulen ME, Johnston S, 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. J Clin Oncol 23: 5314–22

    Article  PubMed  CAS  Google Scholar 

  37. Duran I, Le L, Saltman D, et al. (2005) A phase II trial of temsirolimus in metastatic neuroendocrine carcinoma. Proc Am Soc Clin Oncol 24: A146

    Google Scholar 

  38. von Oosterom A, Reichardt P, Blay J, et al. (2005) A phase I/II trial of the oral mTOR-inhibitor everolimus (E) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM: study update. Proc Am Soc Clin Oncol 24: 9033

    Google Scholar 

  39. Chawla SP (2005) A phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcoma. Proc 17th Symp Mol Targets Cancer Thera 268: 272

    Google Scholar 

  40. Boulay A, Zumstein-Mecker S, Stephan C, et al. (2004) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64: 252–61

    Article  PubMed  CAS  Google Scholar 

  41. Neshat MS, Mellinghoff IK, Tran C, et al. (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 98: 10314–9

    Article  PubMed  CAS  Google Scholar 

  42. Xu G, Zhang W, Bertram P, et al. (2004) Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. Int J Oncol 24: 893–900

    PubMed  CAS  Google Scholar 

  43. Aoki K, Ogawa T, Ito Y, Nakashima S (2004) Cisplatin activates survival signals in UM-SCC-23 squamous cell carcinoma and these signal pathways are amplified in cisplatin-resistant squamous cell carcinoma. Onc Rep 11: 375–9

    CAS  Google Scholar 

  44. Nagata Y, Lan KH, Zhou X, et al. (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6: 117–27

    Article  PubMed  CAS  Google Scholar 

  45. Kokubo Y, Gemma A, Noro R, et al. (2005) Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA). Br J Cancer 92: 1711–9

    Article  PubMed  CAS  Google Scholar 

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  1. Service interhospitalier de cancérologie Bichat-Beaujon, Hôpital Beaujon, 100, boulevard du Général-Leclerc, 92110, Clichy

    M. -P. Sablin, C. Dreyer & S. Faivre

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  2. C. Dreyer
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  3. S. Faivre
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Sablin, M.P., Dreyer, C., Faivre, S. (2008). Développement des inhibiteurs de mTOR en oncologie. In: Les thérapies ciblées. Oncologie pratique. Springer, Paris. https://doi.org/10.1007/978-2-287-36008-4_10

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  • DOI: https://doi.org/10.1007/978-2-287-36008-4_10

  • Publisher Name: Springer, Paris

  • Print ISBN: 978-2-287-36007-7

  • Online ISBN: 978-2-287-36008-4

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