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mTOR Pathway and mTOR Inhibitors in Cancer Therapy pp 133–148Cite as

mTOR and Cancer Therapy: Clinical Development and Novel Prospects

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Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

mTOR, a pivotal signal transduction protein involved in multiple cellular functions in tumors at the level of cancer and stroma cells, represents an attractive target for cancer therapy. Rapamycin and several rapamycin derivatives (rapalogs), inhibiting mTOR function by a kinase-independent mechanism, have been tested in clinical trials in several tumor types. The proof of principle that rapalogs can improve survival has been obtained in patients with advanced poor prognosis renal cell carcinoma and mantle cell lymphoma. How to further explore potential novel indications of rapalogs in the clinic remains challenging and may help accelerating the development of novel mTOR kinase inhibitors. In this review, current data and limitations of rapalogs in terms of doses, schedules, and pharmacokinetics are summarized. Novel pharmacodynamic endpoints that may help the development of rapalogs in clinical trials are also reviewed. Finally, based on current knowledge of tumor biology and clinical results in phase I–II trials, we update potential novel indications for mTOR inhibitors given either as single agent or in combination with other anticancer drugs.

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References

  1. Yang Q, Guan KL (2007) Expanding mTOR signaling. Cell Res 8:666–681

    Article  Google Scholar 

  2. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5:671–688

    Article  PubMed  CAS  Google Scholar 

  3. Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP (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 22:2336–2347

    Article  PubMed  CAS  Google Scholar 

  4. Hidalgo M, Buckner JC, Erlichman C, Pollack MS, Boni JP, Dukart G, Marshall B, Speicher L, Moore L, Rowinsky EK (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. Clin Cancer Res 12:5755–5763

    Article  PubMed  CAS  Google Scholar 

  5. O’Donnell A, Faivre S, Burris HA, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM, Brok C, Jones S, Raymond E, Judson I (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26:1588–1595

    Article  PubMed  Google Scholar 

  6. Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW (2008) Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 26:361–367

    Article  PubMed  CAS  Google Scholar 

  7. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O‘Toole T, Lustgarten S, Moore L Motzer RJ (2007) Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281

    Article  PubMed  CAS  Google Scholar 

  8. Vahid B, Marik PE (2008) Pulmonary complications of novel antineoplastic agents for solid tumors. Chest 133:528–538

    Article  PubMed  CAS  Google Scholar 

  9. Boni J, Leister C, Burns J, Cincotta M, Hug B, Moore L (2007) Pharmacokinetic profile of temsirolimus with concomitant administration of cytochrome p450-inducing medications. J Clin Pharmacol 47:1430–1439

    Article  PubMed  CAS  Google Scholar 

  10. Kuhn JG, Chang SM, Wen PY, Cloughesy TF, Greenberg H, Schiff D, Conrad C, Fink KL, Robins HI, Mehta M, DeAngelis L, Raizer J, Hess K, Lamborn KR, Dancey J, Prados MD (2007) Pharmacokinetic and tumor distribution characteristics of temsirolimus in patients with recurrent malignant glioma. Clin Cancer Res 13:7401–7406

    Article  PubMed  CAS  Google Scholar 

  11. Tanaka C, O’Reilly T, Kovarik JM, Shand N, Hazell K, Judson I, Raymond E, Zumstein-Mecker S, Stephan C, Boulay A, Hattenberger M, Thomas G, Lane HA (2008) Identifying optimal biological doses of everolimus (RAD001) in patients with cancer based on the modelling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 26:1596–1602

    PubMed  CAS  Google Scholar 

  12. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E Ramon y Cajal S, Jones S, Vidal L, Shand N, Macarulla T, Javier Ramos F, Dimitrijevic S, Zoellner U, Tang P, Stumm M, Lane HA, Lebwohl D, Baselga J</aug> (1610) Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008(26):1603–1610

    Google Scholar 

  13. Zhang L, Yu Q, He J, Zha X (2004) Study of the PTEN gene expression and FAK phosphorylation in human hepatocarcinoma tissues and cell lines. Mol Cell Biochem 262:25–33

    Article  PubMed  CAS  Google Scholar 

  14. Baba HA, Wohlschlaeger J, Cicinnati VR, Hilgard P, Lang H, Sotiropoulos GC, Takeda A et al (2009) Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin-resected hepatocellular carcinoma. Liver Int 29:399–405

    Article  PubMed  CAS  Google Scholar 

  15. Nakanishi K, Sakamoto M, Yamasaki S, Todo S, Hirohashi S (2005) Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma. Cancer 103:307–312

    Article  PubMed  CAS  Google Scholar 

  16. Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M (2004) mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 10:8421–8425

    Article  PubMed  CAS  Google Scholar 

  17. Schmitz KJ, Wohlschlaeger J, Lang H, Sotiropoulos GC, Malago M, Steveling K, Reis H et al (2008) Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol 48:83–90

    Article  PubMed  CAS  Google Scholar 

  18. Sieghart W, Fuereder T, Schmid K, Cejka D, Werzowa J, Wrba F, Wang X et al (2007) Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation 83:425–432

    Article  PubMed  CAS  Google Scholar 

  19. Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, Herault A et al (2007) Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45:42–52

    Article  PubMed  CAS  Google Scholar 

  20. Zhang JF, Liu JJ, Lu MQ, Cai CJ, Yang Y, Li H, Xu C et al (2007) Rapamycin inhibits cell growth by induction of apoptosis on hepatocellular carcinoma cells in vitro. Transpl Immunol 17:162–168

    Article  PubMed  CAS  Google Scholar 

  21. Semela D, Piguet AC, Kolev M, Schmitter K, Hlushchuk R, Djonov V, Stoupis C et al (2007) Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol 46:840–848

    Article  PubMed  CAS  Google Scholar 

  22. Rizell M, Andersson M, Cahlin C, Hafstrom L, Olausson M, Lindner P (2008) Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol 13:66–70

    Article  PubMed  CAS  Google Scholar 

  23. Decaens T, Luciani A, Itti E, Hulin A, Hurtova M, Laurent A, Cherqui D et al (2008) Pilot study of sirolimus in cirrhotic patients with advanced hepatocellular carcinoma. J Hepatol 48:A28

    Google Scholar 

  24. Kanamori Y, Kigawa J, Itamochi H, Shimada M, Takahashi M, Kamazawa S, Sato S, Akeshima R, Terakawa N (2001) Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma. Clin Cancer Res 7:892–895

    PubMed  CAS  Google Scholar 

  25. Uegaki K, Kanamori Y, Kigawa J, Kawaguchi W, Kaneko R, Naniwa J, Takahashi M, Shimada M, Oishi T, Itamochi H, Terakawa N (2005) PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma. Oncol Rep 14:389–392

    PubMed  CAS  Google Scholar 

  26. Oza AM, Elit L, Biagi J, Chapman W, Tsao M, Hedley D, Hansen C, Dancey J, Eisenhauer E (2006) Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer–NCIC IND 160. J Clin Oncol 24:18S, A3003

    Google Scholar 

  27. Slomovitz BM, Lu KH, Johnson T et al (2008) A phase II study of oral mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), in patients with recurrent endometrial carcinoma (EC). J Clin Oncol 26:293 s, A5502

    Google Scholar 

  28. Chan S et al (2005) Phase II study of tensirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23:5314–5322

    Article  PubMed  CAS  Google Scholar 

  29. Awada A, Cardoso F, Fontaine C, Dirix L, De Grève J, Sotiriou C, Steinseifer J, Wouters C, Tanaka C, Zoellner U, Tang P, Piccart M (2008) The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics. Eur J Cancer 44:84–91

    Article  PubMed  CAS  Google Scholar 

  30. Baselga J, van Dam PA, Greil R et al (2008) Improved clinical and cell cycle response with an mTOR inhibitor, daily oral RAD001 (everolimus) plus letrozole versus placebo plus letrozole in a randomized phase II neoadjuvant trial in ER+ breast cancer. J Clin Oncol 26:13 s, A530

    Article  Google Scholar 

  31. Jerusalem GH, Dieras V, Cardoso F et al (2008) Multicenter phase I clinical trial of daily and weekly RAD001 in combination with vinorelbine and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab. J Clin Oncol 26:55 s, A1057

    Google Scholar 

  32. Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, Le L, Oza A, Nicklee T, Ho J, Birle D, Pond GR, Arboine D, Dancey J, Aviel-Ronen S, Tsao MS, Hedley D, Siu LL (2006) A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 95:1148–1154

    Article  PubMed  CAS  Google Scholar 

  33. Yao JC, Lombard-Bohas C, Baudin E et al (2008) A phase II trial of daily oral RAD001 (Everolimus) in patients with metastatic pancreatic neuroendocrine tumors (NET) after failure of cytotoxic chemotherapy. Ann Oncol 19(Suppl 8):167

    Google Scholar 

  34. Lee HY et al (2003) Evidence that phosphatidylinositol 3-Kinase-and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival. J Biol Chem 278:23630–23638

    Article  PubMed  CAS  Google Scholar 

  35. Marsit CJ et al (2005) PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 36:768–776

    Article  PubMed  CAS  Google Scholar 

  36. Pandya KJ, Dahlberg S, Hidalgo M, Cohen RB, Lee MW, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group (E1500) (2007) A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500). J Thorac Oncol 11:1036–1041

    Article  Google Scholar 

  37. Milton DT, Riely GJ, Azzoli CG, Gomez JE, Heelan RT, Kris MG, Krug LM, Pao W, Pizzo B, Rizvi NA, Miller VA (2007) Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer 110:599–605

    Article  PubMed  CAS  Google Scholar 

  38. Papadimitrakopoulos V, Blumenschein GR Jr, Leighl NB et al (2008) A phase 1/2 study investigating the combination of RAD001 (R) (everolimus) and erlotinib (E) as 2nd and 3rd line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy (C): Phase 1 results. J Clin Oncol 26:436 s, A8051

    Google Scholar 

  39. Choe G et al (2003) Analysis of the phosphatidylinositol 3-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 63:2742–2746

    PubMed  CAS  Google Scholar 

  40. Chakravarti A et al (2004) The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol 22:1926–1933

    Article  PubMed  CAS  Google Scholar 

  41. Chandrasekar N et al (2003) Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells. Oncogene 22:392–400

    Article  PubMed  CAS  Google Scholar 

  42. Galanis E et al (2005) Phase II trial of tensirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304

    Article  PubMed  CAS  Google Scholar 

  43. Chang SM 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 

  44. Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, Ansell SM, Luyun R, Flynn PJ, Morton RF, Dakhil SR, Gross H, Kaufmann SH (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 

  45. Ansell SM, Geyer SM, Kurtin PJ, Inwards DJ, Kaufmann SH, Flynn PJ, Morton RF, Luyun RF, Dakhil SR, Gross H, Witzig TE (2006) Anti-tumor activity of mTOR inhibitor temsirolimus for relapsed mantle cell lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 24:18S, A7532

    Google Scholar 

  46. Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B (2009) Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27:3822–3829

    Article  PubMed  CAS  Google Scholar 

  47. Aguirre D, Boya P, Bellet D, Faivre S, Troalen F, Benard J, Saulnier P, Hopkins-Donaldson S, Zangemeister-Wittke U, Kroemer G, Raymond E (2004) Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma. Apoptosis 9:797–805

    Article  PubMed  CAS  Google Scholar 

  48. Campone M, Levy V, Bourbouloux E, Berton Rigaud D, Bootle D, Dutreix C, Zoellner U, Shand N, Calvo F, Raymond E (2009) Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours. Br J Cancer 100:315–321

    Article  PubMed  CAS  Google Scholar 

  49. Johnson BE, Jackman D, Janne PA (2007) Rationale for a phase I trial of erlotinib and the mammalian target of rapamycin inhibitor everolimus (RAD001) for patients with relapsed non small cell lung cancer. Clin Cancer Res 13:4628–4631

    Article  Google Scholar 

  50. Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G, Marciano R, Ciardiello F, Tortora G (2008) Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 98:923–930

    Article  PubMed  CAS  Google Scholar 

  51. Motzer RJ, Hudes GR, Curti BD, McDermott DF, Escudier BJ, Negrier S, Duclos B, Moore L, O’Toole T, Boni JP, Dutcher JP (2007) Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma. J Clin Oncol 25:3958–3964

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Medical Oncology, Service de Cancérologie, APHP and INSERM U728, Beaujon University Hospital, Clichy, France

    Sandrine Faivre

  2. Department of Hepatology and Liver Transplantation, APHP and INSERM U841, Hôpital Henri-Mondor, Créteil, France

    Thomas Decaens

  3. Department of Medical Oncology, APHP and INSERM U728, Beaujon University Hospital, Clichy, France

    Eric Raymond

Authors
  1. Sandrine Faivre
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  2. Thomas Decaens
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  3. Eric Raymond
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Correspondence to Sandrine Faivre .

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Editors and Affiliations

  1. Dept. Family Medicine, University of Minnesota, Minneapolis, 55455, USA

    Vitaly A. Polunovsky

  2. Director, Center for Childhood Cancer, Nationwide Children’s Hospital, The Research Institute, 700 Children’s Drive 332, Columbus, 43205, USA

    Peter J. Houghton

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Faivre, S., Decaens, T., Raymond, E. (2009). mTOR and Cancer Therapy: Clinical Development and Novel Prospects. In: Polunovsky, V., Houghton, P. (eds) mTOR Pathway and mTOR Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-271-1_7

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  • DOI: https://doi.org/10.1007/978-1-60327-271-1_7

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