Advertisement

Temsirolimus

  • Michael Schulze
  • Christian Stock
  • Massimo Zaccagnini
  • Dogu Teber
  • Jens J. Rassweiler
Chapter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 201)

Abstract

Temsirolimus, an ester of sirolimus (rapamycin), selectively inhibits the kinase mammalian target of rapamycin (mTOR) and consequently blocks the translation of cell cycle regulatory proteins and prevents overexpression of angiogenic growth factors. It has been found to have antitumour activity in patients with relapsed or refractory mantle cell lymphoma (MCL). In addition, patients with advanced renal cell carcinoma (RCC) and a poor prognosis who received a once-weekly intravenous (IV) infusion of temsirolimus 25 mg experienced significant survival benefits compared with patients receiving standard interferon-α (IFN-α) therapy in a large phase III clinical study. In this study, median overall survival was 10.9 versus 7.3 months and objective response rates were 8.6 % in temsirolimus recipients versus 4.8 % IFN-α recipient group. Temsirolimus monotherapy recipients experienced significantly fewer grade 3 or 4 adverse events and had fewer withdrawals for adverse events than patients receiving IFN-α. The role of temsirolimus in sequential and combination therapy is yet to be found.

Keywords

Vascular Endothelial Growth Factor Renal Cell Carcinoma Endometrial Carcinoma Objective Response Rate Mantle Cell Lymphoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Aass N, De Mulder HM, Mickisch GHJ et al (2005) Randomized phase II/III trial of interferon alfa-2a with and without 13- cis –retinoic acid in patients with progressive metastatic renal cell carcinoma: the European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EOTORC 30951). J Clin Oncol 23:4172–4178PubMedCrossRefGoogle Scholar
  2. Alexandrescu DT, Dasanu CA (2006) Kidney cancer therapy: new perspectives and avenues. Expert Opin Pharmacother 7(18):2481–2493PubMedCrossRefGoogle Scholar
  3. Ansell SM et al (2008) Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma. A phase 2 trial in the North Central Cancer Treatment Group. Cancer 113(3)Google Scholar
  4. 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 22:909–918Google Scholar
  5. Chang SM et al (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23:357–361PubMedCrossRefGoogle Scholar
  6. 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(9):1148–1154Google Scholar
  7. Escudier B (2007) Advanced renal cell carcinoma: current and emerging management strategies. Drugs 67(9):1257–1264PubMedCrossRefGoogle Scholar
  8. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) AVOREN trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370(9605):2103–2111Google Scholar
  9. Galanis E et al (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304Google Scholar
  10. Guertin DA, Sabatini DM (2005) An expanding role for mTOR in cancer. Trends Mol Med 11:353–361PubMedCrossRefGoogle Scholar
  11. Hess G, Verhoef G et al (2008) Phase III study of patients with relapsed, refractory mantle cell lymphoma treated with temsirolimus compared with investigator’s choice therapy. In: 44th annual meeting of the American Society of Clinical Oncology (ASCO)Google Scholar
  12. Hidalgo M, Buckner JC, Erlichman C et al (2006) A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12:5755–5763Google Scholar
  13. Hudes G, Carducci M, Tomczak P et al (2007) Temsirolimus, interferon alfa, or both for advanced renal cell carcinoma. N Engl J Med 356:2271–2281PubMedCrossRefGoogle Scholar
  14. Jemal A, Siegel R, Ward E et al (2007) Cancer statistics, 2007. CA Cancer J Clinic 57:43–66CrossRefGoogle Scholar
  15. Larkin JMG, Chowdhury S, Gore ME (2007) Drug insight: advances in renal cell carcinoma and the role of target therapies. Nat Clin Pract Oncol 4(8):470–479PubMedCrossRefGoogle Scholar
  16. Linehan WM, Zbar B, Bates SE et al (2001) Cancer of the kidney and ureter. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer: principles and practice of oncology. Lippincott Williams & Wilkins, Philadelphia, pp 1362–1396Google Scholar
  17. Martin DE, Hall MN (2005) The expanding TOR signaling network. Curr Opin Cell Biol 17:158–166Google Scholar
  18. Motzer RJ, Bukowsky RM (2006) Targeted therapy for metastatic renal carcinoma. J Clin Oncol 24(35):5601–5608PubMedCrossRefGoogle Scholar
  19. Motzer RJ, Figlin RA, Hutson TE et al (2008) Overall survival with sunitinib versus interferon (IFN)-alfa as first-line treatment of metastatic renal cell carcinoma (mRCC). In: 44th annual meeting of the American Society of Clinical Oncology (ASCO)Google Scholar
  20. Neshat MS, Mellinghoff IK, Tran C et al (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98:10314–10319Google Scholar
  21. Oza AM et al (2005) A phase II study on temsirolimus (CCI-779) in patients with metastatic and/or recurrent endometrial cancer. In: Proceedings of 17th symposium on molecules targets cancer therapy, Philadelphia, USA, 197 AB269, November 2005Google Scholar
  22. Peralba JM, DeGraffenried L, Friedrichs W et al (2003) Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 9:2887–2892PubMedGoogle Scholar
  23. Podsypanina K, Lee RT, Politis C et al (2001) An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten± mice. Proc Natl Acad Sci US A 98:10320–10325Google Scholar
  24. Raymond E, 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 22:2336–2347Google Scholar
  25. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol (Epub ahead of print)Google Scholar
  26. Rosemberg SA, Lotze MT, Muul ML et al (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313(23):1485–1492CrossRefGoogle Scholar
  27. Sabers CJ, Matrin MM, Brunn JJ et al (1995) Isolation of a protein target of FKBP 12-rapamycin complex in mammalian cells. J Biol Chem 270(2):815–822Google Scholar
  28. Szczylik C, Demkow T, Staehler M, Rolland F, Negrier S, Hutson TE, Bukowski RM, Scheuring UJ, Burk K, Escudier B (2007) Randomized phase II trial of first-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma: Final results. J Clin Oncol 25(suppl):Abstract 5025Google Scholar
  29. Thomas GV, Tran C, Mellinghoff IK et al (2006) Hypoxia inducible factors determines sensitivity to inhibitors of mTOR in kidney cancer. Nad Med 12:122–127Google Scholar
  30. Verhoef G, Hess et al (2008) Phase III study of patients with relapsed, refractory mantle cell lymphoma treated with temsirolimus compared with investigator’s choice therapy. In: 13th congress of the European Hematology Association (EHA)Google Scholar
  31. Witzig TE et al (2005a) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23:5347–5356PubMedCrossRefGoogle Scholar
  32. Witzig TE et al (2005b) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23:5347–5356PubMedCrossRefGoogle Scholar
  33. Yang JC, Haworth L, Sherry RM et al (2003) A randomized trial of bevacizumab, an antivascular endothelia growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434PubMedCentralPubMedCrossRefGoogle Scholar
  34. Yu K, Toral-Barza L, Discafani C et al (2001) mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 8:249–258Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Michael Schulze
    • 1
  • Christian Stock
    • 2
  • Massimo Zaccagnini
    • 3
  • Dogu Teber
    • 4
  • Jens J. Rassweiler
    • 1
  1. 1.Department of Urology SLK-Klinikum HeilbronnTeaching Hospital of the University of HeidelbergHeidelbergGermany
  2. 2.Department of UrologySt. Vincentius HospitalSpeyerGermany
  3. 3.Department of Urology “U. Bracci”, Policlinico Umberto IUniversity of Rome “La Sapienza”RomeItaly
  4. 4.Department of UrologyUniversity of HeidelbergHeidelbergGermany

Personalised recommendations